Microwave radiation is one of the most growing environmental workplace factors that exposes too many workers in the various workplaces. Regard to concerns about cancer incidence in these workers and lack of systematic or meta-analytic studies about this object, so, we conducted a meta-analysis to acquire an understanding of the association between cancer risk and occupational exposure to radar radiation. A systematic search was carried out on case-control, cohort and clinical control trial studies that published in the Cochrane Library, PubMed, ISI Web of Science, Scopus and Google scholar databases that accomplished from March 2017 to March 2018 and updated on 30 September, 2018 in English and Persian articles without time limit in publication date. Keywords were selected based on PICO principle and collected from MeSH database. After removal of duplicated studied, taking into inclusion and exclusion criteria, the process of screening was carried out and data were extracted after preparation of the full text of included articles. Article collection was completed by manually searching for a reference list of eligible studies. For quality assessment of included studies, Newcastle-Ottawa scale was used. a total of 533 studies was found in the first step of literature search, only 6 were included with 53,008 sample size according to inclusion and exclusion criteria. Estimated pooled random effects size analysis showed no significant increasing effect of occupational exposure to radar radiation on mortality rate  and relative risk  of cancer with a significant heterogeneity between the selected studies. In conclusion, the results of this meta-analysis study have shown no significant increase in overall mortality ratio and cancer risk ratio from occupational exposure to the radar frequency of workers. But, these results are not conclusive. As regards to some limitation such as fewer numbers of included studies, lack of data about exposure characterizations and demographic characterizations in this meta-analysis, this result is not certain and conclusive. It is recommended to conduct future studies. Microwave (MW) radiation became one of the most significant and fastest growing environmental factors due to intensive development of communication technologies during the last decades. In microwave spectra, radar frequency with 1-300 GHz range has varied applications such as satellite, communications, military, Network, navigation, air-traffic Control, navigation, marine and weather. Therefore, many workers are exposed to these waves . Pulsed MW, which generally affect only certain groups of military or service staff or population living nearby. Concerns have been raised about the safety of the microwave emissions of radars. Radars are detection systems which use MW to determine both moving and fixed objects like aircraft, ships, missiles, etc. Depending on the tasks they use different frequencies of MW . Some common types of radars encountered with daily life include: Air traffic control radars, Weather radars, military, marine and Speed control radars. Therefore, too many workers are exposed to radar radiation . There are many studies on exposure assessment and biological effects of microwave radiation .Previously, many case-controls, reviews and epidemiological studies were conducted on a wide range of electromagnetic radiation to investigate incidence cancers such as testicular, leukemia, brain tumor and other cancers . Also, some studies showed that radar frequency could have an adverse health effects that are divided into thermal and non-thermal effects  cancer is one of the non-thermal adverse health effects due to occupational exposure to microwave and radar radiation. Brain cancer in the police officer  cancer stimulation in cancer cells , significant elevation in non-lymphocytic leukemia and little effect on mortality in US Navy veterans  were some previous considered studies. Substantial military and occupational data indicate a significant effect of pulsed microwaves on cancer grows and other pathological conditions in workers .International Agency for Research on Cancer (IARC) has classified radio frequency electromagnetic fields as possible carcinogenic to humans (Group 2B), based on an increased brain cancer risk that associated to wireless phone use . However, because of differences in the design and extraction of these studies, their results are difficult to interpret. Regard to previous studies that showed there are controversial reports on cancer incidence of workers that occupationally exposed to radar radiation and lack of systematic or meta-analytic studies about this important object, so, we conducted a meta-analysis to acquire an understanding of the association with cancer risk and occupational exposure to radar radiation.Search strategy and study selectionThe present study was carried out based on PRISMA guidelines. A comprehensive search strategy was focused by two independent researchers (VZ and ASV) on English articles without time limits in publication date, that collected from March 2017 to march 2018 and update on September 2018 in the Cochrane Library, PubMed, Scopus, Google Scholar, and ISI Web of Science Database with the use of following search terms (based on PICO principle): (worker OR technician OR occupation OR military OR airline OR navy OR police officer OR Weather) AND  AND  AND  as single or complex terms in titles, abstracts and keywords, that was reported the risk estimate indicators such as Standardized Incidence Ratio (SIR), Odds Ratios (OR), Relative risk (RR) and Mortality Ratio (MR) were collected as eligible studies. This systematic research was completed by a manual search for the reference list of eligible studies.Inclusion and exclusion criteriathe inclusion criteria for selection studies were in design of case–control, cohort and randomized control trial studies, with a control group and referring to the association between occupational exposure to radar radiation and all types of cancer in workers.The exclusion criteria were as follows: 1) studies without control group 2) reviews, case and field studies, 3) studies with inhumane population such as in vitro, in vivo and animal studies. 4) Studies that radar frequencies were out of considered ranges (1-300 GHz) .5) studies with other occupational or non-occupational carcinogenic risk factors .Data extraction and quality assessment After removal of duplicated studied, two reviewers independently according to the pre-specified selection criteria that describe in eligible study section screened the title and abstract of the literature for rebalance of the topic. Then, data extraction was done. Also, any disagreements were resolved by consensus among reviewers. For quality assessment of included studies, Newcastle-Ottawa Scale (NOS) was used . This scale with two different tools for case-control and cohort studies scores, articles for selection, comparison and exposure/outcome assessments. The following information about selected articles were extracted: first author, origin of country, publishing year, gender, population aging, study design, sample size, follow-up period, workplace title, Relative risk (RR), odds ratio (OR), Mortality Ratio (MR).Data synthesis and Statistical analysis 2 test. The random effect model analysis was used for estimating pooled effect size. Publication bias was evaluated by using funnel plot and beg test.All statistical tests were conducted with STATA software package  . Odds Ratio, relative risk and Mortality Risk Ratio with their 95% confidence interval (CI) were used to assess the strength of association between occupational exposure to radar radiation and various cancer risks. Existence of heterogeneity was tested by Cochrane’s Q-test at P < 0.05 level of significance and the percentage of heterogeneity among studies was calculated by using ISearch result and study selectionA total number of 533 studies were found in the first step of literature search in PubMed, Scopus, Google scholar and ISI Web of Science databases. After removal of duplicated references, 272 studies were included in the title, keywords and abstract screening. Then, 219 studies were excluded since they did not meet inclusion criteria. Hence, 54 studies were selected for the eligibility assessment. At the end of the selection process and after the quality assessment, 6 studies remained in the meta-analysis that including 3 case-control studies  and 3 cohort studies  with no randomized control trial study. A manual search of the reference lists added no more articles in this meta-analysis. Flowchart of study selection for inclusion is shown in The included studies in the current meta-analysis were carried out from 1993 to 2016 in various countries USA , Germany , France , Belgium/France  with 53,008 sample size and range of ages 15–69 years that examined the relationship between occupational exposure to radar radiation and cancer strength among workers. The Whole of the studies put the determination of cancers and risk estimates in military workers. All of the included studies were in the design of case-control  and cohort studies . Summarized characteristics of included studies in this meta-analyses base on mortality ratio, Odds Ratio and relative risk were presented in Meta-analysis2=42.4%). A graphical display of estimated results, showed by the forest plot from individual included studies in this Meta-analysis  showed no significant increase in cancer risk in workers who occupationally exposed to radar radiation  with significant heterogeneity between studies  in workers that exposed to radar radiation  and mortality risk (P= 0.9) in workers who occupationally exposed to radar radiation. Funnel plots are shown in The current meta-analysis was carried out to assess the strength of cancer among workers with occupational exposure to radar radiation in different types of study design by included 6 studies  with publishing from 1993 to 2016 and 53,008 sample size. The Whole of the studies put the determination of cancers and risk estimates in military workers. The great majority of studies reported risk estimates with 95% confidence interval. Pooled results, found no significant increase in the overall relative risk and mortality ratio of cancer among workers with occupational exposure to radar radiation in comparison to control group.This seems to be the opposite of the previous meta-analysis that assessed the association between the microwave and radio frequency exposure and cancer risks in both environmental and occupational settings found an increased risk of morbidity and/or mortality from lymphoma, leukemia, melanoma and brain/CNS cancers, following exposure to microwave and radiofrequency . It is noticeable that previous meta-analysis focused on both environmental and occupational exposure in the worker and public population and it clearly did not determine the relationship between occupational radar exposure and cancer risk in the workplace . Whilst our meta-analysis just focused on occupational exposure to radar radiation that lead to a small number of included studies that contained inclusion criteria. In addition, due to few included studies, we could not separate cancer categories along with individual cancer categories and conduct subgroup analysis. So, we have to combine all the results from included studies to make this meta-analysis. However, based on these meta-analysis results, it seems that occupational exposure to radar radiation could not statistically increase cancer risk in related workers. Therefore, it needs to continue case–control, cohort and RCT studies.Also, some previous systematic review without meta-analysis and statistically pooled results, reported some studies that showed occupational exposure to microwave and radar radiation can enhance the risk of cancer .Also, there was a significant heterogeneity between the included studies in this meta-analysis that showed occupational exposure to radar frequency range could not significantly increase in overall relative risk of cancer that is may be arising from a small number of included studies.The IARC Monograph Working Group discussed and evaluated the available literature on the occupational exposures to radar and microwaves . In addition, based on differences in the design and execution of these studies, World Health Organization (WHO) declare that their results are difficult to interpret, so it proposes to conduct further studies particularly case-control studies . However, based on pooled results in current meta-analysis, it seems that the carcinogenicity of radar radiation with occupational exposure in workers is not statistically certain.As we know, microwave energy is not sufficient to break the chemical bonds in DNA directly, but adverse effects may be mediated by indirect mechanisms, such as generation of oxygen free radicals  or a disturbance in DNA-repair processes . Observations to date suggest that oxidative stress and cancer are closely linked. Oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases, including cancer, via transformation of a normal cell to tumor cells, tumor cell survival, proliferation, more resistance, radio resistance, invasion, angiogenesis and stem cell survival . Reactive oxygen species (ROS) are involved in a wide variety of different cancers such as Leukemia , Lymphoma , Prostate  and melanoma . These cancers were reported in some studies that included in this meta-analysis . The results of the current systematic review and meta-analysis, showed that occupational exposure to the radar frequency range did not significantly increase the mortality and cancer risk in exposed workers. However, it should be mentioned that these results are yielded by a few numbers of available studies with no report in occupational dose and time exposure to the radar frequency range. Also considering to some limitation such as fewer numbers of included studies, lack of data about exposure characterizations  and demographic characterizations  it is better to continue further studies about this topic and future review studies include the congress publications without limitation in language. The results of this meta-analysis could be useful in radiation health policy for organizations that active in the field of non-ionizing radiation, especially radar radiation. In conclusion, the results of this meta-analysis showed no significant increase in overall mortality and cancer risk from occupational exposure to radar frequency in workers. As regards to mentioned limitations and few included studies in this meta-analysis, this result is not certain and conclusive. So, it is recommended to conduct future studies. In conclusion, the current meta-analysis was carried out to estimate occupational cancer risk among workers who occupationally exposed to radar radiation. In conclusion, the results of this meta-analysis study have shown no significant increase in overall mortality ratio and cancer risk ratio from occupational exposure to the radar frequency in workers. But these results are not certain and conclusive due to some limitation such as fewer numbers of included studies. In addition, as regard to lack of data about exposure characterizations and demographic characterizations in included studied, so it is recommended to conduct a future case–control, cohort and RCT studies in this topic. Also, the results of this meta-analysis could be useful to provide a preventive radiation program or radiation health policy for which organizations that active in cancer prevention and non-ionizing radiation especially radar radiation.


