Telomere length in peripheral blood leukocytes (PBL-TL) was proposed as a biomarker of cancer risk. Recent scientific evidence suggested PBL-TL plays a diverse role in different cancers. Inconsistent results were obtained on PBL-TL in relation to breast cancer risk and specifically to the presence of BRCA1 and BRCA2 mutations. The aim of the present case-control study was to analyse the correlation between family history of breast cancer or presence of a BRCA mutation and PBL-TL in the hypothesis that TL is a modifier of cancer risk.PBL-TL was measured using the real-time quantitative PCR method in DNA for 142 cases and 239 controls. All the women enrolled were characterized for cancer family history. A subgroup of 48 women were classified for the presence of a BRCA mutation. PBL-TL were summarized as means and standard deviations, and compared by standard analysis of variance. A multivariable Generalised Linear Model was fitted to the data with PBL-TL as the dependent variable, case/control status and presence of a BRCA/VUS mutation as factors, and age in 4 strata as a covariate.Age was significantly associated with decreasing PBL-TL in controls (p = 0.01), but not in BC cases. The telomere length is shorter in cases than in controls after adjusting for age. No effect on PBL-TL of BMI, smoke nor of the most common risk factors for breast cancer was observed. No association between PBL-TL and family history was detected both in BC cases and controls. In the multivariate model, no association was observed between BRCA mutation and decreased PBL-TL. A statistically significant interaction (p = 0.031) between case-control status and a BRCA-mutation/VUS was observed, but no effect was detected for the interaction of cancer status and BRCA or VUS.Our study fails to provide support to the hypothesis that PBL-TL is associated with the risk of hereditary BC, or that is a marker of inherited mutations in BRCA genes. Genomic instability and in particular its most common form chromosomal instability  is thought to be an early event and driving force in tumorigenesis ,2. TelomTelomeres are functional complexes formed by repetitive sequences of DNA and proteins (shelterin) but their exact function and regulation have only recently begun to be understood –7. TelomCorrelations between shortened telomeres and aging related diseases in humans such as cardiovascular diseases , 15, cogThe association of cancer risk with mean PBL-TL has been evaluated in a large number of epidemiological retrospective –27 and pA recent Mendelian randomization study, using germ line genetic variants as variables for telomere length, confirms that longer telomeres reduce risk for some non-neoplastic diseases, but increase risk for some cancers with a large variability across cancer types and tissues Breast cancer (BC) is the most common cancer and the leading cause of death from cancer in women worldwide. While most BC are sporadic in nature, approximately 5–10% are attributed to genetics, arising from autosomal dominant mutations in specific cancer genes, the strongest of which are the two breast cancer susceptibility genes BRCA1 and BRCA2 (collectively named “BRCA”). Women who carry a BRCA mutation have up to an 80% lifetime risk of developing breast cancer . BRCA1 aBased on this background, the aims of the present study were to provide evidence on the association between family history of BC or presence of a BRCA mutation and PBL-TL in the hypothesis that telomere length is a modifier of cancer risk.To these aims we measured PBL-TL in cases and controls subjects characterized for family history of BC and for the presence of BRCA mutations.The subjects considered in this study were a subset from a larger population enrolled to evaluate the association between the presence of a pathogenic mutation in either or both the BRCA genes and increased MN frequencies . The subThe obvious bias deriving from the setting where cases and controls were selected affects the relative frequency of women with a positive family history of BC and/or a BRCA mutation, but does not affect the endpoint of our study, the PBL-TL measurement in different groups of women.All women in the study were informed on the aims and methods of the study and gave a written consent to the use for study purposes of the clinical and family history information and to provide a blood sample which was drawn after provision of the written consent.st or 2nd degree relative were considered to have a positive family history.Detailed cancer family history information was collected by means of a personal interview with pedigree reconstruction up to three generations on both sides of the family. In all analyses, only women with BC in a 1During the study period, BRCA genetic testing was proposed to women according to protocols currently in use at the Hereditary Cancer Unit, and no test was proposed as a consequence of participation to the study. Accordingly, the results of BRCA tests were abstracted from clinical records. BRCA variant classification followed international rules  and variAll research was carried out in compliance with the Helsinki Declaration.The protocol of the study and the consent procedure were approved by the local Ethical Committee of the National Cancer Research Institute of Genoa . From all participants, informed written consent to the study was obtained and recorded.hbg). A “seven-point” standard curve was generated from a serially diluted DNA pool (obtained from 50 DNA samples randomly selected from the case and control samples tested in the present study), ranging from 20 to 0.31 ng in each plate, so that relative quantities of T and S (in nanograms) could be determined from it. All samples and standards were run in triplicate and the average of the 3 T/S ratio measurements was used in the statistical analyses. The PCR runs were conducted in triplicate on a SteponePlus Real Time PCR System (Applied Biosystems). After PCR amplification, the specificity of the product was confirmed by dissociation curve analysis. To test the reproducibility of telomere length measurements, we amplified telomere (T) and hbg (S) in 15 samples that were replicated 3 times on each of 3 different days. The within-sample CV for the average T/S ratio over the 3 consecutive days was 8.5%, which was similar to the CV reported for the original protocol [DNA was extracted from peripheral blood sample using the QIAmp DNA Mini Blood extraction Kit . DNA to evaluate TL was available for 142 cases and 239 controls. TL was measured in PBL DNA using the real-time quantitative PCR method developed by Cawthon  and descprotocol .PBL-TL in the various subgroups were summarized as means and standard deviations, and compared by standard analysis of variance. In order to remove the confounding effect of differences in age between breast cancer cases and controls, and between subjects with and without BRCA mutations, and to assess the presence of interactions between these two variables, a multivariable Generalised Linear Model was fitted to the data with PBL-TL as the dependent variable, case/control status and presence of a BRCA/VUS mutation as factors, and age in 4 strata as a covariate. The coefficients estimated by the model should be interpreted as an adjusted difference, that is, as the weighted average difference in PBL-TL between subjects with and without each factor, estimated across strata of the other factors included in the model, with size of each stratum as weight. All p values are 2-sided. IBM SPSS, version 20 was used for all calculations.The details of the study population are described in st/2nd degree family history of BC was high but not significantly different between BC cases and controls. A higher proportion of BC cases than controls was evaluated for the presence of BRCA mutations .Cases were older than controls  Due to the recruitment of a large number of subjects in the Hereditary Cancer Unit, the proportion of women with a positive 1PBL-TL in the total study population and in subgroups of subjects by case-control is reported in PBL-TL decreases with age in controls (p = 0.01), but not in cases .The analysis of crude data didn’t show any difference in PBL-TL between BC cases and controls. However, mean age-adjusted PBL-TL was lower in cases compared with controls (Mean (S.E.): 2.16(0.06) vs 2.36 (0.07) p = 0.025). PBL-TL was positively associated with age of first pregnancy (p = 0.017) in BC cases. No association between PBL-TL and BMI, age at menarche, number of children, smoking habits, oral contraceptive use and hormone replacement therapy both in BC cases and in controls was detected No association between PBL-TL and family history was observed both in BC cases (p = 0.754) and controls (p = 0.224) . In TablFinally, BRCA/VUS mutation and cancer/control status were included in a Multivariable Generalized Linear Model as Factors, with age in 4 strata as a covariate . The preThe aim of our study was to evaluate the possible association between PBL-TL and the risk factors for breast cancer, mainly focusing on familiar and genetic factors (i.e. BRCA mutations). PBL-TL was measured in a group of healthy women and breast cancer patients with and without family history and in a subgroup of women evaluated for the presence of BRCA mutations.Shorter PBL-TL was observed in our study in BC cases with respect to controls after adjusting for age. Several retrospective –44 and pThe main covariates that were found in previous studies to be associated with PBL-TL were analyzed in the present study. In agreement with what previously found  also in The influence of cigarette smoking was not detected in our study in contrast with some but not all previous studies , 58.No association was found between PBL-TL and the most common risk factors for breast cancer considered in our study, such as age at menarche, age of first pregnancy, number of children, use of oral contraceptive, hormone replacement therapy.The main objective of our study was to investigate the potential association between PBL-TL and familiar factors. All the women enrolled were characterized for cancer family history, considering women with BC in a 1st or 2nd degree relative to have a positive family history. No difference in PBL-TL was observed with respect to family history both in BC cases and in controls. The large majority of studies on PBL-TL in BC didn’t characterize the patients for family history. Our results are at variance with those of a study focused on hereditary BC that reported a significantly shorter PBL-TL in familial BC patients than in the control population and shorter PBL-TL associated with earlier onset of BC in successive generations of affected families .The association between BRCA mutation status and PBL-TL was also investigated in our study in a subgroup of subjects for which data on genetic status were available. A statistically significant association between presence of a pathogenic mutation in the BRCA genes and shorter PBL-TL was observed in BC patients but not in controls. The results are difficult to interpret, because the evidence from the literature on the PBL-TL in BRCA mutation carriers is again conflicting. A number of studies reported shortened telomeres in leucocytes  or didn’A common bias of the studies on cancer patients, including ours, is that the enrollment is usually carried out after the diagnosis and the measurement of the PBL-TL could be affected by the diagnosis or treatment. It was been shown that chemotherapy exerts a transient telomere shortening effect  and teloIn conclusion, our study fails to provide support to the hypothesis that PBL-TL is associated with the risk of hereditary BC, or that is a marker of inherited mutations in BRCA genes, suggesting instead that some of the correlations reported in the past may be due to the confounding effect of the procedures carried out in BC patients after diagnosis.


