Research has evaluated the potential impact of folate on cancer risk with conflicting findings. Studies have demonstrated increased risk, no effect, and decreased risk. This review summarizes findings of mixed results between folate intake, serum levels, gene polymorphisms, and cancer risk based on meta-analyses from the past five years.Low or deficient folate status is associated with increased risk of many cancers. Folic acid supplementation and higher serum levels are associated with increased risk of prostate cancer. Gene polymorphisms may impact risk in certain ethnic groups.Folate has been studied extensively due to its role in methylation and nucleotide synthesis. Further prospective studies are needed to clarify optimal levels for nutrient remediation and risk reduction in those at risk, as well as elucidate the association between high intake, high serum levels, and prostate cancer risk. Future considerations for cancer risk may include gene interactions with nutrients and environmental factors. Folic acid is the synthetic form of the vitamin present in supplements and fortified foods, namely grains and cereals. Dietary folate exists in a reduced state with polyglutamate side chains requiring oxidation and hydrolysis for absorption, whereas folic acid exists as the oxidized pteroylmonoglutamate form making it readily bioavailable . Dietaryficiency . About 5ficiency . There aficiency , 5. ElevS-adenosylmethionine (SAM). SAM is a chief methyl contributor to many reactions in the body, including DNA and RNA methylation [Due to its role in one-carbon metabolism, folate has been studied extensively as a possible mechanism for cancer development. Folate as 5-Methyltetrahydrofolate (5-MTHF) and cobalamin are required for the conversion of homocysteine to methionine in the methionine pathway. Methionine is converted to hylation . Inadequhylation , 7. Furthylation , 7. The hylation , 7.Excess folate intake also poses a concern. Mandatory fortification of wheat flour and enriched cereal grain products aimed at reducing the incidence of neural tube defects has raised questions regarding growth of nascent cancers . MandatoFolic acid, found in fortified foods and supplements, is converted to tetrahydrofolate in the liver by dihydrofolate reductase (DHFR). It has been reported that folic acid in excess of 400 mcg may saturate the DHFR enzyme, resulting in unreduced folic acid, which has been hypothesized as a potential mechanism for carcinogenesis , 9•.Just as overt folate deficiency and excess intake may interfere with cell replication and survival, reduced enzyme efficiency can also interfere with nutrient metabolism and influence disease risk. Methylenetetrahydrofolate reductase (MTHFR) is a key flavoenzyme that catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF). It is encoded by the gene MTHFR. There are two well-described MTHFR gene polymorphisms: C677T and A1298C. The C677T variant may occur in close to 20–40% of the population . Both vaThe relationship between folate and cancer risk remains uncertain, as studies have demonstrated positive, negative, and neutral associations. Also of note, antifolates are used in cancer treatment, however that is outside of the scope of this review. Therefore, the purpose of this paper is to summarize current knowledge of folate’s impact on cancer risk and identify opportunities for future work in this area based on a review of meta-analyses from the past 5 years. Many factors contribute to the findings, including the type and dose of the vitamin , serum levels and method of evaluating, cancer type and presence of gene polymorphisms.This review was conducted to evaluate the impact of folate on cancer risk. PubMed/MEDLINE and the Cochrane database were searched by combining the key words “folate” or “folic acid” and “cancer risk.” Meta-analyses published in the last 5 years in human adults and in English were included. Titles and abstracts were reviewed to select articles related to cancer risk in adults. Articles were excluded if they were related to cancer treatment, childhood cancer risk, or other disease states. Additional articles were obtained from references of relevant papers. A summary of the review articles selected is shown in Tables Several meta-analyses have evaluated the impact of folic acid (FA) supplementation on cancer risk using data from primary prevention trials for a number of conditions reporting cancer incidence. Two meta-analyses of Randomized Controlled Trials (RCTs) and a meta-analysis with 12 RCTs and 7 observational studies, evaluated the impact of FA supplementation, with or without other B vitamins, on cancer risk. Doses of FA ranged between 0.4 and 40 mg/day. Only one study used 5-methyltetrahydrofolate (5-MTHF), the metabolically active form of folate at a dose of 560 mcg/day. However, when that study was removed it did not change results. No significant effect of FA supplementation was found on total cancer risk in two of the analyses •, 33•. OIn subgroup analysis, Qin found a 10% increased risk of cancer in studies where > 60% of participants were on lipid-lowering drugs and hypothesized that statin treatment interacting with homocysteine metabolism in the presence of FA supplementation may impact cancer risk •. Wien rAdditional analyses evaluating risk in specific cancer types found a significant 3% decrease in risk of renal cancer with 100-mcg FA supplementation in a dose-response analysis . When coZhang and colleagues found elevated homocysteine levels and folate deficiency, as determined by serum folate level, to be associated with increased overall risk of cancer in a meta-analysis of 83 case-control studies . Folate Higher or at least adequate levels may also be protective for cervical cancer. Increased risk of cervical cancer was observed with deficiency per serum folate in Asian, but not American studies. Serum levels used to categorize deficiency were different between studies, and some were higher than what is reported in the literature, which may have impacted results. These findings need to be confirmed using consistent cutoffs categorizing deficiency .Two analyses found increased risk of prostate cancer when comparing highest with lowest serum folate levels. Both included five of the same nested case-control studies , 24. OneThe studies in these analyses either compared tertile 3 to 1 or compared low level with high level. Low levels were between less than 4.82 nmol/L and less than 10.9 nmol/L and high between less than 10.3 and 58.2 nmol/L. Only one study found an association, but pooled results were consistent with that study. Serum folate was non-fasting, which could impact results and reflect recent intake. Some studies used a level barely considered adequate as the “high” category making it difficult to interpret these findings. The authors mentioned that there was a low incidence of cancers and could have impacted results . Future Additional analyses found no association when comparing highest with lowest serum levels and risk of renal , pancreaFolate intake is associated with a protective effect for some cancers, little to no effect for others, and a potential for increased risk with higher intake. When comparing the highest to lowest intake of folate, higher intake was associated with a nearly 50% decreased risk for squamous cell carcinoma of the head and neck (HNSCC) ; 35% redDose-response analyses have shown that every 100 mcg/day increase in folate intake was associated with a 4.3% decrease in risk of HNSCC ; 12% decThere was no reduction in risk seen with lung cancer until one study with all females was removed due to heterogeneity. Then, a 10% reduction in risk was observed . The autMeta-analyses of studies for dietary folate and total folate intake found no association with risk of prostate cancer. Low intake in studies ranged from 123.8 mcg/day to 411 mcg/day (diet) and 551.9 mcg/day  and high intake reported as 235 mcg/day to 669 mcg/day (diet) and 934.1 mcg/day . In many studies, low and high diet intake are both below the recommended daily amount or the cutoffs for high with low overlap, making it difficult to discern a true cut point for risk if one does exist , 24.Recent studies regarding folate intake have found little to no association between folate intake and breast cancer, with the exception of those comparing higher alcohol consumption with lower folate intake –16, 52. Du and colleagues found a “marginal negative association” between total folate intake and risk of endometrial cancer . An 11% Gene variants associated with the folate metabolic pathway disturb nutrient bioavailability and contribute to a range of diseases. Methylenetetrahydrofolate reductase (MTHFR) directly affects DNA synthesis and methylation and has been associated with increased risk of certain cancers. In a meta-analysis of 134 case-control studies, the MTHFR C677T polymorphism was significantly associated with increased tumor risk . In straConversely, MTHFR 677TT may have a protective effect against colorectal cancer, in aggressive forms of prostate cancer, and prostate and non-Hodgkin lymphoma among Asians , 45, 49.The presence of the MTHFR A1298C variant has been significantly associated with increased risk for cervical cancer, globally and among Asians . HomozygHomozygosity for SHMT C1420T has been associated with a protective effect against colorectal cancer and overall cancer risk for Asian ethnicity . AnotherA number of factors need to be considered when evaluating and comparing studies, including limitations in the current literature. There is a great deal of heterogeneity in the populations studied, including geographical and ethnic differences, presence of polymorphisms, use of data from both pre- and post-fortification time periods, and inclusion of populations with and without fortification. Also, many studies relating to folate intake are observational and use a one-time food frequency questionnaire, which does not consider change in diet over time, and may not account for other lifestyle factors, including alcohol intake. Different methods and cutoffs are used to categorize highest compared to lowest intake and there is variability in serum levels, with a single serum level used to evaluate risk. Cutoffs overlap making it difficult to discern a true cut point if risk of one exists. The length of time for follow up varies between studies and may not be adequate to evaluate impact on risk. This makes it difficult to form a single conclusion regarding the impact of folate on cancer risk. However, there are populations who appear to be at risk due to either inadequate or excess intake.Inadequate folate intake or deficiency, as measured by serum levels, may increase risk for cancer, including cancers of the head and neck , oral caIn addition, more research is needed to help understand if the protective effects of folate are weaker in populations with a relatively higher intake level from mandatory fortification and/or supplementation. Population concerns regarding fortification and increased cancer risk are challenged in the current research. Fortification status in studies did not have any impact on risk with supplementation •, 33•. FFinally, it is important to note that dozens of enzymes affect the efficiency of folate-related metabolic pathways, and polymorphisms in these enzymes may alter substrate availability of folate and/or other nutrients as well as gene expression. Future research efforts should be aimed at understanding how polymorphisms affect nutrient status in ethnic-specific populations, how nutrient remediation affects enzyme function in the presence of polymorphisms, and how these may influence risk . Also, i