CCND1 gene polymorphism affects acute lymphoblastic leukemia (ALL) development, prognosis and may relate to methotrexate cytotoxicity. Cyclin D1 (CCND1) regulates cell cycle progression during the late G1 and S phase and takes part in methotrexate metabolism. It was hypothesized that CCND1 G870A polymorphism was studied in all items using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and evaluated methotrexate cytotoxicity for ALL patients using liver function tests before and after methotrexate treatment. We followed up patients for one year to determine disease-free survival (DFS) and overall survival (OS) and its relation to the CCND1 genotype. This study included 50 ALL patients and 50 healthy controls, CCND1 polymorphism in ALL prognosis. We found that AA genotype and A allele have a higher risk of developing ALL compared to the control group. Additionally, we found no notable association between CCND1 variant and methotrexate cytotoxicity and no role of CND1 G870A polymorphism is associated with a high risk of ALL development. However, it has no role in ALL prognosis or methotrexate cytotoxicity. Our results suggested that C Childhood acute lymphoblastic leukemia (ALL) represents one of the most common tumors in children with an increased incidence of morbidity and mortality. Genetic susceptibility and exposure to environmental factors play an important role in leukemogenesis Nowadays, Pharmacogenomics tests, including Genome-wide association studies (GWAS), have a direct identification role in genetic alterations, treatment efficacy, cytotoxicity, prognosis, etc. However, the current knowledge gives little data about how genomic determinants can affect ALL susceptibility, chemotherapy, and chance of relapse . Methotrexate (MTX) forms the backbone of maintenance cycles in childhood acute lymphoblastic leukemia (ALL) chemotherapy, including interim maintenance . Major adversities include cytopenias, mucositis, liver toxicity, renal toxicity and skin toxicity. These toxicities enquire dose modification or omission (burn out) MTX-related toxicities may be determined by several factors like dose, duration, genetic susceptibility and risk factors .CCND1 unsettles normal cell cycle process and probably stimulate the development and progression of childhood ALL ,colorectal cancer ,cancer risk .Cyclin D1 (CCND1) is an essential regulator protein of the eukaryotic cell cycle. CCND1 acts mainly during the G1 phase and forms a complex with CDK4 or CDK6 in the mid to late G1 phase. This complex, activated by CDK-activating kinase, will cause phosphorylation of retinoblastoma protein (pRb). Phosphorylated Rb liberates transcription factors like E2F, which is responsible for gene transcription required for entry into the S phase of the cell cycle . Overexpression of A lot of research has been published regarding the effects of genetic polymorphisms on methotrexate (MTX)-induced toxicity and efficacy where it is a pivotal drug in the different treatment protocols, both at low and high doses. MTX acts on a variety of target enzymes in the folates cycle, as well as being transported out and into of the cell by several transmembrane proteins .Methotrexate (MTX), a folic acid antagonist, is a cornerstone in ALL treatment’s maintenance phase. One of MTX mechanisms is that it acts through competitive inhibition of dihydrofolate reductase (DHFR) regulated by CCND1 through increased E2F and thus leads to resistance to methotrexate (MTX) or interfere with its cytotoxicity. This leads to reducing the formation of tetrahydrofolate from dihydrofolate, resulting in the lack of the folate coenzymes leading to impairment of DNA and RNA synthesis .Several gene polymorphism have been investigated concerning susceptibility to ALL including SNPs of carcinogen metabolism genes, folate metabolism genes, DNA repair genes, regulators of lymphoid cell differentiation, tumor suppressors ,transcriptional factors and chemokines, in addition ,various SNPs participating in the metabolism of antileukemic agents inducing therapy toxicity , discontinuation of therapy with risk of relapse .Several studies have revealed that populations with the AA genotype had a significant risk of childhood ALL . Other studies reported the poor outcomes of youth ALL in the 870A allel. Furthermore, studies have shown the relation between methotrexate resistance or toxicity and the studied polymorphism . To the best of our knowledge, no study has linked the relation between childhood ALL susceptibility, Methotrexate resistance or toxicity, and the chance of relapse in one study. This study included 50 patients with acute lymphoblastic leukemia aged from one year to 18 years  diagnosed by peripheral blood and bone marrow morphology, immunophenotyping, and cytogenetic analysis. Also, 50 healthy  subjects matched for age and sex served as the control group. All subjects’ parents in this study gave written informed consent before being included in the study. Thirty-two patients with B-ALL received low dose methotrexate, and 18 patients with T-ALL received high dose methotrexate. The study was conducted in the oncology center, Mansoura University, between April 2016 and October 2017. This study was ethically approved by Mansoura faculty of medicine Institutional research board (IRB), Mansoura University. Genotyping of CCDN1 G870A geneCCDN1 G870A gene was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. First of all, DNA was extracted, it was isolated from EDTA-blood samples by GeneJETTM Whole Blood Genomic DNA Purification Mini Kits from Thermo Scientific  according to manufacturer guideline. Then, analysis of genetic polymorphism using PCR-RFLP technique by two steps: first amplification of extracted genomic DNA that was done by using PCR via thermal cycler  using a reverse primer (CCND1R-21): TTTCCGTGGCACTAGGTGTC and Forward primer (CCND1F-22) AGTTCATTTCCAATCCGCCC .Genotyping of the PCR was carried as follows: 12.5 µl MyTaqTM Red Master Mix (2X) . 1µl DNA template, forward and reverse primers 0.1µl each and 11.3µl nuclease-free water with the final volume of 25µl. PCR condition consisted of an initial denaturation of 95°C for 1 min, followed by 35 cycles of 94°C for 30 sec, 60°C for 30 sec, and 72°C for 30 sec, with a final extension of 72°C for 10 min. The PCR product of 212 bp was detected by agarose gel electrophoresis using 2% agar. Second, the PCR products were then digested with MspI . The digested PCR products were electrophoresed using 2% agarose gel to distinguish between 175 bp band produced by the digestion of A allele and the 141 bp produced by the digestion of the G allele. Heterozygous state yielded both 141 bp and 175 bp bands . Statistical MethodsThe statistical analysis of the data was performed by using excel (Microsoft office 2013) program and SPSS  program  version 20. A Chi-square test was used to compare groups. Quantitative data were presented as median and range, mean and standard deviation. For comparison between two groups, student T-test (for parametric data) and Mann-Whitney test (for non-parametric data) were used. For comparison of more than two groups; One-Way ANOVA (for parametric information) and Kruskal-Wallis (for non-parametric data) were used. For comparison within the same group, paired-sample T-test (for parametric data) and Wilcoxon test (for non-parametric data) were used. The univariate analysis used to evaluate the association of polymorphism with the occurrence of leukemia and hepatotoxicity. Multivariate logistic regression used for hepatotoxicity. For survival analysis, Kaplan-Meier curves were used and compared by the log-rank test.The age of the studied patients ranged from 5 to 18 years. Among the 50 patients, 32 (64%) were males, and 18 (36%) were females. The age of the control group ranged from 3 to 12 years (mean 8.66±3.50). Among the 50 healthy children, 26 (52%) were males and 24 (48%) females. Immunophenotyping of ALL patients revealed 32 (64%) patients B-ALL and 18 (36%) patients T-ALL. In the current study, there was a significant elevation of ALT in T ALL patients compared to control . On the other hand, there is no change regarding AST between studied groups. There was also a significant elevation of post-treatment AST  and ALT  compared to pretreatment in T ALL group. However, there is no significant change in B ALL .Comparison of cyclin D1 variant between cases and control revealed that there was significantly higher AA genotype and A allele in acute leukemia patients when compared to the control group , while other genotyping (GG and GA) showed no significant differences between cases and controls. Also, there was a real risk of developing ALL with AA genotype, and the results were highly statistically significant for AA genotype compared to the GG genotype. The study also revealed significant risk for AA genotype compared to non-homozygosity for AA genotype (AG+GG) .Furthermore, the effect of cyclin D1 genotype on the incidence of hepatotoxicity after one week of methotrexate administration as an indicator of methotrexate toxicity were assessed. we didn’t find any significant differences between hepatotoxic and non-hepatotoxic patients regarding cyclin D1 genotypes despite a highly significant difference in methotrexate level.  and4.Logistic regression analysis was conducted for the prediction of hepatotoxicity in T ALL patients. Age, gender, cyclin D1 genotypes were applied as covariates. None of the covariates were associated with the risk of hepatotoxicity in univariate analysis. ,  and  respectively . No significant differences were found regarding cyclin D1 genotypes in patients with complete remission and partial remission or relapse . At the end of the follow-up period (12 months), the OS of studied ALL cases estimates 98% at six months and 96% at 12 months . As regaAcute lymphoblastic leukemia (ALL) is the most common cancer in children, and although the cure rates exceed 90%, it remains a significant cause of morbidity and mortality in children and adults. The past decade has been marked by extraordinary advances in the genetic basis of leukemogenesis and treatment responsiveness in ALL .2. Using HDMTX shows the marvelous result in treating ALL and prevention of extramedullary leukemia , as MTX can penetrate the blood-brain barrier and blood-testis barrier  refers to infused MTX in doses of more than 1 g/mThe primary target of MTX is the enzyme dihydrofolate reductase (DHFR), which can catalyze the reduction of folate and 7, 8-dihydrofolate to 5, 6, 7, 8-tetrahydrofolate. This will lead to the impairment of nucleic acid synthesis and cellular death. Many proteins involved in the folate metabolic pathway  may contribute to MTX cytotoxicity and clinical elimination . Cyclin D1 is involved in the folate metabolic pathway and has been shown to influence cellular response to MTX. Thus CCND1 influences the clearance of MTX and MTX-associated toxicity partly through the regulation of DHFR and THF .CCND1 G870A polymorphism with ALL risk in 25 ALL patients and 15 healthy controls and found that frequency of the AA genotype was significantly increased in the ALL cases while GG genotype was significantly increased in the control group. In more addition significant association between CCND1 G870A polymorphism and Nasopharangyl carcinoma risk was found in the central-southern Chinese population .The present study revealed a highly significant association between A allele either in heterozygous (AG) or homozygous state (AA) and cases. Besides, there was a real risk of developing ALL with AA genotype, and the results were highly statistically significant for AA genotype compared to the GG genotype. These findings were