Her2 is a transmembrane protein with tyrosine kinase activity, overexpressed in several cancers including BC. Various studies in different populations have shown association of Her2 variants with susceptibility to BC, however these results were inconsistent, inconclusive and controversial. To obtain a common conclusive finding, we performed meta-analysis of 35 case-control studies reported earlier including 19, 220 cases and 22, 306 controls. We observed significant association of Her2Ile655Val polymorphism with susceptibility to development of breast cancer . Subgroup analysis indicated a significant association with susceptibility to breast cancer in African and Asian populations. However, such association was not observed in other ethnic groups. Our findings suggested that Her2Ile655Val polymorphism is associated with breast cancer risk in overall, Asian and African populations, and can be used as diagnostic marker for BC.Breast cancer (BC) is one of the most common types of cancer in women worldwide. Several factors including genetic and environmental have been linked with susceptibility to development of BC.  It has been estimated that 252,710 new cases of invasive breast cancer will be diagnosed in 2017 among women in US alone. Although, breast cancer is most common in females it also rarely diagnosed in male individuals and 2,470 males are estimated to be diagnosed with breast cancer in 2017 in United States2. Among the overall cancer deaths worldwide, approximately 60% of deaths occur in developing countries including India. In Indian woman, majority of cancer related deaths are due to breast cancer1.Breast cancer (BC) is second leading cause of cancer deaths worldwide and approximately 1.7 million new cases are being diagnosed every year and 521,900 deaths occurred in 2012 alone globally3. Estrogen receptor (ER) plays an important role in breast cancer progression and treatment. Approximately 20–30% breast cancers are of Human epidermal growth factor receptor2 (Her2) positive and are highly aggressive in nature4. High levels of Her2 expression was also observed in tamoxifen resistant breast cancers. Human epidermal growth factor receptor family members are a group of molecules having tyrosine kinase activity with no natural ligand found till date. Heterodimerization among the family members leads to autophosphorylation of cytoplasmic domain which leads to cell proliferation7. Her2 is highly expressed in various cancers types viz. breast, endometrial, ovarian, colon, lung, prostrate and cervical cancers. Role of ERBB2/Her2 in physiological processes  as well as in carcinogenesis and metastasis has been well investigated10. Her2 plays major role in the regulation of several pathways such as Raf/Ras/MAPK and PI3K/AKT pathways11. Receptor mediated signaling pathways has pivotal role in the regulation of normal cell function, growth and division. However disruption of these pathways might lead to several cancers15. Her2 positive breast cancers show poor survival rate, treatment with tyrosine inhibitors showing promising results in harboring these aggressive tumors16. Trastuzumab a monoclonal antibody specifically binds to Her2 and disrupts the downstream pathways of Her2 and it is effectively used for the treatment of Her2 positive breast cancers19. However several patients developed resistance to trastuzumab over a period of time20. Recent studies suggested that Her2 Ile655Val polymorphism is associated with cardiac toxicity. Moreover, it has been identified that both the Her2 Ala1170Pro polymorphisms also responsible for increasing the risk of cardiac toxicity in women administrated with trastuzumab22.BC is highly heterogeneous and ~60–70% is of estrogen receptor positive which responds to anti-hormone therapy25. Cell cycle regulatory role of Her2 and its importance in prognosis of breast cancer clearly indicates that polymorphism in coding region of Her2 might be associated with either cancer susceptibility risk or resistance. One such single nucleotide transition mutation in transmembrane domain coding region of Her2 at codon 655  was well investigated in different populations in relation to risk of breast cancer61. Milikan et al.40 reported the association of Valine allele at Her2 655 codon with breast cancer risk. Whereas, Baxter et al.29 and Xie et al.60 found no association with breast cancer risk in women aged <40 years, post menopausal respectively. However, few researchers performed meta-analysis and tried to conclude the possible correlation of Her2 polymorphism with breast cancer risk. Tao et al.56 showed no association in overall analysis, however mild association of Her2 polymorphism with susceptibility to breast cancer in Asian ethnic group was suggested. Another meta-analysis by Chen et al.62 including 32 case control studies revealed comparable distribution of Her2Ile655Val variants among cases and controls in Caucasian, American and European population. Interestingly, Asian ethnic group showed significant association of breast cancer risk with Her2Ile655Val polymorphism. In the present meta-analysis, total of 35 case-control studies were analyzed and investigated for possible association of Her2Ile655Val polymorphism with development of breast cancer. Furthermore, we subgrouped included reports according to ethnicity and the association was analyzed .Genetic epidemiological studies indicated association between single nucleotide polymorphisms and different cancersHer2Ile655Val polymorphism with breast cancer risk, we have performed meta-analysis using 35 case-control eligible studies including 19, 220 cases and 22, 306 controls. Genotype and allele frequency for case and control of each eligible study was extracted and the characteristics of each study are shown in Table To understand association of 2 statistics were used. I2 more than 50 (I2 > 50) with significant p-value (p < 0.05) considered to be presence of heterogeneity among included studies. Among the models tested, heterogeneity was observed in allele comparison, heterozygous and dominant genetic models. However, other genetic comparison models such as recessive and homozygous were homogeneous. Observations of heterogeneity Q test and I2 statistics of each model are shown in Table To evaluate the heterogeneity among the studies Q test with IBegg’s funnel plot and egger’s regression test was performed to assess the publication bias within the studies included in meta-analysis. Results are imputed in Table Her2 polymorphism with increased risk of breast cancer. The overall allele model revealed association between Her2 polymorphism and breast cancer risk with Odds ratio (OR) = 1.130, 95% confidence interval (CI) = 1.051–1.216, p = 0.001. Furthermore, both dominant and heterozygous models showed significant association of Her2 Ile655Val polymorphism with increased risk of breast cancer . However, comparison of genotypes in other genetics models didn’t show significant association   are playing an important role in various cancer types and are capable of serving as diagnostic tools25. One such single nucleotide polymorphism with substitution of isoleucine with valine at codon 655 in transmembrane region of Her2 has been found to be playing an important role in development of cancer72. The transmembrane domain region of Her2 with valine at 655 domain region stabilizes the formation of protein dimer and thus predisposing to an auto-activity of the receptor73. The hydrophobicity and conformational stability of the hydrophobic domains such as transmembrane domains may alter due to Isoleucine to valine change74. Her2Ile655Val polymorphism was well studied for association with breast cancer risk, whereas other polymorphism at 1170 codon of Her2 (Pro1170Ala) was correlated with cardiotoxicity75. Her2Ile655Val polymorphism is not only associated with breast cancer risk but also associated with other cancers such as ovarian and endometrial cancers77. However, these results are inconsistent and a stringent and powerful analysis is required to conclude the association with breast cancer. In the present study we have analyzed the association of Her2Ile655Val polymorphism with increased breast cancer susceptibility using powerful tool comprehensive meta-analysis (CMA). Overall allele comparison genetic model results suggest that valine allele in Her2 655 codon favors the development of breast cancer in worldwide population. Heterozygous, dominant models also prove that Her2 polymorphism is associated with increased risk of breast cancer. Whereas, subgroup analysis showing different results for different ethnic population. Earlier reports by Wang et al.58 and Chen et al.62 demonstrated association of Her2 valine allele with breast cancer risk in Caucasian population. In contrast, our study failed to show such link. The present study has several advantages over earlier reports. We have included more number of studies in the current meta-analysis including larger number of cases and controls.Human epidermal growth factor family members are a group of receptors with tyrosine kinase activity which affects cell proliferation and survivalet al.56 reported the association of Her2 polymorphism with breast cancer risk in Asian population whereas later Wang et al.58 and Chen et al.62 showed no such association with breast cancer. In this present meta-analysis, we have performed subgroup analysis and demonstrated that valine allele is associated with breast cancer risk in Asian population. In addition to that Val-Val + Ile-Val vs Ile-Ile model also prove the susceptibility of Her2 polymorphism with breast cancer. We also observed that subjects with valine/valine genotype are susceptible for the development of breast cancer in African population. These results are in agreement with the study demonstrated by Wang et al.58; however other studies failed to show such association with breast cancer susceptibility. Ethnic groups such as American, European and Afro-American are not showing such association with breast cancer risk. Our present meta-analysis includes all the studies in which either Taqman or RFLP used as detection method. Frank et al. suggested the biasness in the methods used for the detection of polymorphism and suggested that Taqman method is capable of producing false results78. We excluded the studies in which Taqman method used as detection method and performed the analysis. Studies which used other than Taqman method for the detection of polymorphism showed significant association with breast cancer risk in all models.Tao Her2Ile655Val polymorphism is associated with breast cancer risk in Asian, African population but not in other ethnic groups such as Caucasian, European, American and Afro-American. These results suggest that Her2Ile655Val polymorphism could be considered as possible susceptible bio marker for the detection of breast cancer.In conclusion, our present meta-analysis demonstrated that valine allele is susceptible in overall worldwide population and Asian ethnic group. Her2Ile655Val polymorphism”, “Herceptin receptor polymorphism”, “rs1136201” and breast cancer. In addition to the preliminary online database search we have checked the cross references for the potential publications, those possibly missed in preliminary search. Our present study includes recently published (earliest by 2017) 35 case-control studies with 19, 220 cases and 22, 306 controls for Her2Ile655Val polymorphism  using either single or combination of given keywords i.e., “Her2Ile655Val polymorphism with breast cancer risk and (e) studies representing original data. The studies excluded based on the criteria given below: (a) studies published in other languages except English, (b) studies having only case samples, (c) representing risk of other cancers, (d) without genotypic distribution and allele frequency data and (e) reviews and abstracts.The studies which met all the criteria