Case–case comparisons showed associations between nulliparity and high KI67 [OR (95% CI) for Q4 vs. Q1 = 1.54 ]; obesity and high grade [grade 3 vs. 1 = 1.68 ] and current use of combined hormone therapy (HT) and low grade [grade 3 vs. 1 = 0.27 ] tumors. In case–control comparisons, nulliparity was associated with elevated risk of tumors with high but not low levels of proliferation [1.43  for KI67 Q4 vs. 0.83  for KI67 Q1]; obesity among women ≥50 years with high but not low grade tumors [1.55  for grade 3 vs. 0.88  for grade 1] and HT with low but not high grade tumors [3.07  for grade 1 vs. 0.85  for grade 3]. Menarcheal age and family history were similarly associated with HR+ tumors of different grade or KI67 levels. These findings provide insights into the etiologic heterogeneity of HR+ tumors.Limited epidemiological evidence suggests that the etiology of hormone receptor positive (HR+) breast cancer may differ by levels of histologic grade and proliferation. We pooled risk factor and pathology data on 5,905 HR+ breast cancer cases and 26,281 controls from 11 epidemiological studies. Proliferation was determined by centralized automated measures of KI67 in tissue microarrays. Odds ratios (OR), 95% confidence intervals (CI) and  What's new?Limited epidemiological evidence suggests that the etiology of hormone receptor positive (HR+) breast cancer may differ by HR+ tumor subtypes as defined by histologic grade and proliferation level. In this report pooling risk factor data from a consortium of breast cancer studies, the authors found associations between nulliparity and highly proliferative tumors; obesity and high grade tumors; and current use of combined hormone therapy and low grade tumors. These results provide insights into heterogeneity of HR+ tumors that may be reflective of differences in etiological pathways, and could also have implications for risk prediction of aggressive subtypes of HR+ tumors. BCACBreast Cancer Association ConsortiumBMIbody mass indexERestrogen receptorHR+hormone receptor positiveHThormone therapyICRInstitute of Cancer Research, LondonNGSNottingham grading systemORodds ratioPRprogesterone receptorTMAtissue microarrayBreast cancer is a heterogeneous disease at the morphological, molecular and genomic level, defining subtypes with distinct biological and clinical behavior.Histologic grade is an important indicator of tumor aggressiveness that reflects three features including tubule formation, nuclear pleomorphism and mitotic count, which is directly related to proliferation.Accumulating epidemiological data suggest that breast cancer risk factors may be distinctly associated with grade and KI67.In this report, we pooled risk factor data from a consortium of breast cancer studies to examine the relationship of breast cancer risk factors with subtypes of HR+ tumors defined by levels of histologic grade and KI67 expression, determined by centralized automated scoring of tissue microarrays (TMAs) as previously described.A total of 5,905 HR+ invasive breast cancer cases and 26,281 controls were pooled from 11 epidemiological case–control studies with TMAs and risk factor information in the Breast Cancer Association Consortium (BCAC). Study populations were from Europe, Australia and North America. Details of the contributing studies including designs, country of location, method of recruitment, age range, sources and eligibility of cases and controls are provided in Supporting Information Table S1. In brief, this analysis comprised 11 case–control studies (one of them (UKBGS) nested within a prospective cohort study). Six studies  were of hospital‐based or mixed study designs (considered “non‐population‐based” studies), whilst five studies  were population‐based. All participants in each of the study groups provided written informed consent and all studies gained approval from local ethics committees.Data on risk factors were derived from questionnaires that were administered to participants at recruitment in each of the participating BCAC studies. Harmonization, central querying and quality checks on these data were performed by investigators at the German Cancer Research Institute, Heidelberg. The current analysis included risk factors for which there is evidence in the literature to suggest a heterogeneous relationship with clinicopathological characteristics and for which we had data. In this regard, five risk factors were identified – age at menarche, parity, body mass index (BMI), use of combined hormone therapy (HT) and family history of breast cancer. Supporting Information Table S2 shows the number of cases and controls from each study with risk factor information.Data on hormone receptor status were obtained from clinical records. Levels of histologic grade were assigned by local study pathologists in the respective study groups. Tumors were graded as 1 (low grade or well‐differentiated), 2 (intermediate grade or moderately differentiated) and 3 (high grade or poorly differentiated). The extent of proliferation in breast cancer tissues was determined using measures of KI67. Scores were centrally generated at the Institute of Cancer Research (ICR) in London by using a digital image analysis protocol that was developed for the quantification of KI67 in breast cancer TMAs as previously described.2; overweight 25–30 kg/m2 and obese >30 kg/m2) and the case–control analysis was conducted for groups of women stratified according to age (<50 years and ≥50 years) as a surrogate for menopausal status. This was done to account for previously reported differences in the association between BMI and breast cancer risk by menopausal status. For the case–case comparisons, BMI was not differentially related to tumor grade/KI67 levels by age categories ; as a result, case–case analysis was not stratified according to age. HT use was categorized into those who never used HT, former users and current users. Due to very small numbers of those who reported using estrogen only formulations, our analysis involved only those women who took combined estrogen and progesterone formulations. Family history of breast cancer in a first‐degree relative was categorized as yes (if present) or no (if absent). Frequency tables were used to assess the distribution of the risk factors among cases and controls stratified by study design. To test for differences in the distribution of risk factors for cases and controls by study design, we created a dummy variable for design and modeled this as the outcome with the different risk factors as predictors. Box plots and nonparametric Kruskal–Wallis equality of median test were used to assess the distribution of KI67 across categories of histologic grade, overall and by study.Participant ages at diagnosis/ages at interview were categorized into five classes . Age at menarche was categorized into four classes . Parity was defined as nulliparous or parous for case–case and case–control comparisons. For BMI, three well‐defined categories were used ; parity (nulliparous vs. parous); BMI ; HT ; family history (yes vs. no)] and quartiles of KI67  and histologic grade  were estimated. For case–control comparisons, an interaction term between study design (population‐based vs. non‐population‐based) and the risk factor of interest was included to obtain estimates of association by study design. Because of previously reported biases in case–control ORs estimated from non‐population‐based studies,We constructed a polytomous unconditional logistic regression model for each risk factor variable, and performed case–case and case–control comparisons within the same model. For case–case comparisons, odds ratios (OR), 95% confidence intervals and We examined dose–response relationships between risk factors and levels of KI67, by using the median % positive cells in each quartile of KI67 as constraints in an ordered polytomous logistic regression model.Analysis on each risk factor was limited to studies that provided information on that risk factor. Missing values were addressed by creating indicators for missing values in our models. As sensitivity analysis, all risk factors were mutually adjusted for in a multivariate model comprising data from three studies with information on the five risk factors that were evaluated. All analyses, including case–case and case–control comparisons, were adjusted for age and study. All statistical tests were two‐sided and performed using Stata statistical software version 13.1.N = 5 studies) and non‐population‐based (N = 6 studies) designs. While the distribution of most risk factors in cases was similar by study design, most risk factors showed different distributions in population and non‐population‐based studies.Table Overall, the median and mean positive cells stained for KI67 was 4.2% and 8.2%, respectively. Most tumors were of intermediate grade (52%), followed by low grade (26%) and high grade (22%) tumors. As expected, grade 1 tumors had lower KI67 scores compared to grades 2 and 3 tumors . A similar pattern of association between KI67 and histologic grade was seen across studies .vs. grade 1, OR (95% CI) = 1.67 ; p‐value = 0.001 for grade 2 and 1.68 ; p‐value = <0.001 for grade 3 tumors]. As shown in Supporting Information Table S4, these associations were similar following stratification by tumor size  = 0.52).As shown in Table vs. grade 1: OR (95% CI) = 0.45 ; p‐value = <0.001 for grade 2 and 0.27 ; p‐value = <0.001 for grade 3 tumors]. When we tested the associations between tumor grade, KI67 and morphology  in relation to HT use, all three tumor features were associated with HT use in univariate models at p‐value <0.05. However, following mutual adjustment for all three features in a multivariable model, only histologic grade remained associated with HT use (OR (95% CI) = 0.45 ; p‐value = 0.003 for grades 2 vs. 1 and 0.25 ; p‐value = 0.001 for grades 3 vs. 1). Furthermore, as shown in Supporting Information Table S4, HT use remained associated with low grade tumors regardless of tumor size (p_interaction = 0.78). Age at menarche, nulliparity and family history of breast cancer in a first‐degree relative were not differentially related to HR+ tumors defined by levels of histologic grade.Compared to women who never took HT, tumors occurring amongst current users of combined HT were less likely to be high than low grade . There was weaker or no evidence for associations with KI67 levels for age at menarche, BMI, HT and family history of breast cancer in a first‐degree relative.As shown in Table p‐value for between‐study heterogeneity = 0.78). Furthermore, as shown in Figure p‐value for between‐study heterogeneity = 0.76). Among women younger than 50 years of age (Supporting Information Table S7), we observed obesity to be associated with reduced risk of breast cancer across all levels of histologic grade, this association was however weaker for grades 2 and 3 than grade 1 tumors . Current use of combined HT was associated with an elevated risk of low but not high grade tumors . In multivariate analyses with mutual adjustment for the five risk factors that were evaluated in addition to age and study group, nulliparity remained significantly associated with high but not low KI67 expressing