concordant with those of Hou et al., (2005), who studied 183 ALL cases and 190 age and sex-matched healthy controls, and found that CCND1 A allele was more frequent in the ALL group than in the control group. Hou et al., (2005) and Bedewy et al., (2013) who studied the association of The study also revealed significant risk for AA genotype when compared to non-homozygosity for AA genotype (AG+GG) in contrast to Hou et al., (2005) and Bedewy et al., (2013). The impact of the CCND1 A allele on childhood ALL was thought to be due to a higher level of CCND1b resulting in a longer half-life protein, which might affect the transition from the G1 to S phase of cell cycle and in turn cell proliferation 2 for children with high-risk or medium-risk ALL and 3.0 g/m2 for children with low-risk ALL), a stratification analysis was conducted.Because ALL patients were administrated with MTX in different doses .In this study, we studied the effect of cyclin D1 genotype on the incidence of hepatotoxicity after one week of methotrexate administration as an indicator of methotrexate toxicity. We didn’t find any significant differences between hepatotoxic and non-hepatotoxic patients regarding cyclin D1 genotypes. The results of the current study were matched with results of Dulucq et al., (2008) who did not find any association between toxicity parameters investigated and the increasing number of event-predisposing genotypes DHFR haplotype*1, CCND1 870AA, and TS 3R3R. But they thought this was most likely because in these three at-risk genotypes, only the CCND1, but not TS and DHFR, were individually associated with a lower frequency of toxic events . However, in contrast with the results of the present study, Costea et al. (2006) observed that individuals with CCND1 870AA genotype had lower liver toxicity rates. They also found significantly lower rates of these toxicities in individuals with a combination of the CCND1 870AA and MTHFR 677 TT/CT genotypes. This observation may be explained by the variant isoform of CCND1 with a longer half-life and the correlated higher level of DHFR . G870A polymorphism and an increased risk of MTX-related hepatotoxicity was more pronounced in children administrated with MTX in a dose of 5.0 g/m2 (high-risk ALL and medium risk ALL). This discrepancy may be due to different genetic backgrounds and population-specific differences . Furthermore, Xue et al., (2015) have found that subjects with 870AG and 870AA genotypes have significantly higher rates of MTX-related hepatotoxicity. They also found a statistically significant relationship between the hepatotoxicity and the combined genotypes AG/AA, suggesting that the 870A allele may be a risk factor of toxic events. Their subgroup analysis showed that the association of After following up ALL patients for one year, there was no statically significant difference among CCND1 genotypes regarding overall survival and event-free survival . However, there was a clinically significant association between CCND1 AA genotype and poor survival outcome compared to AG and GG genotypes in contrast to Costea et al., (2006) who studied 205 children of French-Canadian origin with ALL and follow them up for 60 months, the analysis of the impact of CCND1 showed that the individuals with AA variant had a remarkably lower probability of 5-year post-treatment EFS compared to those with AG and GG genotypes .Moreover, some other confounding factors may interfere with the present results, such as some unknown gene variations in the folate metabolic pathway. At the same time, the fact cannot be ignored that our chemotherapy regimen is not identical to other research institutions  and some chemotherapeutic drugs used in our center may also influence the evaluation of MTX-related hepatotoxicity.  Cyclin D1 polymorphism may not be contributed to MTX induced hepatotoxicity and couldn’t be useful in the clinical prediction of prognosis.We are studying genetic factors aid in early diagnosis and treatment of ALL. CCND1 AA genotype and A allele are associated with high risk to develop ALL.The sample size was relatively small, so it led to a larger span of 95% CI (0.041 – 24.547). Further studies with a large sample size are needed to confirm the relationship between gene polymorphism and MTX induced hepatotoxicity. In the present study, one laboratory index was only explored (serum aminotransferase). In further studies, other toxicities such as oral mucositis and vomiting should be observed, and the Serum level of MTX should be involved to assess MTX clearance association with CCND1 genotype.


Some data suggest an association between the single nucleotide polymorphisms AGT T704C, ACE I/D, and AT1R A1166C and preeclampsia, but overall, the data are conflicting; the aim of our study was to discover a more stable and reliable association between these polymorphisms and PE risk.A comprehensive literature search for this meta-analysis was conducted. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated to evaluate the strength, and heterogeneity test was conducted. Trial sequential analysis was also performed.A total of forty studies were finally included in our meta-analysis. The AGT T704C polymorphism was associated with PE risk in three genetic models . No heterogeneity was observed in the three genetic models for the ACE I/D polymorphism. For subgroup analysis by geography, no significant association was detected. Significant associations were observed in mixed race, early-onset, late-onset, and more than 200 subgroups for the AT1R A1166C polymorphism; however, only one study was analyzed in these subgroups.Our results indicated the AGT T704C and ACE I/D polymorphisms were associated with an increased risk of PE. Increased risks were also observed for the two polymorphisms in subgroups including Asians, Europeans, Caucasoid, and Mongoloid. Moreover, an increased PE risk with the ACE I/D polymorphism in the severe PE population was also detected. Regarding the AT1R A1166C polymorphism, weak associations were observed, but further studies are required.The online version of this article (10.1007/s10815-020-01971-8) contains supplementary material, which is available to authorized users. Preeclampsia (PE) is a common complication of pregnancy characterized by hypertension and proteinuria after 20 weeks of gestation ; it is oDuring normal pregnancy, the upregulation of renin and aldosterone triggered by the stimulation of the RAAS system maintains the balance of blood volume and blood pressure ; howeverAssociations between the polymorphisms of AGT T704C (the substitution of C to T at exon 2), ACE I/D (the insertion or deletion of an Alu 289 base pair sequence at intron 16), and AT1R A1166C (the change from C to A at 3’UTR) have been widely studied with conflicting results. To our best knowledge, differences in the geographic regions, ethnicity, and sample size could be reasons for the inconsistency. Moreover, the number of gestational weeks and the severity of PE have been reported to be associated with RAAS susceptibility gene polymorphisms [PubMed, Embase, Google scholar, China National Knowledge Internet (CNKI), Baidu Scholar, Wan Fang, and VIP databases were comprehensively searched for studies regarding the associations between ACE insertion/deletion, AGT T704, and AT1R A1166C polymorphisms and preeclampsia susceptibility up to May 13, 2018. No language limitation was set. The following key words were used to discover relevant articles: “angiotensin-converting enzyme,” “angiotensin,” “angiotensin II type 1 receptor,” “ACE,” “AGT,” “AT1R,” “polymorphism,” “variant,” “single nucleotide polymorphism,” “SNP,” “preeclampsia,” “PE,” “hypertension,” and “pregnancy-induced hypertension syndrome.” The references of relevant studies were also screened by hand to identify potential studies. Our work was based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement  The inclusion criteria for studies were as follows: (1) case-control studies discussing the relationship between ACE I/D, AGT T704C, AT1R A1166C polymorphisms, and preeclampsia risk; (2) the diagnostic criteria for preeclampsia were defined as gestational hypertension, assessed as SBP > 140 mmHg, DBP > 90 mmHg, and/or rise in SBP > 30 mmHg or DBP > 15 mmHg on at least two occasions 6 h apart, following 20 weeks of gestation, with marked proteinuria (> 300 mg/24 h), or > 2+ proteinuria as tested by the dipstick method ; (3) theThe following information from eligible studies were extracted by the first two authors: the first author’ name, publication year, country, geography, ethnicity, PE maternal age, gestational weeks, PE degree, the genotype distributions and alleles in the patient and control groups, the result of the Hardy-Weinberg equilibrium, and the scores for quality assessment. For gestational weeks, early-onset PE was defined as gestational age (GA) between 20 and 33 weeks and 6 days, and late-onset PE was defined as GA 34 weeks and above. Severe PE was defined as severe hypertension (blood pressure ≥ 160/110 mmHg at least twice in a 24-h period) and/or severe proteinuria (5 g/24 h), or as hypertension with multiorgan involvement including fetal growth restriction or HELLP syndrome  . Any dis2 statistic . Sensitivity analysis was performed by omitting one study at a time to assess the influence of each study on the pooled results. Subgroup analysis was conducted, stratifying by geography , ethnicity , gestational week , PE degree , and patient sample size . Publication bias was evaluated by a visual inspection of funnel plot and Egger’s test [P < 0.5 was considered statistically significant.The odds ratio (OR) and 95% confidence interval (95%CI) were calculated to investigate the effect strength of the associations between ACE I/D, AGT T704C, AT1R A1166C polymorphisms, and preeclampsia risk. The following genetic models were used: allelic genetic model , dominant genetic model , recessive genetic model , heterozygote genetic model , and homozygote genetic model . The Hardy-Weinberg equilibrium was assessed by the chi-squared test for every study in the control group. Heterogeneity in the meta-analysis was determined by the Cochrane’s Q-statistic test, and the inconsistency was quantified with the Ir’s test . If publr’s test . All anahttp://www.ctu.dk/tsa). TSA was introduced into our meta-analysis. The required information size was calculated based on an overall type I error of 5%, a power of 90%, and a relative risk reduction (RRR) assumption of 10%.TSA   is a methodology that combines an information size calculation  to reduce type I error and type II error for a meta-analysis with the threshold of statistical significance , the dominant genetic model , the recessive genetic model , and the homozygote genetic model  Fig. ). RegardAs shown in Table P = 0.015 for ACE I/D polymorphism; P = 0.627 for AGT T704C polymorphism)  Fig. . The shasm) Fig. , implyinWe performed a TSA for the homozygote genetic model of ACE I/D polymorphism and dominant genetic model of AGT T704C polymorphism Fig. . The resIn pregnant women with PE, downregulated renin-angiotensin system (RAS) activity is observed, resulting in increased vascular responsiveness to angiotensin II . The incPrevious meta-analyses indicated an increased PE risk with high heterogeneity of ACE I/D and AGT T704C polymorphisms, but no association was observed for the AT1R A1166C polymorphism –60. HoweIn the overall analysis of the AGT T704C polymorphism, a 33% increased PE risk of CC + CT genotypes was observed. The 1.26-fold and 1.44-fold increased risk of PE in CT genotypes and CC genotypes, respectively, were also detected compared to TT genotypes. No heterogeneity in the genetic models and