given below have been included in the present meta-analysis: (a) studies published in English, (b) must have case-control or cohort design, (c) have available genotype frequency of both the cases and controls or have odds ratio (OR) and 95% confidence interval (CI) values, (d) evaluating the association of The data extraction was performed by three independent authors  independently and the disagreement about the studies between the authors was resolved and came to a conclusion by conducting a group discussion within the authors. We followed previously established data form to extract the data from the studies and the following data was extracted from each article: first author’s name, year of publication, country, ethnicity, number of case and control samples, genotype distribution, allele frequency for each case and control.https://www.meta-analysis.com/pages/comparisons.php. CMA v3 is a powerful tool to analyze and has several advantages over other software available for computational meta-analysis. Combined odds ratio with 95% CI was calculated and was taken into consideration to apprise the association of Her2 polymorphism with breast cancer risk. Chi-Squared based Q test was performed to analyze the heterogeneity and p-value < 0.05 was considered as significant. In case of no significant heterogeneity fixed effect model was used to assess the combined OR. In contrast, Random effect model was considered to calculate the combined odds ratio with 95% CI among the studies. I2 statistics was used to quantify inter study variability, greater I2 value depicts greater degree of heterogeneity. Publication bias was examined using Begg’s funnel plot. Egger’s linear regression test was employed to analyze and measure the asymmetry of Begg’s funnel plot and the significance of intercept was assessed by t-test. Intercept considering p-value < 0.05 was considered as significant and the publication bias was reduced using “trim and fill” method.The current meta-analysis was performed using comprehensive meta-analysis version 3 software (CMA v3) All those named as authors confirmed the availability of data and materials.Supplementary Info


Although expression of estrogen receptor (ER), progesterone receptor (PR), and cell proliferation marker Ki67 serve as predictive and prognostic factors in breast cancers, little is known about their roles in normal breast tissue. Here in a nested case–control study within the Nurses’ Health Studies , we evaluated their expression levels in normal breast epithelium in relation to subsequent breast cancer risk among women with benign breast disease. Tissue microarrays were constructed using cores obtained from benign biopsies containing normal terminal duct lobular units and immunohistochemical stained for these markers. We found PR and Ki67 expression was non-significantly but positively associated with subsequent breast cancer risk, whereas ER expression was non-significantly inversely associated. After stratifying by lesion subtype, Ki67 was significantly associated with higher risk among women with proliferative lesions with atypical hyperplasia. However, given the small sample size, further studies are required to confirm these results. In a nested case–control study within the Nurses’ Health Study (NHS) and NHSII cohorts, we examined the associations of ER, PR, and Ki67 expression levels in normal breast epithelium with subsequent breast cancer risk among women with a previous diagnosis of benign breast disease (BBD).Development of breast neoplasia involves hormones such as estrogens and progesterone that regulate cell proliferation and apoptosis. The tissue-specific responsiveness to these hormones is partially regulated by the tissue expression of receptors that bind them.3 A 5-μm section from each TMA block was immunohistochemically stained with each antibody . Immunostaining results were interpreted using an automated computational image analysis system ; scoring algorithms are shown in r=0.40–0.48). For each woman, we estimated the mean percentage of stain-positive cells across the cores, by weighting each core by its total cell count. Women were excluded if they had evidence of carcinoma at biopsy or within 6 months of their biopsy, there was not enough tissue on the block for TMA construction, had low cellularity (<100 cells), or had no evaluable marker staining. Details of the methods are described in Briefly, controls were matched to cases on age, calendar year of BBD, and time since biopsy. Archived formalin-fixed paraffin-embedded biopsy blocks were collected from pathology departments for cases and controls. Tissue microarrays (TMAs) were constructed by obtaining 0.6-mm cores of benign lesions and adjacent normal terminal duct lobular units (TDLUs).4–6 Although the expression levels varied slightly by its adjacent lesion type, the differences were not statistically significant  but minimal between other markers (6 and the Spearman correlations were modest for PR (r=0.21) and Ki67 (r=−0.15) . Distributions of population characteristics and marker staining are presented in nificant . The int markers . When co markers  as expecr=−0.15) .P trend=0.68), whereas Ki67 expression was non-significantly but positively associated with subsequent breast cancer risk ; the association was statistically significant when restricted to premenopausal women . Results were similar after adjustment for BBD subtype. After stratifying by BBD subtype, Ki67 was significantly associated with higher risk among women with atypical hyperplasia =0.44, 95% confidence interval (CI)=0.17–1.14, 4 and experimental studies that suggested carcinogenic potentials of PR.8 However, we did not observe a positive association with ER despite the supporting evidence.10 This study has limitations including potential measurement error in markers , which would bias results towards the null.Our finding is consistent with a previous study of women with atypical hyperplasia that reported a fourfold higher breast cancer risk associated with Ki67 expression (⩾2 vs. <2%)These findings contribute to our understanding of breast cancer biology and provide the basis for future studies investigating these markers as potential targets for risk assessment among women undergoing biopsies. However, given the small sample size and potential measurement error in markers, further studies are required to confirm these results.


Recent genetic admixture coupled with striking differences in incidence of estrogen receptor (ER) breast cancer subtypes, as well as severity, between women of African and European ancestry, provides an excellent rationale for performing admixture mapping in African American women with breast cancer risk. We performed the largest breast cancer admixture mapping study with in African American women to identify novel genomic regions associated with the disease. We conducted a genome-wide admixture scan using 2,624 autosomal ancestry informative markers (AIMs) in 3,629 breast cancer cases  and 4,658 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a collaborative study of four large geographically different epidemiological studies of breast cancer in African American women. We used an independent case-control study to test for SNP association in regions with genome-wide significant admixture signals. We found two novel genome-wide significant regions of excess African ancestry, 4p16.1 and 17q25.1, associated with ER-positive breast cancer. Two regions known to harbor breast cancer variants, 10q26 and 11q13, were also identified with excess of African ancestry. Fine-mapping of the identified genome-wide significant regions suggests the presence of significant genetic associations with ER-positive breast cancer in 4p16.1 and 11q13. In summary, we identified three novel genomic regions associated with breast cancer risk by ER status, suggesting that additional previously unidentified variants may contribute to the racial differences in breast cancer risk in the African American population. A majority of the close to 100 breast cancer risk loci that have been identified to date were found using genome-wide approaches in populations of European ancestry women . Follow-African American women have higher breast cancer mortality rates than US women of European ancestry, particularly among younger women, attributable to diagnosis at a later stage often with larger tumors and lymph node metastases . In addiTo this end, we performed a genome-wide admixture mapping in germline DNA in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a collaborative project from four of the largest studies of breast cancer in African American women . This reThe CBCS was approved by the Institutional Review Board at the University of North Carolina at Chapel Hill School of Medicine. The WCHS was approved by the Institutional Review Boards at the University of Medicine and Dentistry of New Jersey (presently Rutgers University), Mount Sinai School of Medicine, and Roswell Park Cancer Institute. The BWHS was approved by the Institutional Review Board at the Boston University School of Medicine. The MEC was approved by the Institutional Review Boards of the University of Hawaii and University of Southern California. Written informed consent was obtained from each participant.Two case-control studies, the Carolina Breast Cancer Study (CBCS) and the Women’s Circle of Health Study (WCHS), and two prospective cohort studies, the Black Women’s Health Study (BWHS) and the Multi-Ethnic Cohort (MEC) comprise the AMBER Consortium ; the fouThe CBCS is a population-based case control study of women ages 20–74, conducted in 44 counties in North Carolina that began in 1993 . Breast The WCHS includes both European and African American women, 20–75 years of age, newly diagnosed with a first primary, and histologically confirmed breast cancer. Cases were identified from 10 counties in New Jersey through the New Jersey State Cancer Registry and through major metropolitan hospitals in New York City serving a large minority population. Controls, frequency matched to cases by 5-years age categories and self-reported race, were identified using random digit dialing in New York City and New Jersey, as well as from the community . RecruitThe BWHS is an ongoing prospective cohort study of 59,000 US women aged 21–69 years from across the United States who self-identify as “black” . BeginniThe MEC study is a prospective cohort that includes over 215,000 individuals from Hawaii and California (primarily Los Angeles) assembled between 1993 and 1996 . Africanhttp://genome.sph.umich.edu/wiki/Exome_Chip_Design.Genotyping of constitutional DNA of CBCS, WCHS, and BWHS samples was performed by the Center for Inherited Disease Research (CIDR) using the Illumina Human Exome Beadchip v1.1 array with custom content. The standard content of this array includes more than 240,000 coding variants, as well as tag SNPs for GWAS hits, a grid of common variants, and ancestry informative markers (AIMs). A more complete description of the exome chip design and standard content is available from Supplementary Table 1) included as standard content in the exome array and typed in AMBER participants, including 3,130 cases, 1,674 ER+ cases and 963 ER- cases (515 triple negative) and 3,698 controls. In addition, genetic data from 499 cases  and 960 controls in the MEC study were available from previous genotyping on an earlier version of the exome array that contained the same AIMs. Final sample size for the current admixture analyses was 8,287 participants: 3,629 cases  and 4,658 controls.Genotype quality control for this study has been described previously . GenotypWe assessed population stratification by calculating principal components of genetic variation using the smartpca program in the EIGENSOFT package . SupplemZ statistics, with a threshold of |Z| > 4.0 considered genome-wide statistically significant. A