tumors . Obesity among women ≥50 years of age remained significantly associated with high but not low grade tumors . Current use of combined HT remained significantly associated with low but not high grade tumors .Case–control comparisons in population‐based studies showed an elevated risk of HR+ tumors with high levels of tumor proliferation among nulliparous women  and was not modified by grade (p_interaction = 0.37). Grade was determined to be the primary tumor characteristic associated with obesity  and this was regardless of KI67 levels (p_interaction = 0.59). Furthermore, HT use was more strongly associated with subtypes characterized by being low grade. We observed grade, not KI67, to be the primary tumor characteristic associated with HT use  and there was no evidence to suggest that this association is dependent on levels of KI67 in the tumor (p_interaction = 0.48).When we examined the associations between nulliparity, obesity, HT use and subtypes of HR+ tumors defined by cross‐classification of levels of KI67 and histologic grade Table , we obseFindings from analyses including almost 6,000 cases with HR+ tumors provide evidence for heterogeneity within these tumors by histologic grade and level of proliferation. Nulliparity was primarily associated with risk of HR+ tumors with high levels of proliferation defined by KI67; whilst BMI and HT were associated with risk of high and low grade HR+ tumors, respectively.Epidemiological studies have shown that nulliparity is more consistently associated with increased risk for HR+ than HR− breast cancer.Postmenopausal obesity is associated with an elevated risk of breast cancer that is more consistent for the HR+ subtype.p‐value for heterogeneity = 0.78). Thus, our findings could reflect a biological role for HT in influencing tumor behavior; however, further studies directly accounting for screening history and mode of detection will be needed to clarify relationships. Postmenopausal obesity has been shown to increase the risk of breast cancer only among women who do not take HT.Use of combined HT has been shown in epidemiological studies to be consistently associated with tumors with favorable biological profile including HR+, lobular or tubular morphology, small and low grade tumors.An important strength of this analysis is that we centrally generated continuous measures of tumor proliferation using automated digital‐pathology algorithms to score KI67. As we previously showed, this provides standardized, highly reproducible measures of KI67 with good agreements with pathologists' quantitative and semi‐quantitative scores.KI67 scores were obtained from TMAs that are generally lower than those obtained on whole sections.Our analyses comprised multiple studies with different study designs, including population and non‐population‐based studies: non‐population‐based studies are particularly prone to biases in case–control measures of association since the distribution of exposures amongst controls often does not reflect that in the source population for the cases. To address this, we limited case–control comparisons to population‐based studies only. Tests of heterogeneity of associations by study revealed no evidence of heterogeneity of effect estimates for both case–control and case–case comparisons. Missing data on risk factors were another limitation in our study, particularly for case–control comparisons. To address this, we limited the analysis for each risk factor to studies with data on that risk factor in both cases and controls and used the conventional approach of creating indicators for missing values on each risk factor in our regression models. As sensitivity analyses, we performed multivariate analyses with mutual adjustment for all five risk factors in three studies with complete information on all covariates and our results remained essentially the same.In conclusion, our findings indicate that the associations between parity, BMI, use of combined HT and risk of HR+ tumors are heterogeneous depending on the levels of histologic grade and proliferation, indicated by KI67. Although correlated, histologic grade and KI67 appear to be distinctly related to breast cancer risk factors. These results provide insights into heterogeneity of HR+ tumors that may be reflective of differences in etiological pathways; however, other factors not evaluated in our study, such as screening, could play a role. Given that grade and proliferation are important prognostic factors in HR+ breast cancer, these findings could have implications for risk prediction of aggressive forms of HR+ tumors. Further studies accounting for multiple correlated tumor characteristics and screening are needed to enable better understanding of these relationships.Each of the individual studies was approved by the local Ethics Committees and written informed consent to participate in the study was obtained from each participant across all study groups. The ESTHER study was approved by the Ethics Committees of the Medical Faculty of the University of Heidelberg and the Medical Association of Saarland. The joint Ethics Committee of Kuopio University and Kuopio University Hospital approved the Kuopio Breast Cancer Project (KBCP). Approval for the MARIE study was obtained from the Ethics Committee of the University of Heidelberg, the Hamburg Medical Council and the Medical Board of the State of Rheinland‐Pfalz. MCBCS study was approved by the Ethics Committee of the Mayo Clinic College of Medicine. The Medical Ethical Review Boards of the Rotterdam Cancer Centre and academic cancer center in Leiden approved the study protocol for ORIGO study. The PBCS study protocol was reviewed and approved by local and the US National Cancer Institute (NCI) IRBs. The RBCS study was approved by the Ethical Committees of the University Hospital Rotterdam, Erasmus University Rotterdam and Leiden University Medical Centre, Leiden. The SEARCH study was approved by the Eastern multi‐center research ethics committee. The kConFab study obtained human ethics approval at all the participating institutions through which subjects are recruited.MA and MG‐C conceived and carried out the analysis; MG‐C supervised the work; FD, MA carried out centralized laboratory work and automated scoring on KI67, respectively; PC performed KI67 data management; MA and MG‐C analyzed the data with support from NC; MA, JCC, HRA, NC, MES, MKS, PDP and MGC were members of the initial writing group for the manuscript; MA, FB, HRA, PC, JB, RM, HB, CS, AM, JCC, AR, PS, FJC, PD, RAEMT, CS, JF, MES, JL, SH, MJH, AH, RF, LBK, kConFab, MKB, QW, MJ, MJS, RK, DFE, AJS, MKS, PDP, MG‐C contributed to TMA/data collection, data generation and/or data management. All authors contributed to manuscript development and writing and gave final approval for its submission.Supporting Information Figure 1Click here for additional data file.Supporting Information TablesClick here for additional data file.


X-ray repair cross-complementing group 3 (XRCC3) is an efficient component of homologous recombination and is required for the preservation of chromosomal integrity in mammalian cells. The association between Thr241Met single-nucleotide polymorphism (SNP) in this gene and susceptibility to breast cancer has been assessed in several studies. Yet, reports are controversial. The present meta-analysis has been designed to identify whether this SNP is associated with susceptibility to breast cancer.The We performed a systematic review and meta-analysis for retrieving the case-control studies on the associations between T241 M SNP and the risk of breast cancer. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to verify the association in dominant, recessive, and homozygote inheritance models.p = 0.0001) and recessive models (OR (95% CI) = 4.092 (1.806–9.271), p = 0.001). The association was significant in Asian population in dominant model (OR (95% CI) = 1.296, p = 0.029). However, the associations was significant in familial breast cancer in mixed ethnic-based subgroup in homozygote and recessive models (OR (95% CI) = 0.451 (0.309–0.659), p = 0.0001, OR (95% CI) = 0.462 (0.298–0.716), p = 0.001 respectively).We included 55 studies containing 30,966 sporadic breast cancer cases, 1174 familial breast cancer cases and 32,890 controls in the meta-analysis. In crude analyses, no association was detected between the mentioned SNP and breast cancer risk in recessive, homozygote or dominant models. However, ethnic based analysis showed that in sporadic breast cancer, the SNP was associated with breast cancer risk in Arab populations in homozygous (OR (95% CI) = 3.649 (2.029–6.563), Taken together, our results in a large sample of both sporadic and familial cases of breast cancer showed insignificant role of Thr241Met in the pathogenesis of this type of malignancy. Such results were more conclusive in sporadic cases. In familial cases, future studies are needed to verify our results.The online version of this article (10.1186/s12881-019-0809-8) contains supplementary material, which is available to authorized users. BRCA1 and BRCA2 participate in the process of HR. Deficiencies in HR have been detected both in BRCA1/2 germline mutation–associated and remarkable fraction BRCA1/2 wild-type breast cancer patients [X-ray repair cross-complementing group 3 (XRCC3) is an efficient component of HR and is required for the preservation of chromosomal integrity in mammalian cells [XRCC3 Thr241Met significantly increased risk of breast cancer. However, they suggested that a single larger study should be performed to assess tissue-specific cancer risk in different ethnicities [XRCC3 Thr241Met and risk of breast cancer. They concluded that this variant is implausible to have a considerable role in breast cancer risk. However, they suggested studies with larger sample sizes to assess probable underlying gene–gene interactions or associations in ethnic-based subgroups [XRCC3 Thr241Met as a susceptibility locus for breast cancer, especially in Caucasians [Breast cancer ranks first among all women’s cancers regarding its incidence and rank second among them regarding its cancer-related mortality rate . Severalpatients . The X-ran cells . Consequnicities . Garcı’aubgroups . Lee et ubgroups . Economoubgroups . He et aubgroups . In anotucasians . Mao et ucasians . Finallyucasians .XRCC3 and breast cancer risk in diverse inheritance models.Therefore, according to inconclusive results of the previous meta-analyses and lack of systematic review in this regard, we conducted a systematic review and meta-analysis to assess the association between the Thr241Met SNP (rs861539) within We conducted the present systematic review protocol according to the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) . We alsoWe searched PubMed, Scopus, EMBASE, Web of Science and ProQuest databases, the key journals , conferences/ congress research papers (as Grey literature) and the reference list of the included primary studies until March 2018 T(1990/01/01:2018/03/31) using the following syntaxes: “x-ray repair cross-complementing group 3” or “XRCC3”and“polymorphisms” or “single nucleotide polymorphism” and “breast tumor” or “breast cancer” and “rs861539” or “c.722C > T” or “p.Thr241Met” or “T241 M”  Studies with available genotype frequencies in both case and control groups. We excluded books, reviews, editorial, letters and articles which did not intend to assess the association between