the positive results from the trial sequential analysis ensured the stability and reliability of our result. In the subgroup analysis stratified for geography, no significant association was detected; however, increased risks were observed in Caucasoid (the 1.30-fold and 1.28-fold increased risk of CC + CT genotype and CT genotype compared to TT genotype) and Mongoloid . In the severe PE degree subgroup analysis, no association was observed both in either severe or mild PE populations, possibly due to the small sample size, more studies are required. In the more than 200 patient sample size, increased risks were observed in the dominant, recessive, and heterozygote genetic models; however, the relatively small number of included studies in the subgroup indicated that these associations need to be interpreted with caution.For the ACE I/D polymorphism, the D allele increased the risk of PE compared to I allele by 1.29-fold; moreover, the DD + DI, DD and DD genotypes increased risk by 17%, 52%, and 55% compared to II, DI + II, and II genotypes, respectively. Significant heterogeneity was observed in the overall analysis. We performed a Galbraith plot analysis to study potential heterogeneity analysis, and after excluding these studies , 45, 46,There were several limitations in this meta-analysis. Firstly, language bias existed in our results; although no language limitation was set, only English and Chinese articles were included. Secondly, the sample size of included studies in the subgroup analysis of PE degree and onset time of PE were relatively small in some groups, implying that our results should be explained with caution. Finally, the potential influence of environment factors on genotype-PE associations is worthy of consideration.Our results indicated that the AGT T704C and ACE I/D polymorphisms were associated with an increased risk of PE. Increased risks were also observed for the two polymorphisms in subgroups including Asians, Europeans, Caucasoid, and Mongoloid. Furthermore, an increased PE risk with the ACE I/D polymorphism in the severe PE population was also detected. Regarding the AT1R A1166C polymorphism, weak associations were observed and further studies are required.ESM 1(DOCX 16 kb)


Polymorphisms in the cytochrome P450 2C19 (CYP2C19) gene have been reported to be associated with coronary heart disease (CHD), but the results were not consistently analyzed among different patient groups. To derive a more precise estimation of these associations, we will conduct a meta-analysis to investigate the polymorphisms of CYP2C19 in all published studies.Electronic databases  will be used to search clinical case-control or cohort studies about CYP2C19 polymorphism and CHD published until November 2020. Two reviewers will independently select the study, extract the data, and evaluate the quality of the study. Odds ratios with 95% confidence interval will be used to evaluate the strength of the association between the CYP2C19 polymorphism and CHD susceptibility under 4 genetic models. Subgroup analysis will be conducted by different ethnicity and genotyping method. Sensitivity analysis will be performed via sequentially omitting each of the included studies 1 at a time. Begg funnel plots and Egger test will be used to examine the potential publication bias. All the statistical analyses will be performed using Review Manager 5.3 and Stata 12.0.This study will provide a better understanding of the association between CYP2C19 polymorphisms and coronary heart disease risk.The publication of this protocol will minimize the possibility of bias due to post hoc changes to the analysis protocol, thus helping to obtain reliable evidence.DOI 10.17605/OSF.IO/R7U93 It is estimated that more than 9.4 million people worldwide died of ischaemic heart disease in 2016. In China, the mortality rate of CHD in urban residents was 115.32/100,000, and that in rural residents was 122.04/100,000. Whether in developed or developing countries, the management of CHD every year is related to huge long-term medical expenses.Coronary heart disease (CHD) is one of the most common cardiovascular diseases in the world, which is characterized by arteriosclerosis and coronary artery stenosis and even obstruction. The incidence and mortality of CHD have been showing a downward trend since the 1970s, mainly due to the improvement of prevention and treatment measures and the reduction of major risk factors. It is well known that the traditional risk factors for CHD include age, smoking, elevated blood pressure, dyslipidemia, diabetes mellitus, irregular eating, obesity, and insufficient physical activity. However, in clinical practice, many patients have been diagnosed with CHD, but there is no clear explanation for their occurrence and progress in the case of premature coronary artery involvement to life-threatening conditions caused by traditional risk factors. Familial aggregation of CHD has been investigated for a long time. Twin studies showed that the heritability of CHD is estimated to be between 41% and 77%. More recently, researchers have proposed genetic risk factors for CHD, which can be identified by the robust genome-wide association studies. In addition, genome-wide association studies showed that there are numerous candidate genes and considerable single nucleotide polymorphisms remarkably associated with CHD, such as VEGF, SCARB1, ADAMTS-7, SCARB1, VEGFA, MADD-FOLH1, CYPs, and APOC3.The complex pathophysiology of CHD depends on a large number of lifestyle and environmental risk factors of its individual. It has been investigated through some studies that provide key information on primary and secondary preventive measures. It is the most polymorphic member of CYP2 C subfamily.CYP2C19 gene mutation can change the activity of human related enzymes, affect the metabolic process of related drugs, and lead to cardiovascular events in patients with CHD. For example, the Allelic variation classified the population according to the catalytic activity of CYP2C19 to ultra-rapid, extensive and poor phenotypes for drug clearance. CYP2C19 gene polymorphism has been proved to be a compelling predictor of clopidogrel resistance, which can lead to failure in the treatment of CHD. Patients with loss-of-function allelic variants (CYP2C19 ∗ 2 and CYP2C19 ∗ 3) are more prone to thromboembolic events. In Zhang's study, the adverse impact of CYP2C19∗2 polymorphisms was found not only in the risk of CHD, but also in the adverse clinical outcomes in CHD patients during a long follow-up period. Ercan reported that among Turkish people, smokers with CYP2C19∗2 mutations have a 3.7 times risk of CHD. The CYP2C19 ∗ 3 genotype was found to be significantly more common in Chinese Uighur populations with CHD.Cytochrome P450 2C19 (CYP2C19), as one of the main cytochromes P450s drug metabolic enzymes in human body, is encoded by chromosome 10 and expressed in the human liver.CYP2C19 gene may be involved in the occurrence and development of CHD. Unfortunately, the results of these studies were not consistently analyzed among different patient groups. Therefore, it is necessary to conduct a meta-analysis of all eligible studies to obtain more convincing evidence on the association of CYP2C19 polymorphism and CHD susceptibility.On the basis of this information, these studies have suggested that the single-nucleotide polymorphism in the 22.1The retrospective review does not involve the evaluation of patients’ personal information or rights, so ethical approval is not required. It cannot be ignored that we have registered the protocol in the Open Science Framework (OSF) in advance, and the registration number is DOI 10.17605/OSF.IO/R7U93. In addition, this systematic review and meta-analysis will be reported in accordance with the preferred reporting items for systematic reviews and meta-analysis protocols 2015.2.2The inclusion criteria will be made based on the PICOS principle :(1)Types of studies: all case-control studies or cohort studies that evaluated the association between CYP2C19 polymorphisms and CHD risk will be incorporated in our review. No restriction will be put on the publication date of the studies.(2)Types of participants: the present meta-analysis will include subjects with CHD, and the diagnosis should be made in accordance with well-established guidelines. The control subjects should be defined as healthy individuals. Regardless of age, gender, or country.(3)Studies that presented original data, or provided the genotypic frequency of both case and control samples or had odds ratios (ORs) with 95% confidence interval (CI) values.(4)Primary outcome: the association between CYP2C19 polymorphisms and risk of CHD.2.3Studies will be excluded from the meta-analysis according to the following criteria:(1)review articles,(2)in vitro or animal study,(3)case reports,(4)conference abstracts,(5)Newcastle–Ottawa scale (NOS) score is less than 6,(6)studies that did not provide allele frequencies or genotypic for samples,(7)CYP2C19 gene polymorphism and non-coronary heart disease,studies on the relationship between (8)overlapping or duplicate studies.2.4Several online databases including Pubmed, ISI Web of Science, Embase, Google Scholar, Wanfang, China Biological Medicine, and China National Knowledge Infrastructure will be searched up to November, 2020. Medical subject headings (MeSH) and synonymous free texts will be combined to improve the comprehensiveness and sensitivity of literature retrieval. The language will be restricted to Chinese and English. The following keywords will be used: (“coronary heart disease” OR “CHD” OR “coronary artery disease” OR “CAD”) and (“Cytochrome P-450 CYP2C19” OR “CYP2C19”) and (“polymorphism” OR “variant” OR “genotype” OR “mutation”). The search strategy for PubMed is shown in Table 2.52.5.1 The flowchart is shown in Figure The researchers of our team have received professional training on the purpose and process of the review in advance. Two reviewers (Yongxin Yang and Yaping Zhang) will perform the selection process independently, with cases of disagreement will be resolved by adjudication by a third reviewer (Ming Ren). The screening process of the article includes reading the title first, then the abstract and the full text to determine whether it meets the inclusion criteria. The researchers will record the reasons for excluding each study in light of the preferred reporting items for systematic reviews and meta-analysis guidelines and report the screening results.2.5.2Each publication will be evaluated thoroughly, and data will be extracted independently by 3 researchers, including year of publication, surname of the first author, ethnicity of each study population, country, mean age, gender, numbers of subjects, genotyping methods, allele frequencies and genotype distribution of CYP2C19 polymorphisms. Group discussions will be conducted to resolve any disagreements in the extraction process. If the data for a paper is incomplete or unconvincing, we will try to contact the author via email. In addition, the Hardy–Weinberg equilibrium (HWE) of genotype distributions in the control group will also be examined.2.5.3 When they encounter disagreement, they will resolve these issues with the help of a third member (Rongxiang Lin). As we all know, the NOS values arrange from 0 to 9. The quality of publication below 6 stars is low, and the quality of research above 6 stars is high. Only studies with more than 6 stars will be included in our study.Two reviewers (Yonglan Wang and Zhuoma Cairang) will independently assess the quality of all included studies based on NOS, which is specifically used to assess the quality of observational