negative Z-score indicates that higher African (lower European) ancestry at that particular locus is associated with higher breast cancer risk while a positive Z-score indicates that lower African (higher European) ancestry is associated with higher breast cancer risk. We performed analyses of breast cancer overall, and by ER and triple negative status. For each analysis, we ran ADMIXMAP using 2,000 burn-in iterations and 8,000 follow-on iterations. The percentage of African ancestry for each individual was determined using ADMIXMAP and compared across controls, all cases and by ER status as well as by site, using logistic regression adjusting for the covariates described above.We used ADMIXMAP software version 3.8.3103  to estimZ| > 4) in AMBER, fine-mapping analyses were performed using typed and imputed data from the African American Breast Cancer (AABC) consortium, which included participants from six epidemiological studies  and 4,658 controls were included in the present analysis. CBCS and WCHS cases had the highest proportion of African ancestry (84.0%) and MEC the lowest (78.0%). Mean African ancestry, adjusted for age, geographic region, DNA source and study site was 81.3% for controls and 81.2% for cases (P = 0.74 for difference of means). A total of 2,624 autosomal AIMs were analyzed (Supplementary Table 1).Table 2 shows the four genome-wide significant regions in case-only analysis  that also had confirmatory results in case-control analysis . We identified two novel genome-wide significant regions, showing evidence of excess African ancestry associated with ER+ breast cancer on 4p16.3 and 17q25.1. The 10q26 and 11q13.2 regions both contain SNPs previously identified in published GWAS of breast cancer in European ancestry women  to test for association of SNPs in the admixture associated regions identified for ER+ and overall breast cancer. We defined significant association at ZFYVE28; the A allele showed a 46% risk increase compared to the G allele (P = 4.0 × 10-6). Consistent with our admixture mapping results , the risk A-allele is more frequent in 1000 Genomes African ancestry samples (AFR), 14%, and AABC, 13%, than in European ancestry (EUR) samples, 1% (Table 3).One SNP in the 4p16 region exceeded multiple test correction threshold, rs112545418 in P = 2.9 × 10-6, is located over 10 Mb from the well-known breast cancer associated FGFR2 gene and is unlinked to SNPs in this region (2r = 0.01). The risk T-allele at this SNP is associated with 87% higher risk of breast cancer, and it is more frequent in AABC (79%) and AFR populations (83%) compared to EUR populations (68%) (Table 3). The frequency differences by race are consistent with our admixture mapping results that excess of local African ancestry at 10q26 is associated with higher risk of all breast cancer.The most significant association with overall breast cancer, rs12244041, at ALDH3B2, rs77274510 in RP11-703H8.9, and rs117564384 in SCGB1D2 in the chromosome 11q13 region were significantly associated with ER+ breast cancer after correction for multiple testing (Table 3). The latter two are only 15,807 bp apart and are in modest LD (r2 = 0.66) in 1000 Genomes AFR populations, while rs116638271, resides ∼5.4 Mb from rs117564384 and is not correlated (2r = 0) with either SNP. In agreement with the admixture mapping results  the risk alleles of the three SNPs were less frequent in 1000 Genomes AFR vs. EUR populations (Table 3). For rs77274510 and rs117564384, the risk alleles had <1% frequency in 1000 Genomes AFR subjects compared to 5.9 and 5.1%, respectively, in EUR samples. For rs116638271 the risk allele had 97% frequency in AFR vs. 100% in EUR. In other words, the protective rs116638271 allele against ER+ breast cancer seems to be specific of AFR populations with a frequency of about 3% but 0% in EUR populations.Three variants, rs116638271 in Z = 3.9 in case-only analysis, and Z = 1.9 with P = 0.058 in case-control analysis). This region contains three overall breast cancer associated variants within an 8.6 Kb region, rs75313515 (P = 2.4 × 10-6), rs75771004 (P = 3.2 × 10-6) and rs116667969 (P = 3.5 × 10-6) that are significant after correction for multiple testing. The first two SNPs are in strong LD while rs116667969 is very weakly correlated with both SNPs (r2 ∼0.40). The minor alleles range from 2.5 to 4% in our analyses; however, none of the variant alleles at these three SNPs are present in the EUR 1000G populations. These three SNPs are within 10 Kb of rs116638271 (r2 = 0.40), one of the three SNPs under this peak shown to be associated with ER+ breast, which suggests that this region contains multiple independently associated variants.The genome wide significant ER+ associated region on chromosome 11 was also suggestive of association in the admixture analyses of overall breast cancer (P = 1.6 × 10-4). The direction of the risk was contrary to what was expected based on the admixture results , as the risk T-allele was less frequent in 1000 Genomes AFR (2.7%) vs. EUR populations (16.1%) (Table 3). Notably it resides adjacent to BRCA1 (17q21.1) and 13 Mb from the 17q23.1 region which contains breast cancer susceptibility SNPs . It does not harbor known susceptibility breast cancer variants and no SNPs were associated with overall breast cancer at nominal P < 0.05. This region contains multiple Crohn’s disease, ulcerative colitis and Type 2 diabetes loci (Supplementary Table 4).The 9q34 region showed excess local African ancestry associated with risk of overall breast cancer (Supplementary Table 3). The 8q24 locus contains breast cancer susceptibility loci as well as loci for other cancers including ovarian, prostate, colorectal, glioma, lymphomas and leukemias, bladder and kidney (Supplementary Table 4). No single SNP reached significance after correction for multiple testing. Two SNPs, rs147582253 (P = 1.9 × 10-5) and rs10112657 (P = 5.8 × 10-5) showed suggestive associations with ER+ breast cancer. The direction of the associations were consistent with the admixture mapping results, as the risk alleles of both SNPs, rs147582253-G (1.7% in African vs. 0% in European populations) and rs10112657-T (3.3% in African vs. 0% in European populations), were more frequent in African ancestry vs. European ancestry populations.We found an excess of local African ancestry in the chromosome region 8q24 associated with ER-positive breast cancer (Supplementary Table 3); both 2q24 and 5p13 contain or are adjacent to breast cancer susceptibility variants. The 2q24 region showed a deficit of local African ancestry associated with ER- breast cancer. The admixture signal in 2q24 is less than 4 Mb from two recently identified SNPs, rs2016394, and rs1550623, associated with breast cancer in European ancestry women in the Collaborative Oncological Gene-Environment Study (COGS)  . Howevery (COGS) ; thus, tTERT gene, which harbors a well-known ER- specific breast cancer associated variant, rs10069690 (P = 2.2 × 10-5). The T allele is far more frequent in African populations (66%) versus Europeans (28%). We found some evidence of one additional independent signal in TERT, represented by the risk increasing C allele of rs37004  at ∼1 Mb from rs10069690. This variant has been shown to be associated with lung cancer risk in the Genetic Association and Mechanisms in Oncology (GAME-ON) consortium .The 18q23 region is novel and showed an excess of local African ancestry associated with risk of ER- breast cancer, however the most significantly associated single SNP, rs58839649 at ity SNPs  and has ity SNPs  (SupplemSupplementary Table 3). While higher African ancestry in the 2q37 and 3p24 loci seems to increase risk of ER- breast cancer as well, higher African ancestry in the 18p11 locus appears to be associated only with risk of triple negative breast cancer. The 3p24.2 region contains well-established breast cancer associated SNPs . The most strongly associated SNP in 4p16, rs112545418, in ZFYVE28, was in moderate linkage disequilibrium (2r = 0.48) with a nearby variant rs17132398, associated with ER-positive breast cancer at P = 1.8 × 10-4. Analysis of rs17132398 using RegulomeDB database  signaling (This region contains no previously reported genome wide significant breast cancer loci, but loci for bladder cancer, as well as other traits and diseases include triglycerides and cholesterol levels, bone mineral density, type 2 diabetes and Parkinson’s disease (database  showed tignaling . The lowFGFR2 associated with increased risk of breast cancer (FGFR2 (FGFR2 in African Americans (FGFR2 and a second region spanning from 131 to 134 Mb on chromosome 10. This second region contains our significant variant, rs12244041 (Table 3; Supplementary Figure The 10q26 showed excess of local African ancestry associated with risk of overall breast cancer and was our strongest admixture association with overall breast cancer. This region contains well established SNPs in t cancer . A recenr (FGFR2  identifir (FGFR2 . The rs2mericans , and it mericans . InteresSCGB1D2. SCGB1D2 expression is high in and almost exclusive to mammary tissue (Although the chromosome 11q13 region has been previously shown to contain breast cancer SNPs , all thry tissue , signifiy tissue , and it y tissue .In summary, this is the largest admixture analysis of African American breast cancer, both in number of subjects and markers, to date. One limitation of this report is the lack of characterization of tumors by grade and stage that may show differential association with locus-specific African ancestry. Nevertheless, the current study includes more than twice the number cases and a higher density of AIMs throughout the genome compared to the previous admixture mapping of breast cancer in AA women . In addiER-N and LS-C performed the statistical analyses and drafted the manuscript. KL supervised the statistical analyses. JB, SY, SH, CH, EB, AO, CA, JP, and KL participated in data analysis and interpretation and provided critical feedback. CH, EJ, LB, JH, RZ, and SD provided data for fine-mapping. CA and JP conceived of the study and participated in the design and coordination of the study. All authors read and approved the final manuscript.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.The reviewer JP and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