XRCC3 Thr241Met SNP and breast cancer risk and those without control group data. Our participants are post- or pre-menopause women with breast cancer which is pathologically confirmed. Studies with male breast cancer cases were excluded. Our exposure is rs861539 (T241 M) that was evaluated with various genotyping methods such as PCR-RFLP, Taq-Man, Sequencing and etc. We performed search in the different mentioned sources and exported the search outputs into the End-Note software. The duplicated primary studies were deleted (only one version of the duplicated documents was kept). The screening phase (selecting included/ probable included versus excluded primary studies using the title or/ and the abstract) were performed. The selection or verification process (selecting included versus excluded primary studies) were performed based on the eligibility criteria. All steps for preparing this systematic review such as searching, screening based on titles of papers and abstracts, selection according to examination of full text of articles, risk of bias assessment and data extraction were done independently by two authors (SD and ZTE). Any disagreement regarding the inclusion/exclusion criteria and data extraction were resolved by consensus of the reviewers.We included: i) all observational studies such as cross-sectional, case-control and cohort studies ii) studies that assessed associations between Thr241Met within Methodological quality assessment (risk of bias assessment) was based on the Newcastle–Ottawa Scale (NOS). Checklist of each study was filled with two reviewers independently. Any disagreements (between two reviewers) were resolved by the discussion or consensus otherwise opinion of third expert reviewer. For assessing total quality status in primary study we used sum score of quality items. According to this score, we classified the papers in three groups  . Data waZ test was applied to assess the significance of the ORs, The heterogeneity between included publications was evaluated using I2 parameter as described previously [p < 0.05) . We combined genotype frequencies to calculate univariable (crude) OR. In addition, combination of adjusted OR values was based on the similarity of adjusted OR values restricted in two models including age-adjusted (association between rs861539 and breast cancer after controlling age of patients) and age and other factors. The random-effects model was used to combine parameters acquired from discrete studies due to methodological variation. Sensitivity analyses were performed using leave-one-out sensitivity analysis to indicate the effect of the quality score on the results. Subgroup analyses were done for evaluating potential sources of heterogeneity based on ethnicity, case selection methods case group , methodological quality status  and-case enrollment strategies .All of data analyses were performed in two distinct groups of familial breast cancer and sporadic breast cancer. Data were analyzed using STATA 13 software. Association between the mentioned SNP and breast cancer risk were analyzed by pooling odds ratio (ORs) with 95% confidence interval (CIs) in three models including dominant (TM + MM vs.TT), recessive (MM vs. TM + TT), and homozygote (MM vs.TT) models using STATA metan module. eviously  where thp-value< 0.1) [Funnel plots, Begg’s and Egger’s test were used to measure publication bias (ue< 0.1) , 11.Figure Initially, we conducted the analysis in the familial and sporadic studies after using the random-effects model. Random model was used for analysis of associations in three inheritance models based on its more conservative nature. Final results for familial and sporadic studies are shown in Tables The forest plots for each model are depicted in Figs. No significant associations were detected between the mentioned SNP and breast cancer risk in any inheritance model either in familial or in sporadic breast cancer cases.p = 0.0001) and recessive models (OR (95% CI) = 4.092 (1.806–9.271), p = 0.001). However, the association was significant in Asian population in dominant model (OR (95% CI) = 1.296 (1.027–1.636), p = 0.029). Based on the calculated Interaction p-value in ethnic-based subgroup analyses (p = 0.0001), we conclude that such subgroup analysis strategy was appropriate and the calculated ORs are significant. However, the associations was significant in familial breast cancer in mixed ethnic-based subgroup in homozygote and recessive models (OR (95% CI) = 0.451 (0.309–0.659), p = 0.0001, OR (95% CI) = 0.462 (0.298–0.716), p = 0.001 respectively).Next, we assessed association between this SNP and risk of familial or sporadic breast cancer in ethnic-based subgroups Figs.  and 5. Ip = 0.002 and OR (95% CI) = 0.868 (0.806–0.934), p = 0.0001 respectively). The Interaction p-value was calculated as 0.655 which shows inappropriateness of such subgroup analysis strategy. No significant associations were found in society-based analysis in familial cases  subgroup . In sporadic cases, the associations were significant in population-based studies in homozygote and recessive models (OR (95% CI) = 0.869 (0.796–0.950), 0.806–0.94, p = 0.p-value = 0.891) but in familial cases we found the association in studies with fair quality in homozygote and recessive models (OR (95% CI) = 0.504 (0.304–0.834), p = 0.008, OR (95% CI) = 0.515 (0.297–0.894), p = 0.018 respectively)  and found no significant association in sporadic . No significant associations were detected either in sporadic or familial cases  , inclusion of grey literature (theses) and duplicate implementation of all steps of systematic review and meta-analysis . In addition, priori principle (establishment and registration of protocol) was applied.Our study had some limitations. Based on the unavailability of sufficient data from the primary studies, we could not assess the association between the mentioned SNP and breast cancer risk in pre−/post-menopause subgroups. In addition, the adjusted OR values of the primary studies were based on different parameters which might influence the validity of this kind of statistical analysis. Finally, there were some limitations in the primary studies and we did not find any genotyping data according to breast cancer subtypes except for 3 studies in triple negative breast cancer. Due to the low number of primary studies, the result of meta-analysis based on breast cancer subtypes was not reliable. So, we did not performed this type of analysis.Taken together, our results in a large sample of both sporadic and familial cases of breast cancer showed insignificant role of Thr241Met in the pathogenesis of this type of malignancy. Such results were more conclusive in sporadic cases. In familial cases, future studies are needed to verify our results.Additional file 1:The search syntaxes for each database. (DOCX 14 kb)Additional file 2:Figure S1. Forest plots of XRCC3 Thr241Met polymorphism and risk of sporadic breast cancer in Study-based subgroups. (D) Homozygote model: MM vs. TT. (E) Dominant model: TM + MM vs. TT. (F) Recessive model: MM vs. TM + TT. (ZIP 21 kb)Additional file 3:Figure S2. Forest plots of XRCC3 Thr241Met polymorphism and risk of familial breast cancer in society -based subgroups. (D) Homozygote model: MM vs. TT. (E) Dominant model: TM + MM vs. TT. (F) Recessive model: MM vs. TM + TT. (ZIP 8 kb)Additional file 4:Figure S3. Forest plots of XRCC3 T241 M Polymorphism and Sporadic Breast Cancer according to NOS subgroup analysis. (A) Homozygote model: MM vs. TT. (B) Dominant model: TM + MM vs. TT. (C) Recessive model: MM vs. TM + TT. (ZIP 22 kb)Additional file 5:Figure S4. Forest plots of XRCC3 T241 M Polymorphism and Familial Breast Cancer according to NOS subgroup analysis. (A) Homozygote model: MM vs. TT. (B) Dominant model: TM + MM vs. TT. (C) Recessive model: MM vs. TM + TT. (ZIP 9 kb)Additional file 6:Figure S5. Forest plots of XRCC3 T241 M Polymorphism and Sporadic Breast Cancer according to case enrollment subgroup analysis. (A) Homozygote model: MM vs. TT. (B) Dominant model: TM + MM vs. TT. (C) Recessive model: MM vs. TM + TT. (ZIP 22 kb)Additional file 7:Figure S6. Forest plots of XRCC3 T241 M Polymorphism and Familial Breast Cancer according to case enrollment subgroup analysis. (A) Homozygote model: MM vs. TT. (B) Dominant model: TM + MM vs. TT. (C) Recessive model: MM vs. TM + TT. (ZIP 9 kb)


Questions were on perception of diet, physical activity, obesity, and breastfeeding as cancer risk factors. In 2015, nutritional/activity factors were perceived as having an important role in cancer development for the majority of those surveyed (diet (90.8%), obesity (76%), and physical activity (70%)) with the exception being breastfeeding (34%). However, there was a moderate perception of the risks of red meat (43%) and salt or salty food (55%) consumption. Perceptions of nutritional risk factors were mostly associated with age and education level. Interestingly, there was a greater perception of nutritional risk factors in 2015 compared to 2010, and the participants’ opinions were also stronger. Efforts should be made on individuals with lower educational level and to promote the beneficial effects of breastfeeding. However, to impact food behavior, measures are needed at the environmental level and not only at the individual one.The French Cancer Barometer, a population-based-survey, is carried out every five years and is, to date, one of the few national studies conducted to investigate individual perception linked to cancer risk factors. The aims of the present study were to describe the perceptions of the French population in 2015 and to assess their evolution over a 5-year period (2010–2015). The French Cancer Barometer surveyed a randomly selected sample of participants aged 15–75 years ( Cancerous disease is always caused by genetic mutations which create a cell division defect and trigger uncontrolled runaway . Apart fNearly one in two people will get cancer at some point in their lifetime, as highlighted in studies conducted in Canada, the United States, and the United Kingdom ,15,16. IMultiple risk factors exist for different cancer sites ,3,4. TheNutrition , physical activity, and weight status  are interrelated . In the Some population-based studies have shown that compliance with cancer prevention guidelines  is associated with a lower risk of cancer ,10. TherFor this population-based study, we used data from the Cancer Barometer conducted in France in 2010 and 2015. This national survey, using computer-assisted telephone interviews, has investigated perceptions and knowledge related to cancer, cancer prevention and cancer risk factors  since 2005. The questions are consistent throughout the time period; however, further questions about nutritional factors  and cancer risks were added in 2010 and asked again in 2015. The survey was conducted in accordance with the Declaration of Helsinki. The complete methodology of the surveys is presented elsewhere ,42.The study was proposed to people aged between 15–75 years in the 2010 and 2015 Barometers, living in France, speaking fluent French and who had never had a cancer diagnosis. In the 2015 Barometer, subjects aged between 75 and 85 years were also included to be more representative of the French population . To be iA list of potentially eligible participants was generated using random digit dialing using number prefixes corresponding to the blocks of numbers assigned by the French