studies.2.5.4Z-test, with P < .05 considered statistically significant. In addition, the Fisher exact test will be used to assess the deviation of CYP2C19 polymorphism frequency from the expected values under the HWE among healthy controls. When P < .05, the study is considered to be inconsistent with HWE. χ2 test-based Q statistic and I2 will be applied to assess the overall heterogeneities. If I2 values < 50% and P > .05, heterogeneity is deemed to be low, and a fixed-effect model will be selected for data integration. Otherwise, a random-effect model will be used.,34 In our study, all statistical analyses will be conducted by using Stata version 12.0  and Review Manager 5.3 .The ORs with their corresponding 95% CIs will be used to assess the strength of the association between CYP2C19 polymorphisms and CHD susceptibility. The pooled ORs will be conducted for 4 genetic . Then the most reasonable genetic model of inherence will be identified based on the relationships between the 4 pairwise comparisons. After identifying the potential genetic model, the genotype count will be collapsed into 2 categories to obtain a combined result. The significance of the pooled ORs will be determined by 2.5.5If there is obvious heterogeneity among studies, we will conduct the meta-regression analysis, subgroup analysis or sensitivity analysis to explore the potential sources of heterogeneity. The confounding factors include ethnicity, year of publication, type of study, total sample size, and RR (ratio of case size to control size).2.5.6Subgroup analysis will be conducted by different ethnicity, genotyping method, total sample size and deviation from HWE, and so on.2.5.7The sensitivity analysis will be carried out by sequentially omitting each of the included studies 1 at a time to measure the reliability and robustness of the research results.2.5.8P-value smaller than .05 is considered statistically significant.Funnel plots will be used to evaluate publication bias if more than 10 eligible studies are included, and the criterion was whether the funnel plot is symmetric or not. If the funnel chart is asymmetric, there may be publication bias. What's more, Begg rank correlation test and Egger test will also be used for checking the potential publication bias, and a 2.5.9 The quality of evidence can be divided into 4 levels: high, medium, low, and very low quality. Researchers should consider certain factors that may reduce the quality of the evidence, such as the heterogeneity between groups, estimate precision of effect, publication bias, and evidence directness. Moreover, large magnitude effect and dose-response gradient that increase the quality of evidence should also be given enough attention.GRADE method will be used to assess the quality of evidence for our findings.3 The disease is regarded as a complex multifactorial disease caused by the interaction between multiple environmental and genetic factors. Traditional risk factors are considered to be the cause of most CHDs, although 15% to 20% of patients have no identified risk factors, making it impossible to prevent adverse cardiovascular events with adequate treatment. Early identification and intervention strategies are essential to reduce the incidence and mortality of CHD in high-risk population. Identifying the genetic components of the disease is the important area in cardiovascular disease research, because clarifying the genes related to CHD will affect all efforts towards understanding of the mechanism level, its prevention and treatment. Fortunately, genome-wide association studies have confirmed some genes related to the susceptibility to CHD in different populations around the world, of which the CYP2C19 gene is well known.Cardiovascular disease is the largest cause of death in the world, especially CHD manifested by angina pectoris or myocardial infarction. Although the mortality rate of CHD has declined, it still causes one-third of all deaths over the age of 35 in the past few decades.CYP2C19 gene polymorphism and CHD susceptibility, there has been no systematic assessment of the cumulative evidence for this association. In this study, we will conduct a systematic review and meta-analysis to combine results from numerous studies and generate a more reliable estimate of risk association to provide guidance for the prevention and treatment of coronary heart disease. The strengths of this study include the following aspects:So far, although many researchers have focused on the relationship between (1)large datasets from all recent eligible studies will be incorporated;(2)for the exploration of heterogeneity, we will try to avoid post-group subgroup analysis; and(3)sensitivity analysis of each genetic model will be performed to improve the reliability of the results.Therefore, publishing the protocol will avoid the potential bias related to data mining as much as possible and will help to obtain convincing evidence.Conceptualization: Yongxin Yang, Yaping Zhang.Investigation: Ming Ren, Yonglan Wang.Supervision: Yongxin Yang.Writing – original draft: Zhuoma Cairang, Rongxiang Lin.Writing – review & editing: Haixia Sun, Jianju Liu.


It is unclear whether bisphosphonates are associated with risk of cancers. Therefore, this meta-analysis aimed to evaluate the effect of bisphosphonates on overall cancers.A search in Pubmed, Embase, Cochrane Library and Web of Science databases was conducted, from the inception date of each resource to September 26, 2019. The summarised effect estimates with 95% CIs were calculated using a random-effect model. Heterogeneity and publication bias were explored.Thirty-four articles were included in this study . The results revealed that bisphosphonates significantly decreased the risk of colorectal cancer , breast cancer  and endometrial cancer , but no significant association was observed in all-cause cancer. Furthermore, nitrogen-containing bisphosphonates only had protective effects both on breast cancer  and endometrial cancer . Non-nitrogen-containing bisphosphonates tended to increase the risk of liver cancer  and pancreas cancer .Bisphosphonates are significantly associated with risk reduction of colorectal, breast and endometrial cancer, especially nitrogen-containing bisphosphonates. It should be noted that non-nitrogen-containing bisphosphonates might increase the risk of liver and pancreas cancer. Large prospective cohort studies are needed to find the causal association between bisphosphonates and risk of cancers. Since then, some epidemiological studies were also conducted on the association between bisphosphonates and the risk of some types of cancers, but the results of these studies were controversial.14 To date, most meta-analyses were focused on the association between the use of bisphosphonates and the risk of some specific types of cancers.24 For instance, Yang et al.19 suggested that the use of bisphosphonates might decrease the risk of colorectal cancer by 11% , while Oh et al.25 found no significant association between the use of bisphosphonates and colorectal cancer . To the best of our knowledge, there was currently only one meta-analysis by Deng et al.26 on the use of bisphosphonates and the risk of all-cause cancers, which only included 13 cohort studies and analysed the association in mixed genders and females.In recent years, preclinical studies have suggested that bisphosphonates have direct and indirect antitumour properties, including inhibition of tumour cell adhesion and proliferation,28 but the number of bisphosphonate users is expected to increase globally. For example, in the United States alone, there are approximately 40 million bisphosphonate prescriptions each year. Considering the widespread use of bisphosphonates, it is essential to explore the association between bisphosphonates and cancers.Bisphosphonates are widely prescribed for preventing and treating osteoporosis,This systematic review and meta-analysis was intended to (1) analyse possible association between the use of bisphosphonates and the risk of overall cancers and individual types of cancers based on observational studies, (2) stratify analysis by different types and duration of bisphosphonates.29 We firstly searched relevant studies in the databases of Pubmed, Embase, Cochrane Library and Web of Science from the inception date of each resource to September 26, 2019, by two study investigators (Li and Cheng) independently. Detailed search terms were shown in Supplementary Table This systematic review and meta-analysis was conducted following the PRISMA guidelines.Study design was observational study  addressing the association between the use of bisphosphonates and risk of any type of cancersThe exposure was defined as one or more prescriptions of bisphosphonatesThe outcome was the incidence of cancersStudies reported effect estimates, including odds ratios (ORs), relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CIs), or provided sufficient data to calculate themIf there were duplicate articles, the most recent published or the most complete data would be includedLanguage was restricted to English.The selection criteria of this meta-analysis were composed of inclusion and exclusion criteria. Studies were included in this meta-analysis if they complied with the following criteria:Cross-sectional studies, reviews, comments or conference abstractsStudies were in vitro or animal experimentsStudies without enough data to calculate the effect estimatesAccordingly, these studies were excluded:Data extraction and quality assessment were independently implemented by two researchers (Li and Liu) by using standardised forms, and any disagreement was resolved through discussion until consensus was reached. The following information was extracted from each study: first author, year of publication, population location, study design, study period, sample size, the number of cases, participants’ age and sex, type and duration of bisphosphonates, type of cancers, adjusted confounding factors and the available effect estimates with the corresponding 95% CIs. The original authors of studies would be contacted, if the required information was missing.30 The NOS assessed quality from the following three aspects: selection, comparability and exposure (case–control studies) or outcome (cohort studies). The total score of NOS was nine stars. Studies with a score of more than 6 stars were considered as relatively high quality. Conversely, studies with a score of less than 6 stars were considered as relatively low quality.The quality of each included study was assessed using the Newcastle–Ottawa Scale (NOS).31 The maximally adjusted risk estimates with 95% CIs were pooled by using random-effect models to obtain a more conservative outcome. Then, the heterogeneity among studies was evaluated by using the Cochrane’s Q statistic and the I2 statistic.32 The low, moderate and high degrees of heterogeneity in this study corresponding to that of the I2 cut-offs were 25%, 50% and 75%, respectively.RRs were often used as indicators to assess the association between the use of bisphosphonates and risk of cancers, and HRs were similar to RRs. We pooled the risk estimates of case–control and cohort studies in the primary meta-analysis because ORs and RRs could provide similar risk estimates when the outcomes were rare.33 Then, the subgroup analysis was carried out to study the association between the use of bisphosphonates and various types of cancers based on different types (nitrogen- and non-nitrogen-containing bisphosphonates) and duration (<1 year and ≥1 year) of bisphosphonates.To explore the sources of heterogeneity among studies, random-effect meta-regression analysis based on the