This pooled analysis of two case-control studies involved 560 subjects  aged 40–75 years from Northeastern Poland. Diagnoses of breast cancer in 140 women and lung cancer in 140 men were found. The food frequency consumption of 21 selected food groups was collected using a 62-item Food Frequency Questionnaire (FFQ)-6. The ‘Polish-adapted Mediterranean Diet’ score which included eight items—vegetables, fruit, whole grain, fish, legumes, nuts and seeds—as well as the ratio of vegetable oils to animal fat and red and processed meat was developed (range: 0–8 points). Three DPs were identified in a Principal Component Analysis: ‘Prudent’, ‘Non-healthy’, ‘Dressings and sweetened-low-fat dairy’. In a multiple logistic regression analysis, two models were created: crude, and adjusted for age, sex, type of cancer, Body Mass Index (BMI), socioeconomic status (SES) index, overall physical activity, smoking status and alcohol abuse. The risk of breast or lung cancer was lower in the average (3–5 points) and high (6–8 points) levels of the ‘Polish-aMED’ score compared to the low (0–2 points) level by 51% (odds ratio (OR): 0.49; 95% confidence interval (Cl): 0.30–0.80; p < 0.01; adjusted) and 63% , respectively. In the middle and upper tertiles compared to the bottom tertile of the ‘Prudent’ DP, the risk of cancer was lower by 38–43% (crude) but was not significant after adjustment for confounders. In the upper compared to the bottom tertile of the ‘Non-healthy’ DP, the risk of cancer was higher by 65% . In conclusion, the Polish adaptation of the Mediterranean diet could be considered for adults living in non-Mediterranean countries for the prevention of the breast or lung cancers. Future studies should explore the role of a traditional Mediterranean diet fitted to local dietary patterns of non-Mediterranean Europeans in cancer prevention.Lung cancer in men and breast cancer in women are the most commonly diagnosed cancers in Poland and worldwide. Results of studies involving dietary patterns (DPs) and breast or lung cancer risk in European countries outside the Mediterranean Sea region are limited and inconclusive. This study aimed to develop a ‘Polish-adapted Mediterranean Diet’ (‘Polish-aMED’) score, and then study the associations between the ‘Polish-aMED’ score and  Based on statistics from the GLOBOCAN , the numIn Poland, the number of cancer cases has more than doubled over the last three decades and in 2013, was about 156 thousand, including 95 thousand deaths . Cancer aetiology is multi-factorial and includes some predictors which cannot be modified, such as age, genetic predisposition and some environmental factors, whereas lifestyle factors, including smoking, physical activity and diet, are modifiable and can be changed ,5. Althoa posteriori analyses, mainly the Principal Component Analysis (PCA), which is based on observed correlations among dietary variables [a priori approaches based on previous knowledge regarding the health effects of dietary constituents and predefined diet quality scores, like the Mediterranean diet score or the Healthy Eating Index [An approach for assessing associations with cancer that is focused on single foods or nutrients is not sufficient due to diet complexity ,9. An alariables ,12,19,20ng Index ,24,25,26The traditional Mediterranean diet is characterized by high consumption of vegetables, legumes, fruits, fish, nuts, wholegrains including non-refined cereals, and olive oil (which is rich in mono-unsaturated fatty acids), low-to-moderate consumption of minimally processed dairy products, regular but moderate intake of wine during meals, low consumption of red meat, poultry, highly processed and energy-dense foods rich in saturated fatty acids and sugar . The Meda posteriori-derived dietary patterns with breast or lung cancer risk in adult Poles.In the current study, it was hypothesized that the Polish adaptation of the Mediterranean diet could be considered for adults living in non-Mediterranean countries for the prevention of breast or lung cancer. Thus, the aim of the study was twofold: (1) to develop the Mediterranean diet score adapted to the Polish diet (‘Polish-adapted Mediterranean Diet’ score), and (2) to study associations between the ‘Polish-adapted Mediterranean Diet’ score and The study was approved by the Bioethics Committee of the Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn on 2 October 2013 (resolution no. 29/2013). All subjects gave their written informed consent for inclusion before they participated in the study.Two separate study protocols with case-control designs were developed. These studies were conducted in 2013–2016 among adults from Northeastern Poland. The cancer sample involved women with breast cancer and men with lung cancer, diagnosed from biopsy histopathology results. All cancer cases were newly-diagnosed (primary diagnosis). The time from cancer diagnosis until participation in the study ranged from 7 days to 28 days (18 days on average) a. Cases The control sample were women who received a negative result from ultrasonography (USG) and/or mammography (MM) of the breasts and men who received a negative result from digital X-ray examination (RTG) and/or a computed tomography (CT) of the chest. The time since the cancer exclusion until participation in the study did not exceed 6 months b. ControThe cancer and control samples were chosen through a convenient and non-random selection. Breast cancer cases were patients diagnosed in the surgical oncology ward at the Hospital Ministry of Internal Affairs with Warmia and Mazury Oncology Centre in Olsztyn. Lung cancer cases were patients from pulmonary and oncology hospital wards in the Independent Public Complex of Tuberculosis and Lung Diseases in Olsztyn. The control sample were women and men who attended national screening programs for the early diagnosis of breast and lung cancer, respectively. The control sample was matched by size, age, sex and Body Mass Index (BMI) with cases. Details of the sample collection and study designs are shown in Dietary data were collected using a validated 62-item Food Frequency Questionnaire (FFQ-6) developed by Wadolowska and Niedzwiedzka . A validIn the study, an interviewer-administered version of FFQ-6 was used. Respondents were asked about food frequency consumption (6 categories to choose from) within the last 12 months prior to involvement in the study. The frequency of consumption was recalculated and expressed as times/day as follows: ‘never or almost never’ = 0; ‘once a month or less’ = 0.025; ‘several times a month’ = 0.1; ‘several times a week’ = 0.571; ‘daily’ = 1; ‘several times a day’ = 2 times/day. Some of the food items were combined by summing their frequency consumption into 21 food groups .The Mediterranean diet score (MED), described by Fung et al. , was modThe ‘Polish-aMED’ score was developed using medians of the frequency of consumption (times/day) of eight dietary items, calculated from the initial control sample as reference cut-offs . Points 2), overall physical activity , smoking status  and abuse of alcohol  and 95% confidence interval (95% CI) were calculated. The references (OR = 1.00) were the control sample and the bottom tertile or lowest level of each DP. Two models were created: crude and adjusted for the potential confounders mentioned above. The level of significance of the odds ratio was assessed with a Wald test [p-value < 0.05 was considered statistically significant.The frequency of consumption of 21 food groups (expressed as times/day) was standardized and included in the Principal Component Analysis (PCA) with varimax rotation . To idenald test . The staIn comparison with the controls (non-cancer), more cases of breast or lung cancer were identified in individuals who came from a village, had a lower education level or lower socioeconomic status, were less physically active, including physical activity at work and in leisure time, or were smokers, including former smokers .a priori-developed ‘Polish-aMED’ score was found for the frequency consumption of seven (out of eight) components—vegetables (r = 0.49), whole grain products (r = 0.47), fruits (r = 0.46), nuts and seeds (r = 0.44), fish (r = 0.34) and legumes (r = 0.33)—and a negative correlation for one of its components—red and processed meats  and 63% , respectively, when compared to the low level (0–2 points) as a reference  and 38% , respectively, when compared to the bottom tertile as a reference. This association was not significant after adjustment. In the upper tertile of the ‘Non-healthy’ DP, the risk of cancers was higher by 65%  when compared to the bottom tertile as a reference. The ‘Dressings and sweetened-low-fat dairy’ DP was not significantly associated with the risk of breast or lung cancers (In the average (3–5 points) and high (6–8 points) levels of the ‘Polish-aMED’ score, the risk of breast or lung cancer was lower by 51%  which can neutralize free radicals and reduce oxidative DNA damage . Since tnic acid . Thus, tAn inverse association between the Mediterranean diet and cancer incidence has been reported in most studies, but not in all. In a Greek-Cypriot case-control study , a GermaThe current study found that the ‘Prudent’ pattern reduced the risk of breast and lung cancer by 38–43%. However, this beneficial effect disappeared after adjustment, so the association was weaker than for the ‘Polish-aMED’ pattern. Besides the ‘Polish-aMED’s components, the ‘Prudent’ DP also included juices, cereals, dairy, eggs and white meat. These dietary items contain both beneficial components and those considered to be unhealthy when eaten in greater amounts . Similar to the present study, no significant association was found between breast cancer risk and the ‘cereals/milk/dairy’ DP , ‘vegetaN-nitroso compounds, heterocyclic amines and polycyclic aromatic hydrocarbons, which have been related to cancer promotion through inflammatory effects as well as the generation of free radicals and promotion of oxidative stress [In the present study, high adherence to the ‘Non-healthy’ DP increased the risk of breast or lung cancer by almost 2-fold and confirmed the findings related to the ‘processed & fast food’ DP in the authors’ previous study . These fe stress . Howevere stress , Greek ‘e stress  and Calie stress  diets weIn the current study, no associations were found between the ‘Dressings and sweetened-low-fat dairy’ pattern and breast or lung cancer risk. This pattern included dairy with a potentially beneficial effect on health (even though it was sweetened), and dressings with higher fat content with potentially negative effects on health. This may have influenced the neutral character of the final results in regard to cancer incidence. In other studies, similar patterns were not selected, so a direct comparison of our results is impossible. a posteriori-derived dietary patterns in this area. Overall, the data highlight the beneficial effects of the ‘Polish-adapted Mediterranean Diet’ and the harmful effects of the ‘Non-healthy’ pattern on breast and lung cancer risk in adults from Northeastern Poland. These findings may be helpful for improving cancer prevention and making public dietary recommendations that are generalized and not focused on one type of cancer. Further studies in the Polish population as well as in other non-Mediterranean populations are needed to clarify the associations between diet and cancer risk.To the authors’ best knowledge, this is the first Polish study regarding the association between Mediterranean patterns and breast or lung cancer risk, and the second study regarding There were some limitations in the current study, including the case-control design which is susceptible to recall and selection bias. The matching design in closely-related cases and controls often shows stronger diet–disease associations than other study designs . Howevera priori and a posteriori) to identify dietary patterns. By using both approaches for the same dataset, complementary outcomes were provided, which allowed us to broadly assess the respondents’ diets [The strengths of the study are the identification of dietary patterns which represent the overall combination of usual consumed food and the consideration of the overall health effects (synergistic or opposed) of many single dietary items . Secondls’ diets . Thirdlys’ diets  to colleThe present study provides interesting insight into the strong beneficial effects of high and average adherence to the ‘Polish-adapted Mediterranean Diet’, and the harmful effects of high adherence to a ‘Non-healthy’ dietary pattern on breast and lung cancer risk among adults from Northeastern Poland. The adaptation of the Mediterranean diet to the Polish diet was developed by including total oil consumption instead of just olive oil, and excluding alcohol. The study’s findings provide a good basis for recommending the Polish adaptation of the Mediterranean diet for adults living in non-Mediterranean countries for the prevention of breast and lung cancer. Furthermore, this study reinforces evidence that an unhealthy dietary pattern consisting of highly processed foods with a high content of sugar and animal fat, should be avoided to prevent cancer. Future studies should explore the role of the traditional Mediterranean diet fitted to local dietary patterns of non-Mediterranean Europeans, in real-life scenarios, to determine whether it could be a valuable lifestyle strategy for cancer prevention.