regulator. When several people used the same phone number, the Kish method  was applBVA Group who are accredited to conduct population-based phone surveys.An information letter was first sent to all the potentially eligible participants of the survey. They were then contacted by phone and verbal consent was obtained. When the subject was contacted but was unavailable, an appointment was made. When no one answered the phone, at least 40 attempts were made to carry out a survey (at different times of the day and different days of the week). When subjects were contacted and available, inclusion criteria were verified before asking the closed and multiple-choice questions from the list. Computer-Assisted Telephone Interviewing (CATI) Software was used by the interviewers as a phone assistance device to manage phone calls, appointments and the progression of the survey. The subjects’ responses were anonymous and self-reported. The study was conducted in accordance with French Data Protection Commission (CNIL) guidelines and carried out with assistance from the The 2010 and 2015 surveys started with sociodemographic questions and general information-related questions for the participants. The following information was collected: sex, age, city, education level, current or previous employment, and monthly family income in Euros per consumption unit . In the analysis, three income ranges were considered: €0–1100/CU, €1100–1800/CU, and >€1800/CU. These ranges are based on the minimum wage and national data on individual salaries, representing three social classes: low income, middle income, and high income. (1)“Do you think that diet has a ‘very important’, ‘somewhat important’, ‘somewhat unimportant’ or ‘not at all important ’role in cancer development?”.(2)“In your opinion: frequent consumption of :  cancer risk. The question was repeated for participants who responded ‘Don’t know’. If they still could not answer, the response ‘Don’t know’ was recorded. In our survey, participants were surveyed on cold meats  and not on processed meat in general as eating cold meats is of cultural significance in France.Question (2) was adapted for physical activity, overweight and obesity, and breastfeeding (for women only)—“In your opinion, :  cancer risk”.(3)“Do you feel that you are ‘very well, ‘somewhat well’, ‘somewhat poorly’ or ‘very poorly’ informed on the health effects of ?”.Regarding the links between nutritional factors and cancer risk, three main multiple-choice questions were presented:All statistical analyses were conducted using SAS enterprise guide 7.13. First, descriptive analyses were used to describe the participants’ characteristics and perceptions. Proportions were described as ‘very low’ when under 30%, ‘low’ when between 30% and 40%, ‘moderate’ when between 40% and 60%, ‘high’ when between 60% and 70%, and ‘very high’ when higher than 70%. These cut-offs are based on a Gaussian curve, with a theoretical mean of 50, and standard deviation of 10. Chi-squared tests were performed to study differences in sociodemographic variables associated with participants’ perceptions. Finally, logistic regressions were performed to evaluate the associations between sociodemographic variables and the perception of nutritional factors in cancer risk. A stepwise analysis was performed to define the explanatory variables of each regression model. Variables added to the models were: age, sex, monthly family income, education level, occupation, and perceived levels of information on the effects of diet and physical activity on health.For Question (1) and (2), the responses ‘very important/well and ‘rather important/well’ were combined, as were the responses ‘somewhat unimportant/poorly’ and ‘not at all important/very badly’, to obtain a clear result on the number of participants perceiving the cancer risks linked to nutritional factors and their level of information (well informed versus poorly informed) or not.n = 3345 in 2010 and n = 3508 in 2015). p <0.05) and who have had someone close to them diagnosed with cancer reported a greater perception of the effects of diet on cancer development  (not tabulated).In 2015, diet was perceived by the participants as having an important role (90.8%) in cancer development. Different sociodemographic factors were associated with this perception, as presented in The importance of diet in cancer risk varied also regarding the types of food. As presented in p < 0.05). Regarding age, the impact of fruit and vegetables, red meat, and cold meat consumption on cancer risk had a greater perception among older people, while the effect of salt and salty foods consumption on health had a greater perception among young people. Regarding education level, participants with higher education levels had a greater perception of the impact of food consumption on cancer risk, except for salt and salty foods, but the differences were not significant. Regarding occupation, red meat was the only food not significantly associated. Finally, the links between cancer risk and fruit and vegetable, red meat, cold meat, and salt and salty food consumption were more perceived by participants with higher family income and higher perceived levels of information regarding the effects of diet on health.The multivariate analysis revealed how food perceptions toward cancer risk varied according to sex, age, family income, education level, occupation, and perceived level of information regarding the effects of diet on health. Four logistic regression models are presented in Regular physical activity was perceived by 70.0% of the participants as lowering cancer risk see . MultivaOverweight and obesity was perceived by 75.7% of the participants as increasing cancer risk see . Multivap <0.01), those with a higher education level (secondary and university), and women from the working class , while there was a lower perception of breastfeeding benefits among women who had never worked compared to employees .Breastfeeding was perceived by 34.0% of the female participants as lowering mothers’ breast cancer risk see . Multiva2 = 29.6, degrees of freedom = 4, p <0.001). Notably, there was a greater perception of cold meat (+14.4%) and salt and salty food (+18.5%) consumption in 2015 than in 2010.There was a greater perception among participants of the role of diet see  and of tIn 2015, participants had a stronger opinion than in 2010, as significantly fewer responded “Don’t know” to the different questions see . HoweverThere is a greater perception of risk factors linked to nutrition, physical activity, overweight and obesity, and breastfeeding in 2015 than in 2010. This finding is encouraging and highlights that French people are more aware of cancer risks. However, the findings should be interpreted with caution in national surveys comparing two different samples  as this could lead to misinterpretations ,27. PartThe strengths of the Cancer Barometer lie essentially in two points: (1) a representative sample of the French population is surveyed, and (2) a review is conducted every five years. The findings of this study are thus generalizable to the French population and can be used to adapt cancer prevention programs by improving community-wide interventions. Regarding the exploration of cancer risks attributed to nutritional factors, this is also one of the first studies investigating public awareness on this subject in such detail.Physical activity, weight status, and diet are perceived by the majority of the participants as having an important role in cancer development. However, when we look at each food group known to be associated with cancer risk , the awaBreastfeeding is ultimately the nutritional factor with the lowest perception as lowering cancer risk. This could be due to a lack of communication in France about the benefits of breastfeeding for women. Breastfeeding is beneficial for the baby , but it also lower women’s cancer risk, risk of osteoporosis, and can be helpful for post-childbirth recovery  . HoweverPerception of the impact of nutritional factors on the onset of cancer is linked with sociodemographic characteristics. In our study, sex, age, education, occupation, and monthly income were frequently associated with participants’ perceptions. For example, there was a lower perception of the benefits of physical activity and the risks of overweight and obesity among participants over 24 years of age, less educated people, and those with low incomes. In France, as in many other countries, the prevalence of overweight and obesity has remained higher among the least educated . It appeThe first report on ‘Food, nutrition and the prevention of cancer’ was published in 1997 by the WCRF and AICR. This report was subsequently updated in 2007 and in 2018 . The impFrench National Cancer Institute website (www.e-cancer.fr) and updated as needed. Information on nutritional factors, alcohol and tobacco, and cancer risks has also been provided through posters, print media, television and radio each year. For example, in 2016, posters were displayed in pharmacies to raise people’s awareness. In 2019, television commercials were broadcast. Furthermore, the survey’s findings have been made available to French public health agencies such as the French National Authority for Health. Unfortunately, we have had no feedback on how public health agencies have used the findings. In the future, we should establish a method to evaluate how useful the findings of the Cancer Barometer are and how they are used by public health agencies.International nutritional guidelines for cancer prevention exist  and are Due to the importance of demographic factors on individuals’ perceptions, community-wide and health education interventions can be designed to increase knowledge and awareness of those less aware of the cancer risk associated with diet. Proof-of-concept and feasibility studies , using qSome limitations need to be pointed out. During the study, a national report on nutrition and cancer risk was published in France . ParticiThese two national surveys at two time points, 2010 and 2015, highlight the need to improve prevention policies concerning cancer risk and nutrition.People with a lower perception of the links between nutrition and cancer risk are lower socio-economic groups and individuals with lower education levels. Therefore, policies should be designed within a proportionate universalism framework in order to reach the general population  with a proportionate targeting that takes into account the social gradient. Thus, community-wide could be proposed. However, to promote healthy food choices, it is essential that policies target the nutritional environment. Examples of such mesures include levies and taxes, advertising regulation or nutrition labelling (e.g. Nutri-Score adopted in France), which may encourage product reformulation and therefore lead to a food offer improvement. By making healthy food more accessible, affordable and visible, environmental measures are more likely to impact food behavior and to support the information disseminated through prevention campaigns. Regarding breastfeeding, interventions targeting the entire French population seem more appropriate, as there is a low perception of this factor among women as lowering cancer risk and this factor is a social issue. The next French Barometer surveys could be improved with questions assessing the participants’ reasons for their perceptions.