residual maximum likelihood (REML) method and subgroup analysis for all-cause cancers were conducted by study design, population region and sample size. According to the different molecular modes, bisphosphonates were classified into two groups, including nitrogen-containing bisphosphonates  and non-nitrogen-containing bisphosphonates (such as clodronate and etidronate).34 and was quantitatively examined by Egger’s linear regression tests.35 If there was publication bias, we would adjust the effect by using the trim-and-fill method.36 For statistical tests, a two-sided P < 0.05 was considered statistically significant. All statistical analyses were performed using STATA version 15.1 .The sensitivity analysis was performed by omitting one study and calculating the pooled risk estimates with 95% CIs of the remaining studies. Furthermore, the potential publication bias was evaluated with funnel plots,49 11 nested case–control studies,59 6 case–control studies65 and 1 case cohort study66) were included in the current meta-analysis.The flow diagram describing detailed literature searches and selection process is shown in Fig. The main characteristics of the included studies are summarised in Table P = 0.02), breast cancer  and endometrial cancer . There was no statistically significant association between the use of bisphosphonates and oesophageal cancer  as well as other types of cancers. The heterogeneity between studies was high in colorectal cancer , pancreas cancer  and liver cancer , while the heterogeneity of the remaining studies was moderate and low. We found that the association between the use of bisphosphonates and risk of all cancers was not statistically significant , with moderate heterogeneity between studies . Detailed meta-analyses for each type of cancers are in Supplementary Fig. Fig. P < 0.01). We found no evidence that population region  and study design (P = 0.65) influenced the association between the use of bisphosphonates and risk of all cancers  and endometrial cancer , but this effect was only observed in non-nitrogen-containing bisphosphonates on breast cancer . Notably, non-nitrogen-containing bisphosphonates tended to increase the risk of liver cancer  and pancreas cancer .The subgroup analysis was conducted based on different types of bisphosphonates for various types of cancers Table . NitrogeI2 = 92%) had a greater protective effect on breast cancer than their use of less than 1 year . Moreover, we observed a significant risk reduction for the use of bisphosphonates upto at least 1 year on prostate cancer . However, there was no significant association on other types of cancers . Besides, the association was not materially changed in this analysis in other types of cancers   the use of bisphosphonates might have a protective effect on colorectal, breast and endometrial cancer, but no significant association was observed with respect to all-cause cancer as well as other types of cancers. (2) Moreover, nitrogen-containing bisphosphonates could reduce the risk of breast cancer by 6% and endometrial cancer by 30%; non-nitrogen-containing bisphosphonates could also reduce the risk of breast cancer by 12%. However, non-nitrogen-containing bisphosphonates might be associated with an increased risk of liver and pancreas cancer. (3) The use of bisphosphonates upto at least 1 year had a greater protective effect on breast cancer than their use for less than 1 year, but such result was not found in other cancers.26 The difference is that their study only included 13 cohort studies. Because this study had more sample size and the total number of cancer cases, we could examine more types of cancers and obtain higher statistical power. As we found that the sample size might be one of the sources of heterogeneity, we speculate that the use of bisphosphonates has a weak protective effect on all-cause cancer, which needs more sample size to explore this association.With regard to all-cause cancer, our results are largely consistent with previous meta-analyses in similar contexts, supporting that the association between bisphosphonates and the risk of all-cause cancer is not statistically significant.68 and endometrial cancer,24 but no significant link was observed in ovarian cancer.24 This might be due to the oestrogen receptor (ER) involved in the anticancer effect of bisphosphonates.69 Furthermore, the study by Chlebowski et al.41 showed that bisphosphonates reduced the risk of ER-positive breast cancer by 30% . However, the data on the association between bisphosphonates and ER-positive female cancers are poor, as we could not conduct subgroup analysis based on ER. Further studies are needed to focus on the use of bisphosphonates and their protective effect on the different subtypes of female cancers to confirm these findings.With regard to female cancers, our findings are consistent with previous studies that bisphosphonates could reduce the risk of breast25 showed that there was no significant association between bisphosphonates and the risk of oesophageal cancer , which was consistent with our results and other three meta-analyses.26 However, Andrici et al.70 found that bisphosphonates might increase the risk of oesophageal cancer . Similarly, the results regarding the association between bisphosphonates and the risk of gastric cancer are inconsistent.55 Clinical reports have found that bisphosphonates can cause gastrointestinal problems, such as erosive oesophagitis and gastric ulcers;72 these patients are more likely to receive the upper gastrointestinal endoscopy to accelerate the discovery of upper gastrointestinal cancer. In addition, because oesophageal adenocarcinoma of the distal oesophagus is very similar to the adenocarcinoma at the junction of the gastro-oesophagus, it is difficult to accurately distinguish them in clinical diagnosis. Original studies rarely report the results of subgroup analysis of the precise site of upper gastrointestinal cancer, as we are unable to perform pool analysis. We should focus on distinguishing the particular subtypes of oesophageal and gastric cancer when analysing the effects of bisphosphonates on gastric and oesophageal cancer in future studies. With respect to colorectal cancer, our study indicated that bisphosphonates could reduce the risk of colorectal cancer by 11%, which was similar with other five meta-analyses,19 but Deng et al.26 and Oh et al.25 suggested that the association between bisphosphonates and the risk of colorectal cancer was not statistically significant. It is well known that bisphosphonates are commonly used for osteoporosis because they have lower bone mineral density (BMD). Previous studies have shown that BMD is associated with cancer, which means that if not adjusted, it might be a confounding factor that masks the protective effect of bisphosphonates.74 For other types of cancers, the results are basically similar to previous studies, and the number of related studies is few.75The effect of bisphosphonates on gastrointestinal cancers is controversial. The study by Oh et al.77 such as lung,78 breast79 and colorectal cancer.80 We only observed that nitrogen-containing bisphosphonates could reduce 30% risk of endometrial cancer and 6% risk of breast cancer. However, there was no significant association between the use of nitrogen-containing bisphosphonates and risk of colorectal and lung cancer in our study. Simultaneously, we found that non-nitrogen-containing bisphosphonates might be associated with an increased risk of liver and pancreas cancer, which might be due to the greater toxicity on liver and pancreas. Clodronate (non-nitrogen-containing bisphosphonate) might cause evaluation of aminotransferase.81 Moreover, there were rare studies of liver disease developing in patients who use non-nitrogen-containing bisphosphonate.83 In addition, from the limited information, we could not find any possible mechanism to explain the association between non-nitrogen-containing bisphosphonates and the risk of pancreas cancer, but we should pay attention to the safety of using this drug. In the future, it might be necessary to further explore the pharmacological mechanisms of non-nitrogen-containing bisphosphonates.Experimental studies have suggested that nitrogen-containing bisphosphonates have potential antitumour effects. They could reduce the viability of tumour cells by binding to the kinase domain of the human epidermal growth factor receptor 1/2 (HER1/2), and resulting in an overall reduction in global downstream signalling that was driven by overexpression of the HER family,68 which showed that using bisphosphonates upto at least 1 year  seemed to be greater protective on breast cancer than using them for less than 1 year . However, Ou et al.23 suggested that bisphosphonate was not associated with risk of breast cancer when the usage time was less than 1 year , but a significant 26% reduction was found upto at least 1 year , which was consistent with the study by Newcomb et al.61 Patients with the long-term use of bisphosphonates might have a healthier lifestyle and higher adherence to the drugs, so the benefits observed in the analysis might be overestimated.84 Thus, further studies are needed to consider this potential bias and find the best duration and dose of bisphosphonates.Notably, we did not find that the duration of bisphosphonates had an effect on specific cancers, except breast cancer. For breast cancer, our results were consistent with a meta-analysis by Liu et al.,60 demonstrated a small but significantly increased risk of oesophageal cancer in women, not in men. Generally, women prescribe bisphosphonates for prevention and treatment of osteoporosis, while men are more likely to prescribe bisphosphonates for iatrogenic osteoporosis.86 Hence, most of the participants in included studies were women, and the number of men was much smaller. To date, there is still a lack of studies on the association between bisphosphonates and risk of cancers in people of different genders. Secondly, some studies have reported that supplemental calcium and vitamin D might have a protective effect on colorectal cancer, which are usually prescribed with bisphosphonates.88 Some included studies did not control for calcium and vitamin D when analysing the association between bisphosphonates and the risk of colorectal cancer.58 In addition, only a few studies adjust the use of statins, hormone replacement therapy (HRT) and family history of cancers, which are also related to cancers.49In this study, the evidence we have on the use of bisphosphonates and risk of cancers is based mainly on observational studies. Many studies are not able to adequately control confounding factors related to cancers. Wright et al.89 Although all included studies attempt to adjust confounding factors, there are still potential confounders that are not considered, which might affect our results. Thirdly, we are unable to perform subgroup analysis of precise sites of oesophageal and gastric cancer, because the original studies rarely report the results in this aspect. Finally, although we have explored several sources of heterogeneity with meta-regression model and subgroup analysis, it still cannot fully explain the heterogeneity in the studies.This study has several strengths. First, there are many articles and a large number of participants included in this study, which increases the statistical power of the analysis. Furthermore, we explore the sources of heterogeneity by meta-regression and subgroup analysis. Finally, this systematic review and meta-analysis has an update to the summary articles in this field. However, several limitations of this study must be mentioned. Firstly, our study includes observational studies  that might differ in the design of researches and lack individual information. In addition, evidence from observational studies is weaker than that from randomised controlled trials. Secondly, the meta-analysis of observational studies is susceptible to confounding factors that exist in original studies because most of the included studies use large and anonymous databases.In conclusion, the results of this meta-analysis suggest that the use of bisphosphonates is associated with a decreased risk of colorectal, breast and endometrial cancer, but not significantly associated with the risk of oesophageal and other types of cancers. Furthermore, we find that nitrogen-containing bisphosphonates appear to have more antitumour effects, but non-nitrogen- containing bisphosphonates might be associated with an increased risk of liver and pancreas cancer. In addition, the use of bisphosphonates for at least 1 year has a greater protective effect on breast cancer than their use for less than 1 year. We recommend that further large prospective cohort studies are needed to explore the causal association between bisphosphonates and cancers, and more studies of potential mechanism are required. After a careful benefit-and-risk assessment, whether nitrogen-containing bisphosphonates are expected to be used in populations at a high risk for the malignancies needs further discussion.Supplementary files