Current evidence from randomised controlled trials on the effects of dietary fibre intake on breast cancer risk is inconsistent. We conducted a meta-analysis to determine the effectiveness of dietary fibre intake in reducing breast cancer risk. We searched for prospective and case-control studies on dietary fibre intake and breast cancer risk in the English language through March 2016. Twenty-four epidemiologic studies obtained through the PubMed, Embase, Web of Science, and Cochrane Library databases were systematically reviewed. A random-effects model was used to compute the pooled risk estimates by extracting the risk estimate of the highest and lowest reported categories of intake from each study. The meta-analyses showed a 12% decrease in breast cancer risk with dietary fibre intake. The association between dietary fibre intake and breast cancer risk was significant when stratified according to Jadad scores, study types, and menopause status. Dose-response analysis showed that every 10 g/d increment in dietary fibre intake was associated with a 4% reduction in breast cancer risk, and little evidence of publication bias was found. Thus, dietary fibre consumption is significantly associated with a reduced risk of breast cancer, particularly in postmenopausal women. Breast carcinoma is the most common carcinoma in women worldwide. Ecological and migrant studies have provided strong evidence that environmental factors, including lifestyle and dietary factors, are related to breast carcinoma risk –3. For eEpidemiological studies have shown conflicting results for the relationship between intake of dietary fibre and breast cancer. Dietary fibre reduce the risk of breast cancer may likely by decreasing the level of estrogen in the blood circulation . ResultsThus, our aim was to clarify the two in a large, geographically and culturally heterogeneous cohort. Pre-specific stratified analyses were performed to assess the impact of various study characteristics on outcomes. We also evaluated whether a dose-response relationship existed between the two.We selected 24 articles from the 47 studies, Which on the relationship between dietary fibre intake and breast cancer Figure . A totalP = 0, I2 = 59.1%). Figure Figure Table P = 0.002), and the heterogeneity was not observed (P = 0.43).Since the data required in the three studies are not provided , 18, 28,P > 0.05; Figures We performed Begg's test and Egger's test in all studies. They both indicated little evidence of publication bias  included in this meta-analysis, yielding a low statistical power [The results from our subgroup and sensitivity analyses were strong, which was not significant associated with the geographic region, influence factor of studies, Jadad score, study types, or menopause status. A significant negative correlation between dietary fibre intake and breast cancer risk was observed in many subgroups, for example, postmenopause women, those with a Jadad score of 3 and 5, developed countries, developing countries, influence factor over 3 or lower than 3, and in case-control studies. Estrogen may have different metabolic pathways in premenopausal and postmenopausal women , no linkal power , 33. In al power , which sal power , which aal power , which sThe following mechanisms may explain the inverse association between dietary fibre intake and breast cancer risk. Dietary fibre is composed of a variety of monomers forming carbohydrate polymers, which cannot be digested and absorbed by the small intestinal in the human body. These polymers mainly include cellulose, hemicellulose, pectin, hydrophilic colloid substances, lignin from plant cell walls, and other components that cannot be degraded by human digestive enzymes , 35. TheOur study has strengths. Our meta-analysis involved enlarged number of studies and participants to date. Besides, we conducted the dose-response analysis to quantify the relationships between dietary fibre intakes and risk of breast cancer.Despite our important findings, there were a few potential limitations that should be noted. First, unmeasured or uncontrolled confounders should always be accounted for in the selected studies . Although most of the studies have an extensive coverage of adjustment, while other residual confounding factors should be considered for further investigation. Second, random errors in dietary fibre intake may have an effect on the outcome, which is inevitable. Third, due to the current articles were mainly based on data from Europe and the United States, our hierarchical analysis shows that geographical changes in a large extent contributed to the substantial heterogeneity.Our results have a guiding significance in breast cancer. Worldwide, the most common cancer in women remains breast carcinoma, after years of medical development, the 5 year survival rate of breast cancer is not high. Moreover, in some European regions and the United States the intake of dietary fibre are about 22 g/day, this is far below the recommended intake . The exiIn summary, this meta-analysis of epidemiological studies demonstrates that dietary fibre intake was associated with a significant dose response relationship between breast cancer risk and breast cancer risk. Due to the large burden and high incidence of breast cancer, measures for prevention of breast cancer are necessary, and increasing the dietary fibre intake in the diet of the general population may have important prevention of breast cancer.http://www.ncbi.nlm.nih.gov/pubmed/), Embase (http://www.embase.com/), Web of Science (http://wokinfo.com/), and the Cochrane Library (http://www.thecochrane library.com/) databases through March 2016. Both case-control and cohort studies published in the English language were searched for using the search terms ‘dietary fibre OR fibre OR fibre’ and ‘breast cancer OR breast neoplasms’. In addition, we manually searched through the reference lists of original articles, recent reviews, and meta-analyses. However, we did not contact the authors for the unpublished studies.We performed a systematic search for relevant publications by searching PubMed  the exposure of interest was intake of total dietary fibre; (2) the endpoint was breast cancer incidence; (3) the study design was prospective, i.e. cohort or case-control study; and (4) the relative risk (RR) and corresponding 95% confidence interval (CI) values were reported for the highest and lowest categories of dietary fibre intake. If the same population was considered in more than one study, we included the study with the maximally adjusted model.We recorded the following study characteristics: (1) last name of the first author; (2) publication year; (3) menopause status; (4) geographic area; (5) duration; (6) age range; (7) no. of cases/sample size; (8) exposure range ; (9) RR from the most fully adjusted model for the highest and lowest dietary fibre intake and the corresponding 95% CI; (10) adjustment for potential confounders in multivariate analysis; and (11) the Jadad score, a scale used to measure the quality of each trial, which ranges from 0 to 5 according to the descriptions of randomisation, blinding, and reporting of participant withdrawals .Q and I2 statistics to examine statistical heterogeneity across studies [Incidence rate and hazard ratios ratios were deemed as RR. In highest and lowest categories of dietary fibre intake in meta-analyses, the RR estimate from each study was weighted by the inverse of the variance to calculate RR and 95% CI. We calculated the  studies . A rando studies  was used studies , were noPre-specified subgroup analyses were performed according to geographic regions, influence factor of the studies, study types, Jadad scores, and menopause status to assess the potential effect modification of these variables on outcomes. We conducted a sensitivity analysis to investigate the influence of a single study on the overall risk estimate by omitting one study in each turn. In addition, we performed meta-regression analyses to explore the possible explanations for heterogeneity among trials.To quantify the dose-response relationship between dietary fibre intakes and breast cancer incidence, we conducted a dose-response analysis based on data for different categories of the average dietary fibre dose . StudiesP < 0.05 were considered statistically significant, unless otherwise specified.To determine the presence of any publication bias, we performed both Egger's and Begg's tests , and ins


The association of passive smoking with hormone receptor-positive breast cancer did not differ from that with hormone receptor-negative breast cancer (Pheterogeneity > 0.05). There was evidence of interaction between passive smoking intensity and menopausal status in both overall group (P = 0.02) and hormone receptor-positive breast cancer group (P < 0.05). In Caucasian women, lifetime exposure to passive smoking is associated with the risk of breast cancer independent of tumor hormone receptor status with the strongest association in postmenopausal women.Tobacco smoking is inconsistently associated with breast cancer. Although some studies suggest that breast cancer risk is related to passive smoking, little is known about the association with breast cancer by tumor hormone receptor status. We aimed to explore the association between lifetime passive smoking and risk of breast cancer subtypes defined by estrogen receptor and progesterone receptor status among non-smoking Caucasian women. A hospital-based case-control study was performed in 585 cases and 1170 controls aged 28–90 years. Information on lifetime passive smoking and other factors was collected via a self-administered questionnaire. Logistic regression was used for analyses restricted to the 449 cases and 930 controls who had never smoked actively. All statistical tests were two-sided. Adjusted odds ratio of breast cancer was 1.01 : 0.72–1.41) in women who experienced exposure to passive smoking at work, 1.88 (95% CI: 1.38–2.55) in women who had exposure at home, and 2.80 (95% CI: 1.84–4.25) in women who were exposed at home and at work, all compared with never exposed regularly. Increased risk was associated with longer exposure: women exposed ≤ 20 years and > 20 years had 1.27 (95% CI: 0.97–1.66) and 2.64 (95% CI: 1.87–3.74) times higher risk of breast cancer compared with never exposed (P Tobacco smoking is defined as an agent with limited evidence in breast cancer by the International Agency for Research on Cancer . This imLack of significant association in active smokers is followed by underestimation of passive smoking (mainstream smoke and sidestream smoke) as a risk factor for breast cancer. Relative to mainstream smoke, sidestream smoke contains a higher ratio of human carcinogens and some of them may induce mammary tumors , 7. HoweExperimental studies have shown that carcinogenic metals/metalloids, such as cadmium, chromium and arsenic determined in tobacco induce estrogen receptor (ER) α activation and indicate estrogen-like activity, that, in part, suggest smoking as a risk factor for breast cancer , 23. ThiWe performed a hospital-based case–control study of breast cancer among Caucasian women in the Hospital of Lithuanian University of Health Sciences. The cases  were women aged 28–90 years with new histologically confirmed breast cancer (C50 and D05 according to ICD10) diagnosed between 1 March 2007 and 10 January 2011, who required surgical intervention at the Department of Surgery and were free from other cancer diagnosed in the past. The controls  were women without a personal history of cancer hospitalized