Tooth loss has been reported to be associated with the risk of liver cancer in several prior studies in economically advantaged countries. Whether this relationship is also evident in economically disadvantaged populations is not known.We analyzed data from the Nutrition Intervention Trials, two randomized placebo-controlled trials of vitamin/mineral supplementation in Linxian, China. Participants who reported having lost permanent teeth were examined to determine the number of teeth remaining. In the 30-year follow-up period, 329 liver cancers were diagnosed and 368 chronic liver disease deaths occurred. Tooth loss was categorized based on loess smoothed age-specific predicted quartiles. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the two outcomes.2  had a significantly increased risk, while persons with a BMI <23.0 kg/m2 did not . No relationships with chronic liver disease mortality were observed.Overall, persons in the highest quartile of age-specific tooth loss had an increased risk of liver cancer  which was not statistically significant. Results varied by sex and body mass index (BMI), however. Women in the highest quartile of age-specific tooth loss had a significantly increased risk , while men did not , and persons with a BMI > 23.0 kg/mIn a rural, economically disadvantaged population, persons with the highest levels of age-specific tooth loss had an increased risk of liver cancer. The results, which were stronger among women and persons with greater BMI, suggest that periodontal disease may increase risk of liver cancer. Liver cancer is the sixth most commonly occurring cancer in the world and the second leading cause of cancer mortality . All majA factor that may be related to risk of liver cancer is periodontal disease, a common condition common among adults , with riUsing tooth loss as a proxy variable for periodontal disease, three prior studies have prospectively evaluated the association between tooth loss and risk of liver cancer –15. A coThe Nutrition Intervention Trials were two randomized placebo-controlled trials of vitamin/mineral supplementation in Linxian, China, a rural county with high rates of esophageal and gastric cancers. Both the General Population Trial  and the The study protocols were approved by the Institutional Review Board of the National Cancer Institute. The study was registered as ClinicalTrials.gov number NCT00342654.At the time of study recruitment, participants completed a baseline questionnaire and received a dental examination. Participants who reported, via questionnaire, having lost permanent teeth were examined to determine the number of teeth remaining. Number of teeth lost was categorized into the following groups: 0, 1–3, 4–6, 7–10, 11–20, and 21–32 teeth lost.As extent of tooth loss is positively related to age, loess smoothed age-specific predicted values for number of teeth lost were used for risk calculations . The medIn the trial (1985–1991) and post-trial (1991 onward) follow-up periods, incident cancer cases and causes of death were identified using several methods that captured near complete ascertainment. In the trial period, village health workers visited all participants, and trial staff reviewed records at all local and regional hospitals and the local cancer registry on a monthly basis. New cancer diagnoses and causes of mortality were confirmed by a panel of American and Chinese experts. In the post-trial period, village health workers continued monthly visits, with all new cancer diagnoses and causes of mortality confirmed by a panel of Chinese experts. These expert reviews consisted of review of diagnostic material, including pathology and cytology slides, ultrasonography reports, computerized tomography scans, clinical histories, biochemical results, and endoscopy and surgery reports.st, 2016, 329 incident liver cancers were diagnosed and 368 chronic liver disease deaths had occurred.Diagnoses of incident liver cancer were based on biochemical assays, clinical examination, ultrasound, and computerized tomography scans. Chronic liver disease mortality, including deaths due to cirrhosis, were identified by symptoms , biochemical assays and computerized tomography scans. As of March 31a priori, were age at study randomization, sex, body mass index (BMI), education, cigarette smoking, alcohol use and study trial . Age was self-reported at the time of start of the intervention and analyzed as a continuous variable. BMI was calculated from the measured height and the measured weight and categorized based on World Health Organization recommendations for Asian populations [2, 18.50–22.99 kg/m2, 23.00–27.49 kg/m2, and ≥ 27.50 kg/m2. Education was categorized into the following groups: no formal school, 1–5 years of education, primary school, middle school or higher, and other. Smoking status was categorized into never, former, and current smoking. Alcohol use was categorized as none vs. any drinking in the previous 12 months. Diabetes was examined as a potential covariate; however, positive diabetes status was self-reported by only 0.1% of the study population. Positive hepatitis status, self-reported by 3.6% of the study population, was also examined as a potential covariate, however, as the term ‘hepatitis’ lacks specificity, it was not included in the models. As the exposures were unrelated to trial intervention assignments, the models only adjusted for trial participation, rather than trial intervention.Potential covariates, specified ulations  into theBlood samples were collected from participants at baseline in both trials. Serum markers to determine HBV and HCV infection status were analyzed in two previous nested case-controls studies in the Linxian trials population , 22. Ant2 as continuous variables; stratification using 1-year age groups; and stratification using 5-year age groups. No meaningful difference was seen among these methods, thus age at randomization and age2 were used in all models for conventional tooth loss. All p-values were two-sided with a significance level of α = 0.05.Follow up time began at the start of intervention  and ended with the first diagnosis of liver cancer, death (from any cause), or March 31, 2016, resulting in 650,235 person-years of follow up. The frequency and proportion of covariates were calculated overall and within categories of age-specific tooth loss. Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) for the two outcomes, liver cancer incidence and chronic liver disease mortality. For conventional tooth loss, three methods to were compared to control for age: adjustment for age at randomization and age2 using loess smoothed age-specific predicted cut-offs, sex, BMI, education, cigarette smoking, alcohol use, and study trial. Tests for trend were constructed using either the number of teeth lost or the quartile of age-specific tooth loss as continuous variables. The proportional hazards assumption was tested using an interaction between tooth loss and log (follow-up time), as a continuous variable, in models that included adjustment for confounding. No violations of the assumptions were observed. The following sensitivity analyses were performed to assess the robustness of the findings: (1) Restricted to participants ≥ 50 years old at randomization, as periodontal disease is the main cause of tooth loss in older populations; (2) Restricted to persons who never smoked to address concerns of confounding by cigarette smoking [2 vs. ≥ 23.0 kg/m2) were conducted, based on recent animal studies of sex differences in inflammatory markers [Measures of association were estimated with adjustment for age at randomization and age smoking ; (3) Exc markers , 25 and  markers , 27. AllTable 1. The majority of the study population had a BMI of 18.5–22.99 kg/m2 (65.7%), had less than a primary school education (71.4%), were non-smokers (70.1%) and did not consume alcohol (77.0%).Demographic characteristics of the study population by age-specific tooth loss quartile are shown in Table 2 shows the adjusted association of tooth loss with incident liver cancer and chronic liver disease mortality. In regard to liver cancer, there was no association with ever/never loss of permanent teeth  or with number of teeth lost (ptrend = 0.22). Persons in the highest quartile of age-specific tooth loss, however, had an increased risk of liver cancer  although the result did not attain statistical significance. With regard to chronic liver disease mortality, there were no significant associations with ever/never loss of teeth , number of teeth lost (ptrend = 0.33), or with age-specific tooth loss in the highest quartile .Table 3 displays the results of analyses stratified on sex. Although there was no indication of interaction by sex (pinteraction = 0.67), the stratified analyses found women with the greatest number of teeth lost had a significantly increased risk of liver cancer  while the men did not . Similarly, women in the highest quartile of tooth loss had a significantly increased risk of liver cancer  while the men did not . There were no associations with chronic liver disease mortality among either men or women.Table 4 are the results of the analysis stratified on BMI. Among participants with a BMI ≥ 23.0 kg/m2, persons in the highest age-specific quartile of tooth loss had a significantly increased risk of liver cancer . Restricting the analysis to persons with a BMI ≥ 25.0 kg/m2 further strengthened the relationship (data not shown), however the estimates lacked precision as only 9.7% of the cohort had a BMI in this range. While the test for interaction with BMI was not significant (pinteraction = 0.28), the association between tooth loss and liver cancer was not evident among persons with a BMI < 23.0 kg/m2 . Similarly, there was no association between chronic liver disease mortality in either strata of BMI.Shown in The results did not change when the analysis was restricted to persons ≥ 50 years of age or restricted to persons who never smoked (data not shown). The results also did not change when the first two years of follow-up were excluded or in a subset analysis of persons with known HBV/HCV status (data not shown). Similarly, exclusion of the persons in the Dysplasia Trial did not affect the results (data no shown).2.In this prospective study in a rural Chinese population, persons in the highest quartile of age-specific tooth loss had an increased risk of liver cancer. The increased risk was more notable, and statistically significant, among women and among persons with a BMI > 23.0 kg/mThree previous prospective studies have examined risk of liver cancer with tooth loss, one among a population of male Finnish smokers , one amo2, a factor that was also associated with higher risk of liver cancer associated with tooth loss.Why the associations between tooth loss and liver cancer varied among the studies is not certain, but several differences exist among the studies. The lack of association reported in the study of Japanese octogenarians may have been due to it being a small study of only 697 participants with a limited number of cancer deaths. In addition, liver cancer is more commonly diagnosed at ages younger than 80 years, so persons who live to be octogenarians are likely to be a healthier group of people who are at lower risk of cancer, overall. In the Japanese case-control study, the association seen with loss of 12–23 teeth, but not with the loss of a greater number of teeth, is curious, but as no further stratified analysis was presented, it is not clear whether the results differed by sex or other characteristics. In the study of male Finnish smokers, tooth loss of all levels was associated with a significantly increased risk of liver cancer. The lack of association among the men in the current study, in contrast to the Finnish study, could be due to a number of variables given that Finland, in contrast with Linxian, China is a high-income country with an economically-advantaged population. Nevertheless, in the current study, there was an association between the highest level of tooth loss and liver cancer among women. The association among women, but not among men, may be related to women having a higher prevalence of tooth loss (78.5% vs 72.1%) and being more likely to be in the highest quartile of age-specific tooth loss (31.2% vs 19.9%). Women were also more likely to have a BMI > 23.0 kg/mTooth loss can be the result of periodontal disease, but can also be the result of trauma or caries. A comprehensive oral health examination among ~600 participants of the cohorts, however, found that high levels of moderate to severe periodontal disease were present, while caries were less common . These rStrengths of this study include its large sample size, prospective design, and extensive length of follow-up (up to 30 years). In addition, number of teeth lost, the primary exposure of interest, was determined by physical examination rather than self-report. Large variation in the primary exposure allowed robust estimation of a dose-response relationship. Methods for identification of cancer cases and causes of mortality assured essentially complete ascertainment of both outcomes. This population was highly homogeneous regarding occupation and socioeconomic status. We controlled for age using several methods, including categorizations based on loess smoothed age-specific predicted cut-offs. Further, we controlled for important risk factors for liver cancer including BMI, alcohol use, and cigarette smoking.1, a known liver cancer risk factor. Previous research, however, reported low levels of aflatoxin B1 exposure in Linxian [A limitation of this study was a lack of complete ascertainment of HBV/HCV status for the study population. The subset analysis of persons who were tested for HBV and HCV indicated, however, that the results were not affected by adjustment for viral status. The study also lacked information on exposure to aflatoxin B Linxian .This study is the first to evaluate the effects of tooth loss on liver cancer incidence and chronic liver disease mortality in a rural, economically disadvantaged population. The increased risk of liver cancer with the highest levels of tooth loss, a relationship particularly evident among women, suggests that periodontal disease may be a risk factor for liver cancer. Further study of this relationship is clearly warranted as the identification of modifiable risk factors for liver cancer may have the potential to decrease the burden of the world’s second greatest contributor to cancer mortality.