The International Agency for Research on Cancer (IARC) has classified shift work as a possible human carcinogen. The results of systematic on this topic is contradictory. This systematic review and meta-analysis, therefore, aimed to update the current evidence regarding the relationship between night-shift work duration and breast cancer risk.PubMed, Web of Science, and Scopus as well as reference list of included studies were searched until December 19, 2020. Observational case–control or cohort studies investigating the relationship between the duration of night-shift work and breast cancer in women were included, which all quantified night-shift work exposure. All statistical analyses were done by Stata version 11.2.2 = 71.3%), and for long-term night-shift workers (≥ 10 years) was 1.08 , with moderate to substantial statistical heterogeneity observed in both analyses. The results of subgroup analysis showed that flight attendants with long overnight flights were at an elevated risk of breast cancer, but unmeasured confounders limited these results. The risk of breast cancer in case control studies, adjusted for reproductive factors and family history of breast cancer as well as studies with high quality was increased in both short term and long term night-shift workers.Our literature search was resulted in retrieval of 4854 publications from which 26 eligible studies with 1,313,348 participants were included in the meta-analyses. The pooled relative risk (RR) and 95% confidence intervals (CIs) of breast cancer for short-term night-shift workers (< 10 years) was 1.13 (95% CI 1.03–1.24, p = 0.008, IThis systematic review found a positive statistical relationship between night work and breast cancer risk in short-term night-shift workers but no increase was observed in the long-term night-shift workers. The most widely identified invasive cancer among women is breast cancer (BC), afflicting one in eight women . 25% of Khakbazan et al.  reportedAn issue taken into account in numerous epidemiological studies over the past decade is the effect of shifts on BC . Shift wShift work exists in many industries and factories such as the oil industry, power plants, and iron and steel industries, fields related to medicine, midwifery, and nursing, and fire department, law enforcement, and water, electricity, and telephone services . This tyThe disruption in the circadian rhythm following exposure to light at night (LAN) has long been considered as a possible cause of BC , 14. TheIn 2019, the IARC re-assessed night-shift work (NSW) and described it as a "probable" carcinogen (IARC Group 2A) . HoweverMoreover, the duration of NSW has not been considered by some meta-analyses . Due to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were adopted for reporting this systematic review and meta-analysis. PubMed, Web of Science, Google Scholar, and Scopus were browsed up to December 19, 2020. There was no limit on the initial date applied. The key words employed to identify the studies were: "shift work" OR "night work" OR "night-shift work" OR "rotating-shift work" AND "breast cancer" OR "breast carcinoma" OR "breast neoplasm". Boolean operators , truncation, and MeSH terminology were used appropriately for the systematic identification of data (Table Studies were included in the review if they had the following criteria (1) were peer-reviewed case–control, observational nested case–control, or cohort studies (2) quantified NSW in all job categories including work on domestic and/or intercontinental overnight flights), (3) provided risk ratios, odds ratios, hazard ratios, and 95% CIs for BC incidence confirmed by histopathology or through data available from Cancer Registry in females aged at least 18 years old. There was no restriction regarding country, race, publication language, and date. Excluded studies were (1) studies that reported the duration of night-shift work as ‘‘ever vs never’’ (2) those involving nighttime light exposure that was involuntary or non-work related, sleep duration, or subjects included with recurrent BC, and (3) studies that their full texts were not accessible. Identified studies using the Endnote X8.1 software were retrieved and managed.At first, the titles and abstracts and then, the full texts of the studies were reviewed, separately, by two authors, and any inconsistency was discussed by a third author. There was only one case of disagreement regarding the inclusion of articles with the same population (entry of the most recent articles or articles with a larger population). Hand searching was carried out to identify further relevant studies.The outcome variable of this study was breast cancer, which was defined as having positive diagnosis of BC based on the medical records or through data available from cancer registry.Two researchers (EM and an assistant) independently evaluated the methodological quality of individual studies using the Newcastle–Ottawa Quality Assessment Scale. Newcastle–Ottawa Scale (NOS) was examined for Cohort and case–control studies in terms of interrater reliability and construct validity in a previous study which reported a high degree of agreement across its domains . The staRelevant variables included the first author's name, year of publication, geographic location of participants, type of study , occupation of participants, years of follow up, source of data about outcome and exposure, definition of exposure, number of BC cases and controls (for case–control studies), cohort size (for cohort studies), risk estimates and 95% CIs for BC incidence and nightshift work duration category, source of funding and confounders for which risk estimates were adjusted. Data extraction was done separately by two researchers (EM and an assistant) using duplicate spreadsheets for validating the data extraction process. "Night shift work" was the main exposure variable, and the absence of night work was the preferred control group.The duration of NSW exposure was reported in the studies included in this systematic review as an open (≥ 30 years) or closed 15–29 years) time periods. Using the midpoint for closed time periods and the minimum points for open time periods, single numeric values was assigned to each one. According to the assumption that a longer duration of NSW may be correlated with a higher incidence of BC, NSW exposure was divided into two groups: short-term (< 10 years) and long-term (> 10 years) NSW. After rounding the median of all allocated range values, the cutoff point between short-term and long-term NSW of 10 years was obtained [ years tiSubgroup analyses were carried out by study type , occupation , geographical area , adjustment of studies for reproductive factors (yes or no), as well as a family history of BC , quality category (high or moderate) and reporting the source of funding (yes or no) regarding short-term and long-term exposures separately.2 statistic was greater than 50% [To test the relationship between NSW and BC, risk ratios (RRs) were used. Adjusted risk assessments were preferred over crude measures where available. Then, pooled risk estimates were determined using random-effect models for the short-term and long-term NSW groups that were used due to substantial heterogeneity (p < 0.05) present in some studies. In studies that have reported multiple RRs for NSW duration, if there was more than one stratification in each short- or long-term category, we used the method of combining effect sizes across multiple comparisons within individual studies introduced by Borenstein et al. . Using tthan 50% . In ordethan 50%  and Beggthan 50%  tests foDetails of the literature review and study selection process are shown in Fig. Overall, the nested case–control studies included a total of 3574 BC cases and 10,530 controls, the case–control studies comprised a total of 18,275 BC cases and 19,341 controls, and the cohort studies consisted of a total of 23,492 BC cases from an at-risk population of 1,261,628 individuals. The study population included individuals pulling rotating or overnight shifts, including nurses , 68, 73,Twenty one studies had "high" quality assessment scores , 72–75 aMeasurement and stratification of NSW exposure duration varied substantially between the studies. Twenty six studies provided risk estimates with a median exposure duration of 5 years (IQR 4–6) falling under the short-term NSW group (< 10 years) , 55–75. 2 = 71.3% and p < 0.001)  , BC risk was significantly increased , occupation , geographical area , adjustment of studies for reproductive factors (yes or no), as well as family history of BC  , quality category (high or moderate) and reporting the source of funding (yes or no) regarding short-term and long-term exposures separately. In some of the subgroups, a significantly increased BC risk was observed in women involved in NSW Table .A statistically significant association was found between short-term NSW and risk of BC in the case–control subgroup . In flight attendants, the short-term NSW increased the risk of BC . There was no significant association identified between short-term NSW and risk of BC in North America . Stratification of the studies by occupation revealed that there was no significant relationship between long-term NSW and risk of BC . As far as the geographic area is concerned, the association between long-term NSW and risk of BC was significant only in Europe  . Also, heterogeneity was observed in six subgroup analyses  . In the long-term NSW group, the heterogeneity was removed in case-control studies, cohort studies and, the studies from North America (I2=0.0%). In this group, heterogeneity was observed in three subgroup analyses The heterogeneity in the long-term NSW was low , but the increase did not observe in the long-term night-shift workers .The first meta-analysis in this regard was reported in 2005 on six studies, revealing an increase in the risk of BC among night workers  . Erren eIjaz et al.  observedHowever, in Wang et al. study , the metAccording to the results of the subgroup meta-analysis, employment in NSW (as short term and long term) do not increase the risk of BC risk. According to our results and the meta-analyses by Dun et al.  and TravSimilar to the findings of