to other departments  of the hospital within the study period. Controls presented with a wide spectrum of non-neoplastic disorders and diseases of (a) eye , (b) ear-nose-throat , (c) nervous , and (d) cardiovascular  systems. Controls were individually matched to cases by age (±5 years) in a 2:1 ratio. To assess passive smoking/breast cancer association analyses were restricted to the 449 cases and 930 controls  who had never smoked actively. The study protocol was approved by the Kaunas Regional Biomedical Research Ethics Committee . Written consent to complete the questionnaire and collect biological media specimens was received from each individual.Both cases and controls completed a self-administered structured questionnaire previously demonstrated to be valid and reliable for collection of demographic and socioeconomic characteristics, medical history, height and weight, family history of cancer, reproductive history, and lifestyle characteristics .A woman was defined as being a passive smoker if she reported living/working with someone who smoked inside her home and/or in the workplace. Duration of exposure was assessed by the number of years of exposure at home and/or at work specified by every woman. In the case of exposure experienced both at home and at work, a longer duration reported was included in the analyses.The ER and progesterone receptor (PR) levels were measured in specimens of breast tumor tissue by immunohistochemistry at the Department of Pathological Anatomy .Baseline characteristics of cases and controls were summarized using means and standard deviations (SD) for continuous variables, and frequencies and percentages for categorical variables. Characteristics were compared between cases and controls using either unpaired t-test (for continuous variables) or chi-squared test .According to tumor hormone receptor status cases were stratified as follows: ER+, ER-, PR+, PR-, ER+/PR+, ER+/PR-, ER-/PR+, and ER-/PR- ; cases wAccording to the answers on the intensity of exposure to passive smoking women were grouped into 4 categories: never exposed, exposed at work only, exposed at home only, exposed at home and at work, and into 3 categories defined by duration of exposure: never exposed, ≤ 20 years, and > 20 years.Unconditional logistic regression models were used to estimate the association between exposure to passive smoking and breast cancer subtypes calculating the odds ratios (ORs) and their 95% confidence intervals (CIs). The models were adjusted for (a) age and (b) age, number of births, estrogen-active (fertile) period, hormone therapy during menopause , family history of breast cancer in first and/or second degree of relatives , alcohol use , body mass index, education , marital status , diabetes mellitus , and thyroid diseases . In these analyses, estimates of association per 1 category increase in exposure to passive smoking were obtained; for some analyses estimates for exposed at work only vs. never exposed, exposed at home only vs. never exposed, and exposed at home and at work vs. never exposed as well as for ≤ 20 years exposure vs. never exposed, and > 20 years exposure vs. never exposed were also reported.The interaction between menopausal status and intensity or duration of exposure to passive smoking (per 1 category increase) was tested using a likelihood ratio test. Heterogeneity in the estimated associations of passive smoking with each breast cancer subtype was tested using a Cochran Q-test. The level of statistical significance was set at 0.05. All reported P-values are 2-sided. The analyses were performed using the software package Stata 10 .Of non-smoking cases, 77.3% had invasive ductal carcinoma, 8.7% invasive lobular carcinoma, 14.0% other histological types of breast cancer. The ER+ and PR+ were determined for 66.6% and 43.2% of the cases . The ER Cases and controls were non-smoking Caucasian women of the same age, similar with respect to marital status, family history of breast cancer, age at menarche, number of births, menopausal status, and body mass index . However< 0.001).Exposure to passive smoking was more often experienced by cases than controls . Mean dutrend < 0.001). When stratified by menopausal status, the association appeared stronger among postmenopausal women. The interaction between menopausal status and exposure to passive smoking was significant (P = 0.02) when the intensity of exposure was analyzed  in women exposed at work only, 1.88 (95% CI: 1.38–2.55) in women who experienced exposure to passive smoking at home, and 2.80 (95% CI: 1.84–4.25) in women exposed at home and at work, all compared with never exposed . A signianalyzed .trend < 0.001) and 1.54 , respectively, for ER+, 1.20  and 1.41 , respectively, for ER-, 1.34  and 1.47 , respectively, for PR+, and 1.36  and 1.53 , respectively, for PR- breast cancer. Regardless of the exposure to passive smoking variable (intensity or duration) used in the analyses, there was no evidence of heterogeneity in the association comparing ER+ and ER- (P > 0.05) or PR+ and PR- breast cancer (P > 0.05). The association appeared stronger among postmenopausal women than premenopausal women. Significant interaction between menopausal status and intensity of exposure to passive smoking was found for both ER+ (P = 0.03) and PR+ (P = 0.02) breast cancer  for ER+/PR- breast cancer, which was different from the passive smoking/ER-/PR- association (Pheterogeneity = 0.05), with an OR of 1.34  for ER+/PR+ breast cancer, not significantly different from the passive smoking/ER-/PR- association (pheterogeneity = 0.35), and with an OR of 1.20  for ER-/PR- breast cancer. Increased duration of exposure was related to higher risk of breast cancer independently of tumor hormone receptor status (Pheterogeneity > 0.05). When stratified by menopausal status, the association was stronger among postmenopausal women than premenopausal women; however, significant interaction between menopausal status and intensity of exposure to passive smoking was found only for ER+PR+ breast cancer (P = 0.02) (There were significant positive associations between passive smoking and (1) ER+/PR-, (2) ER+/PR+, and (3) ER-/PR- breast cancer . A 1 cat = 0.02) .In this hospital-based case-control study of breast cancer among non-smoking Caucasian women, we observed a 1.9-fold increase in breast cancer risk for women exposed to passive smoking at home, a 2.8-fold increase for those exposed at home and at work, and a 2.6-fold increase in breast cancer risk for women experienced passive smoking > 20 years. Two large prospective studies completed in Europe and the US observed greater risk of developing breast cancer in women exposed to passive smoking , 25. IncAs breast cancer has different subtypes according to hormone receptor status, their etiological and risk factors may vary . Our resUntil now epidemiological studies provided little evidence for passive smoking and breast cancer association in postmenopausal women , 19, 33.Inconsistency of reported findings could be related to some issues such as the relatively small number of cases in subgroup analyses , 13 or lAn increased risk of postmenopausal cancer determined in the studies, including the present one, opposes anti-estrogenic effects of tobacco smoke . AlthougEpidemiological findings on breast cancer risk related to passive smoking at work are not consistent. We, as well as other authors , 26, 30,We assessed lifetime exposure to passive smoking at home, without distinction the exposure experienced in childhood. The studies published previously showed inconclusive results on passive smoking during childhood and breast cancer association where some authors , 54 but In this study, in which controls were individually matched to cases by age, to estimate the association we used unconditional logistic regression (adjusted for age and other risk factors) rather than conditional logistic regression. Conditional logistic regression was more powerful and showed stronger effects in the overall sample; however, when considering different breast cancer subtypes defined by hormone receptors and, especially, by menopausal status, the small number of individuals with certain breast cancer subtypes led to wide CIs around the estimated associations, especially for premenopausal women.One of the main limitations of this case-control is using hospital’s patients free of cancer as controls, but not randomly recruited controls, i.e. representatives of the general population in terms of health. This recruitment of controls is prone to selection bias because the controls are different from the population they are meant to represent. However, in this study, cases and controls were elderly (age mean 60.34 ± 12.18 of the cases and 59.31 ± 12.30 of the controls) and postmenopausal women (75% of cases and controls) that begin to have health related issues represented by the general population. Therefore recruitment of controls from different departments of the hospital may reflect health issues in this population. Some authors reported that hospital controls were comparable with population controls for most demographic and lifestyle characteristics .Another limitation of case-control studies is that information on exposure is subject to recall bias that deals with the systematic difference between cases and controls in the accuracy of the information reported, because cases are more likely to recall their exposure to potential risk factors. To avoid recall bias in the assessment of lifetime exposure to passive smoking, firstly, we did not disclose study hypothesis. Secondly, in hospital-based case-control all women were with “a disease” and, therefore, had the same attitude to report information on potential risk factors. Thirdly, we did not ask women for very detailed information  that is difficult to recollect.We also had relatively small numbers of individuals, mainly cases, in subgroups by menopausal status and tumor hormone receptor status that limited our analyses.However, an increase in risk of breast cancer related to passive smoking that we observed in this study could not be explained by biases and confounding factors common in case-control studies or by chance because, firstly, we invited all the patients that met selection criteria within the study period at the departments of the hospital selected randomly and did not disclose the hypothesis. Both cases and controls were representative of patients in a hospital which provides medical services for the population, and had equal conditions and presumptions answering to the same questions. Therefore, the probability of systematic differences in reporting between cases and controls was low. Secondly, we collected data on all aspects of lifetime exposure to passive smoking  and its duration which enabled us to establish a reference group that had been unexposed to either active or passive smoking. Thirdly, we adjusted for all known confounders for breast cancer.In conclusion, the study among Caucasian women provides evidence on the association between lifetime exposure to passive smoking and risk of breast cancer independent of tumor hormone receptor status with a stronger risk demonstrated among postmenopausal women. Further studies are necessary to define whether the association with passive smoking varies by menopausal status independently of other risk factors. Since passive smoking is a modifiable factor, the findings are very important to public health and primary health care workers that could inform and advise women to avoid this exposure.S1 Data(DTA)Click here for additional data file.