Background: Breast cancer is among the most common life-threatening public health problems of global concern including Ethiopia. Knowledge and awareness about the disease will help to reduce the number of cases who present at late stages of the disease. The objective of this survey was to assess the knowledge, perception and risk awareness about breast cancer among female medical and health science students of University of Gondar, Ethiopia.Methods: A cross sectional survey was conducted from May 03 to June 01, 2017 at University of Gondar, Ethiopia. Three hundred students were proportionally selected from nine departments using simple random sampling method. Using a structured questionnaire data on risk factors, symptoms and perception about breast cancer and its management approach was collected. Data were entered to and analyzed using SPSS version 21.Results: A total of 300 students had fully completed the survey making the response rate 95.24. The participants' mean age was 21.4 years with the standard deviation (SD) of 2.13 years. The overall level of knowledge on breast cancer was low. Majority of the participants were unaware for complex risk factors such as first child after the age of 30 years (51%), early onset of menses (55.3%), and menopause after the age of 55 years (47.7%) are liked with breast cancer even though they acknowledged old age, family history, and smoking as possible risk factors for breast cancer. Pain in the breast region, change in the shape of the breast, and nipple discharge were the most frequently correctly identified symptoms of breast cancer. Majority of the study participants had also correct beliefs about breast cancer management and its outcomes. however, they had negative perception of breast cancer treatment by considering it to be a long-term and painful process. In binary logistic regression analysis department (p = 0.000) and year of study (p = 0.008) were found to be an independent predicting factors for knowledge among the study participants.Conclusions: The overall level of knowledge on breast cancer and clinical breast examination guidelines was found to be low even though majority had positive perception toward the treatment and its outcomes. Hence, intensive breast health awareness campaign, which should also stress on the importance of early detection and reporting, is necessary to improve the knowledge about breast cancer. Breast cancer is one of the top most public health concern jeopardizing the lives of many peoples worldwide , 2. ThisGlobally, the incidence of breast cancer has increased from 641 000 in 1980 to 1 643 000 in 2010 with an annual increment of 3.1% , 6. The The exact reasons for the occurrence of breast cancer have not been fully understood. However, numerous researchers have identified a number of predictors that can increase one's likelihood of getting breast cancer. They called them risk factors and includes family and individual backgrounds of breast cancer; delayed menopause (>55 years); early menarche <12 years); late age at first full-term pregnancy (>30 years); alcohol use; aging; never breastfeeding a child; exposure to contraceptives; tobacco smoking; high fat diet; obesity ; recent and long-term consumption of hormonal replacements; physical inactivity; high-dose x-ray to chest , 12. years; lAlthough in developed countries, screening of such malignant tumor is usually performed using mammograms, the access to most women in sub Saharan countries are limited. From the existing situation it is uncertain to have amendments in the upcoming days . Breast In Ethiopia poor awareness is the core concern and there is also stigma and misconceptions/understanding about cancer, that all cancer cases are incurable. Associated with this little work was done so far to promote the awareness that most cancer cases can be prevented, even cured if detected early, and quality of life can also be improved .As the principal focus of the present study was students, it strengthens cancer detection and prevention strategies at an early age, creates education opportunities for shaping health behaviors into adulthood and also encourage discussions between students and their guardians as well as relatives. Therefore, the purpose of the present survey was to explore the knowledge, perception and risk awareness toward breast cancer among female medical and health science students of University of Gondar, Ethiopia.An institutional based cross sectional study was employed among female medical and health science students of University of Gondar (UOG). UOG is among the first born universities in Ethiopia and located 737 km from the capital of Ethiopia, in northwest direction. It has 5 campuses such as Atse Tewodros, Maraki, College of Medicine and Health Sciences (CMHS), Atse Fasil, and Meles Zenawi. At present, with the nine academic offices it offers about 56 undergraduate and 64 postgraduate programs in regular, distance, extension and summer programs.Female students who had interest to complete the self-administered questionnaire were included. However, students with already existing disease and unable to understand the questionnaire were excluded.Appropriate sample size was estimated using a single proportion formula d, marginal error (d = 0.05); Z, the required degree of accuracy at 95% confidence level, which is 1.96; P = 0.5 (50%) level of knowledge, as there was no study conducted in the study area to the best of literature search made. Using the above formula, the sample size was calculated as follows:Where n is the need sample size; Since the sample was drawn from the gross population of 1463, which is <10,000, the required final sample size was determined after applying the correction factor;whereConsidering 5% for probable non-respondent, the required final sample size was 315.The final sample was distributed proportionally across different departments. Using simple random sampling technique the required samples from each department were recruited in the study Figure .Three principal investigators were responsible for conducting the data collection. The data were obtained through self-administered questionnaire. The tool used was adopted from prior studies conducted in this area and prepared in English –23. The P < 0.05 and confidence interval (CI) of 95% were used as cut points.The collected data using quantitative method was entered to and analyzed using Statistical packages for social sciences (SPSS) version 21 statistical software. Frequencies, percentages, tables, flow chart were used to describe study variables. Binary logistic regression analysis was done to examine the association among different variables. For determining statistically significant associations, The study was ethically approved by the ethical review committee of School of Pharmacy (SoP), University of Gondar (UoG) with an approval number of UoG-SoP-140/2017. Informed consent was gained from each participant before the start of the study. They were also informed that involvement in the study was fully voluntarily and withdrawal at any stage if they refused to participate was assured. Information obtained from the survey was kept confidential. In addition, patient identifiers were not used.In the current study, out of the total interview guides/questionnaires of sample of 315 students who were interviewed 300 were included in the analysis, and 15 encounters were excluded due to incompleteness making the response rate 95.24%. The average age of the study respondents were 21.4 years with the standard deviation (SD) of 2.13 years.More than two third 188 (62.7%) of the participants had no previous participation in breast care awareness. However, they had interest to participate in activities that encourages breast cancer awareness 234 (78.0%) , early onset of menses (55.3%), and menopause after the age of 55 years (47.7%) are liked with breast cancer. Pain in the breast region, Change in the morphology/shape of the breast and nipple discharge were the most frequently correctly identified symptoms of breast cancer. Moreover, 168 (56.0%) of the participants were aware about once a month recommendations for practicing breast self-examination (BSE) and 108 (36%) for once a year clinical breast examination (CBE) Table .The overall level of knowledge was described by nineteen questions on breast cancer for general knowledge, risk factors and symptoms of breast cancer. Although the overall level of knowledge on breast cancer was low, high level of knowledge was observed in questions related to general knowledge about breast cancer 70 23.3%)  were found to have 16.1% less likely to have good knowledge of breast cancer compared to public health officer students. On the other hand, students under first year of study  were found to have 1.661 times more likely to have poor knowledge of breast cancer compared to fifth year students , early onset of menses (55.3%), and menopause after the age of 55 years (47.7%) are liked with breast cancer. This finding was comparable with studies done in Malaysia, Egypt, Oman and Britain , 23, 29.Most of the study participants identified pain in the breast region as a symptom for breast cancer followed by swing in the morphology/shape of the breast and nipple discharge. However, more than one third of the respondents had less knowledge about under armpit lump and painless breast lump as cautioning signs of the disease. This finding concurs with the reports from Malaysia, Egypt, Nigeria, and Oman , 23, 28.Numerous respondents had the factual perception about breast cancer management and its outcomes. however, they had negative view of the tumor treatment by seeing the length of treatment and painful process, which was similar with the report from Malaysia and Nigeria , 28. ThiBinary logistic regression analysis was performed and factors such as department and study year were recognized as independent predictors for disease related knowledge among the study participants. Pharmacy students (AOR = 0.839 CI = 0.312–2.255) were 16.1% less likely to own good knowledge of breast cancer when equated to public health officer students. The study also mentioned that the odds of having poor knowledge toward the disease were 1.661 times higher among students enrolled under first year of study  compared to fifth year students. This might be due more exposure and familiarization about breast cancer and related health issues in different courses, trainings and seminars will be embraced as academic year goes up.As a drawback, although this research is the first in its kind in the study setting that can be used as an input for implementing basic projects, it is conducted only in one institution that the generalization to all over university students will be in question. With this, we highly recommended a large scale and multi centered survey that comprises diverse participants to validate our output and provide more representative findings.In this study, the overall level of knowledge on breast cancer was low. Majority of the participants were unaware for complex risk factors such as first child after the age of 30 years, early onset of menses, and menopause after the age of 55 years are liked with breast cancer. However, small proportion of the participants were aware about clinical breast examination guidelines. Pain in the breast region, change in the shape of breast and nipple discharge were the most frequently correctly identified symptoms of breast cancer. On the other hand, majority of the participants acknowledged old age, family history, and smoking as possible risk factors for breast cancer and they had also positive perception toward breast cancer treatment and its outcomes. Department and year of study were found to be an independent predicting factors for knowledge among the participants.Bearing in mind the greatest prominence of knowledge, perception and risk awareness about such tumor, institutions and different stakeholders working on cancer should offer a tailored health promotion and awareness creation to university youngsters, in line with cultivating facilities that let them do the screening examination regularly. In addition, the country ministry of education and health has to work on incorporating capacity building regular trainings regarding such disease avoidance and early detection in such organizations.