previous meta-analyses, we also found in the subgroup analysis that the risk of BC increases in flight attendants, with long or overnight flights , 29, 31.If the analyses were stratified by the study design, the risk of BC was increased in case–control studies but no increase was seen in cohort studies which is in line with the results reported by Dun et al. , He et aThe lack of association between long-term NSW and BC could be due to the healthy worker effect. A healthy worker effect is a special form of selection bias common to occupational cohort studies that occurs because healthy individuals are less likely to be unemployed than are unhealthy individuals , 84. TheOne of the strengths of our systematic review and meta-analysis was that in the present study, due to an updated literature search, some recent publications, that were not included in previous meta-analyses, were reviewed , 71, 75.Our study had several limitations. Firstly, considerable variability of study design,, study population, sample size, definition of NSW, mode of exposure quantification, risk estimates, and adjustment for pertinent confounders, may restrict the generalizability of our findings to specific populations. Secondly, our included studies showed various rates of bias, specifically the recall bias associated with self-reported exposures, as seen in many observational studies. Certain included studies (69%) were designed as (nested) case–control, hence particularly susceptible to recall bias, which can lead to heterogeneity and contradictory results between papers. However, in every study, the authors apply different methods in order to reduce the recall bias, as mentioned previously.. Finally, we might have missed some studies in local languages.Accordingly, in future studies, exposure must be measured with an objective scale in cohorts with long follow up. In addition, for common confounders, not all studies are obtained or adjusted, further reducing the strength of the exposure-outcome association. It is also recommended that authors focus on the quality of reporting of different sections of articles  and report their articles on the basis of quality assessment tools.The present meta-analysis showed a positive statistical relationship between NSW and BC risk in short-term night-shift workers but no increase was observed in the long-term night-shift workers. Night-shift workers including flight attendants were associated with increased BC risk. Our subgroup analysis revealed that flight attendants with long overnight flights were at an elevated risk of BC. In this case, however, more studies are needed for more robust results. Also, according to the results of the subgroup analysis, the risk of BC in case–control studies adjusted for reproductive factors and family history of BC, as well as studies with high quality were increased in both short term and long term NSW. We recommend that, BC screening services should be integrated to the routine care for women with night-shift jobs. We suggest further studies with adequate information and exact definition regarding NSW and its duration.Additional file 1. Funnel plots of the articles performing short and long-term versus never night-work—shift work analysis—Trim and fill test for short and long-term night-shift work—Begg's and Egger's test for publication bias—Risk of bias graph—Quality assessment of included studies—PRISMA checklist


Existing data from several reports on the association between lipid profile and ovarian tumour (OT) suggests divergent conclusions. Our aim was to examine whether circulating lipid profile: total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) differed between cases and non-cases of OT.I2 statistics, the effect of individual studies on the overall effect size was tested using sensitivity analysis and funnel plot was used to evaluate publication bias.Electronic repositories; PUBMED, EMBASE and Cochrane library were explored through December 2019 to retrieve published articles for inclusion in the meta-analysis after quality assessment. Heterogeneity was assessed using I2 statistics ranged between 97 and 99%. Mean circulating TC  and HDL  were significantly lower among OT cases compared to non-OT cases.Twelve studies, involving 1767 OT cases and 229,167 non-cases of OT were included in this meta-analysis and Decreased TC and HDL profiles were observed among subjects with OT in this collection of reports. The implications of TC and HDL in tumour manifestations and growth need to be validated in a large multi-ethnic longitudinal cohort adjusting for relevant confounders. Ovarian cancer is the most deadly gynaecological malignancy among women, comprising diverse groups of neoplasm . It accoSeveral studies have reported the relationship between lipid profiles; total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL) and ovarian tumour (OT) with different conclusions. For example, Camuzcuoglu et al.  and BukhDrawing vivid inferences from prior population-based studies on lipid profile and OT risk appears difficult because of disparities in participants’ selections, study designs, etc. In addition, scientific evidence on this subject is of great significance to clarify whether alterations in circulating lipid profiles are sufficient to promote OT risk or these alterations are only a reflection of previously compromised health status.To this effect, a comprehensive analysis, comprising previous studies across diverse population would be necessary. Therefore, this study investigated the true difference in circulating lipid profiles  among subjects with and without OT using a meta-analytical approach.https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018099728) and conducted using the MOOSE guidelines  of serum lipid profile  were extracted independently by two reviewers and differences in data extractions were resolved in recourse to a third reviewer. To ensure uniformity of estimates, mean values of TC were transformed to (mg/ into SD .I2 test statistics. A random-effects model was used to obtain mean estimates under considerable heterogeneity (i.e I2-test > 50% or P < 0.05), but a fixed-effect model was applied to obtain mean estimates when I2-test < 50% or P > 0.05. The random effect model postulates mean estimates of lipid profile(s) differed across studies, but follow a distribution and pooled mean is estimated as the average mean difference with an assumption that differences in mean estimates are symmetrically distributed. However, the fixed effect estimates assumed that observed differences are primarily an after-effect of chance [Heterogeneity of pooled effect estimate and the magnitude of variation across studies was assessed using f chance , 15.P < 0.05 was considered statistically significant. Sensitivity analysis of pooled mean estimates was assessed using a leave-one-out method and publication bias was assessed using a funnel plot.Statistical analysis was conducted using Review Manager 5.3 and two-tailed Of the 1619 records obtained from the primary literature search, 377 duplicates and 1079 records were excluded after examining titles and abstracts. Also, 151 records were excluded after full-text evaluation and 12 studies  comprisimg/dL, P = 0.04 was significantly lower among OT cases compared to non-OT subjects  among OT subjects with malignant and/or advanced tumours. TC and LDL profiles were insignificantly different, but HDL profile was significantly lower between OT and non-OT subjects in studies with low risk of bias.Stratifying our meta-analysis by age Table , TG profFifty percent of studies included in the meta-analysis suggested a low risk of bias Table S. The biaThere was no significant evidence of publication bias from the funnel plots Figure S in the mOverall pooled mean estimates differed insignificantly upon the exclusion of a single study at a time Table S, but fewTo the best of our knowledge, this is the first meta-analytical study reporting true mean differences of circulating lipids and OT risk. Total cholesterol and HDL profiles were significantly lower among OT subjects, but TG and LDL profiles were insignificant in OT risk. We opined that these results highlight the significance of lipids in OT outcomes. The quality of reports included in our meta-analysis may largely influence these associations, but the findings of the stratified analysis represent a significant strength and modest evidence for significant alterations of lipid profile in OT risk is likely.Whether altered lipid profiles are a causal or consequential factor of OT risk is debatable. However, our findings aligned with the plausibility of the latter. Circulating lipid profiles are largely subject to alterations in the occurrence of tumour events . CholestHDL and LDL are prominent cholesterol-transporting agents vital in evaluating lipid profile in cancer signalling , 30. In In addition, there is evidence of a modest inverse association between TC or HDL and breast cancer risk . The antAlso, LDL differed insignificantly between OT and non-OT subjects in this current meta-analysis. This finding has been well reported in studies , 45 fromOur study has both strengths and limitations. Our report is the first meta-analysis highlighting the significance of lipid profile and risk of ovarian neoplasm. The higher statistical power arising from a large number of participants in our report potentially offer credibility to our findings. In addition, our funnel plots could not rule out the potential for publication bias in this meta-analysis. However, most studies included in our meta-analysis were cross-sectional (owing to limited cohort reports) and limited studies age-matched cases with controls in the eligible studies. The number of studies on this subject is comparatively rare, making the clarification of our findings quite challenging. Our findings must be interpreted with caution given a temporal sequence of causal association cannot be inferred and perhaps prone to reverse causality. In spite of the biological plausibility of the association between lipid profile and OT risk, there are many confounders involved in OT carcinogenesis. Overweight/obesity and its associated co-morbidities significantly promote OT risk among women . SimilarOur meta-analysis presents evidence of a modest significant association between circulating HDL and risk of OT. It is vital to elucidate the implications of HDL in tumour manifestations and growth. There is a need to validate these findings using large multi-ethnic longitudinal cohorts effectively adjusting for age, menopausal status, preclinical prejudice and other key confounding factors.Additional file 1. Supplementary Table S1: Critical assessment of included studies using the Newcastle-Ottawa Scale (NOS). Supplementary Figure S1: Funnel plot of lipid profile; total cholesterol (A), triglyceride (B), HDL (c) and LDL (D) between cases and non-cases of ovarian tumours; summarizing the publication bias in the meta-analysis. Supplementary Figure S2: Graphical illustration of the results of the critical assessment of studies; Is the Case Definition Adequate? (S1), representativeness of the Cases (S2), selection of Controls (S3), definition of Controls (S4), comparability of cases and controls on the basis of the design or analysis (C1), ascertainment of exposure (E1), same method of ascertainment of exposure for cases and controls (E2), overall risk of bias of all studies included. Supplementary Table S2: Sensitivity Analysis (using one study leave out method) of pooled mean differences of Lipid profiles between cases and non-cases of ovarian tumour.Additional file 2. A Meta-analysis Of Observational Studies in Epidemiology (MOOSE) Checklist.