Women with high factor scores of the sweet pattern also showed a decreased risk of breast cancer . No marked association was observed between a vegetarian pattern or a salty pattern and breast cancer. These findings indicate that dietary patterns of the traditional Chinese and the sweet may favorably associate with the risk of breast cancer among Chinese women.This study aims to examine the association of breast cancer with dietary patterns among Chinese women. A population-based case-control study was conducted in Jiangsu, China. Newly diagnosed primary breast cancer patients were recruited as cases (n = 818). Controls (n = 935), selected from the general population, were frequency matched to cases. A validated food frequency questionnaire was used to assess dietary intake. Dietary patterns were identified by factor analysis and multivariable odds ratios (OR) and 95% confidence intervals (CI) were estimated. Four dietary patterns were identified: salty, vegetarian, sweet and traditional Chinese. The traditional Chinese pattern was found to be robustly associated with a lower risk of breast cancer among both pre- and post-menopausal women (4 However, there has been a remarkable increase in recent years , waist and hip circumference [used to calculate waist-hip ratio (WHR) as waist circumference (cm) divided by hip circumference (cm)] were conducted.All eligible persons were invited to Wuxi Maternal and Child Health Hospital, which is the largest women and children healthcare hospital in Wuxi City. Using standard protocols and structured questionnaires, epidemiologic data was collected by trained investigators through face-to-face interviews. The questionnaire included detailed information on known or potential risk or protective factors for breast cancer, including demographic information, socio-economic status, dietary habits, reproductive history, disease history, This study was approved by the Ethical Committee of Jiangsu Provincial Center for Disease Control and Prevention. All participants were fully informed and gave written consent.An interviewer-administrated food frequency questionnaire was used to collect information of individual food consumption in the previous 12 months. The validity and the reliability of this questionnaire in terms of food consumption have been documented elsewhere . This quExploratory factor analysis was used to identify dietary patterns using principal component analysis approach . The fac2 and > = 28 kg/m2) and WHR (< 0.8 and > = 0.8) in the logistic regression model. Reproductive related variables, including age at menarche (continuous), age at first live birth (continuous) and abortion (yes or no) were additionally introduced into the model in order to see their influence on the association.Factor scores of dietary patterns were divided into quartiles to allow a robust estimation of the associations which were not driven by extreme values. The chi-squared test was used to compare the difference between categorical variables. In our study, multivariate logistic regression was applied to assess the odds ratio (OR) and their 95% confidence intervals (CI) of breast cancer risk by quartiles of each dietary pattern factor scores. Age (continuous), education level , household income 5 years ago (continuous) and residence  were selected as potential confounders based on the comparison of baseline characteristics between case and control subjects, as well as on the results of literature review. As menopausal status is one of the most important known confounders in breast cancer related analyses , all anaP values were two sided, and statistical significance was determined at the P < 0.05 level.SPSS  was used for data analyses. All vs. 24.8 thousand, P < 0.001) but higher proportion of illiterate to low education (P < 0.001). The case group was higher in both average BMI and WHR than the control group (both P < 0.001). Though there was no statistically significant difference either in age of menarche or age of first live birth between cases and controls, the case group reported more frequently to be post-menopausal (P < 0.001), but they reported a lower percentage of abortion experience .Descriptive characteristics of the population by case-control status are shown in etc. The vegetarian pattern (factor 2) largely consisted of more vegetarian food, such as soy, fruits and coarse cereals, but contained less meat and fried food. The sweet pattern (factor 3) was characterized by various kinds of sweet foods or beverages, such as soft drinks, sugar strengthened beverages and cakes. The traditional Chinese pattern (factor 4) mainly includes meat, vegetable/fruit, whole cereal  and eggs. The four factors explained 32.9% of the variance in food intake, with patterns of salty, vegetarian, sweet and traditional Chinese patterns accounting for 11.72%, 11.32%, 7.53% and 5.76%, respectively.In principal components analysis, four dietary patterns were identified. Factor scores of the four patterns and the name assigned to each pattern are presented in Compared with the lowest quartile (Q1) of the traditional pattern, the highest quartile (Q4) had a lower mean age but higher household income, so for the sweet pattern. Rural residents had a higher percentage of salty and traditional patterns in Q4, whereas urban residents had a higher percentage in Q4 of both salty and traditional patterns. High education group accounted for higher proportion in Q4 of all patterns but the salty. In terms of intakes of variety foods, the Q4 group of salty pattern consumed the most oil, salt, pickles and soy sauce across different quartiles of dietary patterns . Similarly, the Q4 group of vegetarian pattern group had the most vegetables and fruits (37 g/d) and sweet pattern had most soft drinks (18 ml/d), sugar strengthened beverages (24 ml/d) and cakes (7 g/d). The highest intake of whole grains (387 g/d), poultry (99 g/d), aquatics (21 g/d) and eggs (83 g/d) were found in the fourth quartile of the traditional Chinese pattern .vs. Q1: OR among pre-menopausal women was 0.47, 95% CI: 0.28–0.79, P for trend = 0.017, OR among post-menopausal women was 0.68, 95% CI: 0.47–0.98, P for trend = 0.030). The traditional Chinese pattern (factor 4) was also found to be related to a lower risk of breast cancer and this association was not influenced by menopausal status. The ORs of breast cancer across quartiles of the traditional Chinese pattern among post-menopausal women were 0.64 (95% CI: 0.45–0.90) for Q2, 0.45 (95% CI: 0.32–0.63) for Q3 and 0.68 (95% CI: 0.48–0.97) for Q4, while those among pre-menopausal women were 0.53 (95% CI: 0.33–0.85), 0.53 (95% CI: 0.32–0.86) and 0.47 (95% CI: 0.29–0.76), respectively  and WHR (< 0.8 and > = 0.8), we found that the associations between traditional Chinese pattern, sweet pattern and breast cancer were still significant. By introducing reproductive related variables  into the model, we observed that the highest quartile of sweet pattern, as well as the Q3 and Q4 quartiles of traditional Chinese pattern, were robustly related to a decreased risk of breast cancer, among both pre- and post-menopausal women (both P for trend < 0.05) (Data not shown).After stratification by BMI . Differentially, the sweet dietary pattern established in this study was found to be protective against breast cancer. Overall, since the sweet foods involved in the previous mentioned dietary patterns was analyzed together with other foods , it is difficult to judge whether their observed effect was due to the intake of sweet food/beverages or that of other kinds of food eaten together , which had been proven to be related to different dietary patterns [A population-based study design, strictly adhering to a standard protocol for data collection, a relatively large sample size, together with other strict quality control measures  and a sweet pattern may protect against breast cancer among women in China, whereas a vegetarian pattern and a salty pattern appear not to be associated in this population.