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In this case-control study, we enrolled 364 breast cancer patients and 364 age-matched controls. DII scores were calculated from dietary intake evaluated by a 106-item food frequency questionnaire. The DII score was significantly higher in cases than in controls. After adjusting for potential confounders, the odds ratio (OR) of breast cancer was higher in the highest DII tertile : 2.34–5.80, p for trend < 0.0001) than in the lowest tertile. We found that higher DII scores were related to an increased risk of breast cancer for estrogen receptor (ER)+/progesterone receptor (PR)+ tumors regardless of menopausal status , but not for ER−/PR− status. Our results suggested that the DII scores are positively associated with breast cancer risk in Korean women and that this relationship is more robust in ER+/PR+ tumors.Breast cancer is the most common cancer in women globally, and the risk of developing breast cancer is associated with inflammation. The present study aimed to examine the association between the Dietary Inflammatory Index (DII Breast cancer is the most common cancer and is one of the main causes of cancer mortality in women globally. Based on the 2018 GLOBOCAN estimates, approximately 2.1 million new breast cancer cases and 0.6 million breast cancer deaths occurred worldwide . Thus, bEstrogen receptors (ERs) and progesterone receptors (PRs) are hormone receptors found on breast cells that pick up hormone signals resulting in cell growth ,5. BreasChronic inflammation is an important contributor to the development and progression of cancers, including breast cancer. Chronic inflammation can cause DNA damage and stimulate chronic cell proliferation, which are important factors in carcinogenesis ,13. A la®), a literature-derived and population-based dietary scoring system, was recently developed to assess the inflammatory potential of the diet [The Dietary Inflammatory Index  in the Republic of Korea, from July 2007 to September 2008. Among those patients, 415 patients agreed to participate in the study. We excluded participants with previous histories of other cancers, those who were unable to cooperate in the interview, and women who reported implausible daily energy intake . After those participants were excluded, 398 patients were eligible for the analysis.The 2503 cancer-free controls were recruited among women who received regular health check-ups at the Center for Early Detection and Prevention at the same hospital between October 2007 and December 2008. Among those women, 1687 agreed to participate in the study. Based on eligibility criteria, we excluded 1109 subjects with insufficient dietary intake information, a history of malignant neoplasms or other benign breast diseases, a lack of information on menopausal status, or implausible self-reported daily energy intake . After exclusion, 578 women were eligible for inclusion in the control group, and the controls were frequency-matched to cases within a 5-year age distribution. Ultimately, data from 728 subjects (364 cases and 364 controls) were included in the final data analysis . InformeThe dietary intake of the participants was assessed using a 106-item semi-quantitative food frequency questionnaire (SQFFQ). The reliability and validity of the SQFFQ have been previously reported . SubjectTo calculate DII scores, dietary assessment data from the SQFFQ were used. The method was originally devised by Cavicchia et al. , and was1, vitamin B2, niacin, vitamin B6, vitamin B12, folic acid, vitamin A, vitamin C, vitamin D, vitamin E, β-carotene, iron, magnesium, selenium, zinc, flavan-3-ol, flavones, flavonols, flavonones, anthocyanidins, isoflavones, garlic, ginger, onion, green tea, pepper, and alcohol. Energy was not used to compute the DII because all components of the DII were adjusted for energy intake using the energy density approach, which was calculated per 1000 kcal of energy [A higher DII score indicated a higher intake of proinflammatory foods, while a lower score showed a higher consumption of anti-inflammatory foods . In the f energy . The worf energy ,32,33.Sociodemographic, lifestyle, reproductive, and medical history data were collected using a structured questionnaire by a trained dietitian at the time of initial recruitment prior to cancer diagnosis. Education level was categorized into four groups: ≤elementary school, middle school, high school, or >high school. Occupation was divided into four groups: housewife, profession or office worker, sales or service, or others. Smoking status was classified as past/never or current, and alcohol consumption was classified as never or ever. Physical activity was calculated using the short form (version 20. April 2004) of the International Physical Activity Questionnaire (IPAQ) and was summarized in units of metabolic equivalent (MET). Then, physical activity was classified into four categories (unit: MET-min/week): <396, 396–1272, 1272–2772, or ≥2772. Marital status was categorized as married, single, or others. Reproductive factors included age at menarche, parity, menopausal status, type of menopause, and postmenopausal hormone use. Information on the first-degree family history of breast cancer was also collected.2).Anthropometric characteristics were also determined using standardized methods. Height and weight were measured to the nearest 0.1 cm and 0.1 kg, respectively. BMI, which reflects obesity status, was defined as weight (kg)/height . Two-sided p-values were considered to determine statistical significance.Sociodemographic characteristics and lifestyle-related variables are expressed as the means with their SDs (continuous variables) or numbers with percentages . Differences between cases and controls were examined by Student’s y intake . The DIIp < 0.0001), occupation (p = 0.04), parity (p < 0.0001), and daily total energy intake (p = 0.01). In addition, age at menarche (p = 0.001), postmenopausal hormone use (p = 0.0004), and type of menopause (p = 0.02) were also significantly different between cases and controls in the group of postmenopausal women. The mean DII scores were 0.05 ± 2.59 and 1.03 ± 2.41 in the controls and cases, respectively (p < 0.0001), indicating a more proinflammatory diet in the case subjects.The general characteristics of the study subjects are shown in p < 0.0001). No significant differences were observed between controls and cases in flavones, flavonones, ginger, and alcohol intake.–4.42 in the highest DII category, p for trend <0.0001) than in the lower tertile groups. After adjusting for potential confounders, we also observed a significant positive association between DII and the risk of breast cancer. Individuals in the highest tertiles showed a higher risk of breast cancer  than those in the lowest tertiles. In the multivariate-adjusted model, the OR for breast cancer in the highest DII group of premenopausal women and postmenopausal women was 2.11  and 6.13 , respectively, compared to the lowest DII group.In this study, a higher DII score was associated with an increased OR of breast cancer. p for trend <0.0001) compared to that of individuals in the lowest tertile. After adjusting for confounding variables, the positive association was more pronounced in postmenopausal women with ER+/PR+ status . In addition, the multivariate-adjusted OR and 95% CI for breast cancer were higher in the highest DII group  compared to those of the lowest tertile group with the ER− and PR− (ER−/PR−) status. However, no significant association was found between DII score and ER−/PR− status in premenopausal women.The OR and 95% CI of breast cancer risk characterized by ER and PR status according to DII score are shown in The present case-control study demonstrated the association between the inflammatory potential of diet, as measured by DII scores, and the risk of breast cancer among Korean women. We showed that DII scores were positively associated with breast cancer risk. These results support the hypothesis that women consuming a more proinflammatory diet may be at increased risk for breast cancer. The association between higher DII and an increased risk of breast cancer was also observed in patients with ER+/PR+ and ER−/PR− status .Chronic inflammation is associated with cancer development, particularly in the context of breast cancer ,13,36. OThe DII was recently developed as a tool to measure the inflammatory potential of the diet . A high Previous studies have evaluated the relationship between nutrients and certain food items and circulating inflammatory markers ,45,46. TSeveral mechanisms have been proposed to explain the effect of diet on breast cancer: the antioxidant effect , inhibit2 BMI) breast cancer patients was higher in the postmenopausal group than in the premenopausal group. In the current study, dietary inflammatory potential appeared to have a stronger impact on postmenopausal women who are prone to developing breast cancer.The literature published to date has suggested that the effects of diet on breast cancer may vary depending on several factors, such as menopausal status and molecular profiles of the tumor . AlthougThe ER and PR status of breast cancers may explain the emergence of breast cancer subtypes with different etiologies ,9. A numThere are several strengths in the present study. To reduce errors in the collected data, data were gathered in face-to-face interviews to enable comprehensive information collection on related lifestyle factors, thus reducing the possibility of misclassification and measurement errors. In particular, to our knowledge, this study may be the first hospital-based case-control study to investigate whether the DII has a positive association with the risk of breast cancer according to the hormone receptor status of the tumor in Korean women. A number of studies have been conducted on the relationship between diet and breast cancer risk in the context of specific nutrients or foods . HoweverDespite these strengths, this study has several limitations. First, recall bias and selected bias may have affected the results because this is a case-control study. Generally, the cases might have better recall than the controls. In addition, the controls might have been more health-conscious than the cases, and hospital-based controls may have exaggerated their healthier habits compared to their community-based counterparts. Second, cancer patients may differ from controls in their recall of dietary habits. Therefore, the interviewer tried to collect information as soon as possible after diagnosis, which was typically right after surgery. Third, we used SQFFQ to estimate subjects’ dietary intake, which may result in an incorrect quantification of the actual consumption. Although well-trained interviewers performed the survey using a validated SQFFQ and pictures of portion sizes, measurement errors in dietary intake are inevitable. In addition, women may underestimate their dietary intake on self-reports because of social desirability . For thiIn conclusion, the present study found that a more proinflammatory diet is positively associated with an increased risk of breast cancer in Korean women, especially those with some risk factors, such as postmenopausal status and hormone receptor status. In the future, large-scale prospective epidemiological studies are required to investigate whether the identified inflammation-related dietary factors affect circulating inflammatory markers, such as CRP, and circulating cytokine levels, and the development of breast cancer in Korean women.