MAP3K1) SNPs rs889312 A>C, rs16886165 T>G and breast cancer risk have been widely evaluated, but the results were inconsistent. To derive a conclusive assessment of the associations, we performed a meta-analysis by combining data from all eligible case-control studies up to date.The genome-wide single-nucleotide polymorphisms (SNPs) profiles can be used as diagnostic markers for human cancers. The associations between mitogen-activated protein kinase kinase kinase 1  with 95% confidence intervals (CIs) were used to assess the strength of associations in fixed-effect or random-effect model. False-positive report probability (FPRP) was calculated to confirm the significance of the results.A total of 59670 cases in 20 case-control studies were included in this meta-analysis. Significant associations with breast cancer risk were observed for SNPs rs889312 and rs16886165 polymorphisms with a per-allele OR of 1.11 (95% CI: 1.09–1.13) and 1.14 (95% CI: 1.09–1.20) respectively. For rs889312, in subgroup analysis by ethnicity, significant associations were identified in Europeans and Asians, but not in Africans. When stratified by estrogen receptor (ER) expression status, rs889312 was associated with both ER-positive and ER-negative breast cancers. Results from the FPRP analyses were consistent with and supportive to the above results.The present meta-analysis suggests that rs889312-C allele and rs16886165-G allele might be risk factors for breast cancer, especially in Europeans and Asians. BRCA1, BRCA2, ATM, CHEK2, BRIP1 and PALB2, contribute to breast cancer susceptibility. However, these mutations explain only a small portion of the disease risk and the majority of genetic variations that contribute to the breast cancer risk remains unclarified, especially those of low penetrance genes. Genome-Wide Association Study (GWAS), an examination of disease-related genetic variations across the human genome, provides a powerful tool in identifying such mutations/polymorphisms genome-wide. Some common low penetrance genetic variants that might confer increased risk to breast cancer have been identified recently Globally breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in females, with an estimation of 1 million new cases and over 400,000 deaths per year MAP3K1) gene, which is located in the chromosome 5q11.2, encodes a serine/threonine kinase which is involved in the mitogen-activated protein kinase (MAPK) signaling pathway. MAPK signal transduction regulates the transcription of important cancer genes including c-Myc, c-Elk1, c-Jun and c-FosMAP3K1 was identified to be associated with breast cancer risk by GWAS MAP3K1 rs16886165 was associated with increased risk of breast cancer under heterozygote codominant and homozygote codominant genetic models Mitogen-activated protein kinase kinase kinase 1  polymorphisms among diverse ancestry populations.Up to date, a number of studies have investigated the relationship between polymorphisms in MAP3K1” or “mitogen-activated protein kinase kinase kinase 1” or “rs889312” or “rs16886165” and “polymorphism” or “variation”. All potentially relevant studies were retrieved, and the abstracts were screened to exclude clearly irrelevant studies. The remaining articles were read to determine whether they contained information on the topic of interest. We also examined the reference lists from the main reports and reviews to identify additional relevant studies.We conducted a comprehensive literature search in Pubmed, ISI web of knowledge, Embase and Cochrane databases up to September 2013 using the following terms: “breast cancer” or “breast carcinoma” and “MAP3K1 (rs889312 and rs16886165) polymorphisms, (3) had odds ratio (OR) with its 95% confidence interval (CI) or genotype distribution information for estimating OR (95% CI).Eligible studies had to meet the following criteria: (1) original papers containing independent data which have been published in peer-reviewed journals, (2) case-control studies which evaluated the association between breast cancer risk and Two investigators independently reviewed and extracted data with any discrepancies resolved by consensus. For each eligible study, the following data were extracted: first author's surname, year of publication, country of origin, population ethnicity, source of control subjects, genotyping method, age, the values of OR with its 95% CI, total numbers of cases and controls, the genotype counts in cases and controls, matching criteria, whether genotype distribution of control group was consistent with Hardy-Weinberg equilibrium (HWE). Ethnic groups were categorized as European, Asian and African . Different case-control groups in one study were considered as independent studies if the data was available.Methodological quality was assessed using a classification method known as “extended-quality score”. The criteria cover diagnostic criteria, the degree of matching of controls, genotyping examination, Hardy-Weinberg equilibrium in the control population, and bias in data processing. Each paper was scored of ‘high’, ‘median’ or ‘poor’ quality. Detailed procedure of the quality assessment was performed according to literature 2I-test was performed to assess possible heterogeneity among studies 2x test. Pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated using fixed-effects (Mantel-Haenszel method) The meta-analysis evaluated the association between rs889312 and the risk of breast cancer, for the: (1) allele contrast model (C vs. A), (2) the heterozygote codominant model (AC vs. AA), and (3) the homozygote codominant model (CC vs. AA) model http://jnci.oxfordjournals.org/content/96/6/434/suppl/DC1).For each statistically significant association, the false-positive report probability (FPRP) analysis was performed using the method reported by Wacholder et al. Based on the above criteria, a total of 20 eligible studies involving 59,670 cases and 66,862 controls met all selection criteria for the pooled analyses P = 0.000, I2 = 27.0%; AC vs. AA: OR = 1.09, 95% CI: 1.05–1.13, P = 0.000, I2 = 20.0%; CC vs. AA: OR = 1.21, 95% CI: 1.15–1.28, P = 0.000, I2 = 31.9%; P = 0.000, I2 = 0.0%; Overall, the rs889312 polymorphism was significantly associated with increased breast cancer risk under all genetic models . For Asians, two genetic comparisons produced significantly increased risks , but the heterozygote codominant model did not reach statistically significance. Among Africans, we did not detect any significant association under all genetic models  and ER-negative tumors of 1.08 , encodes a 196-kDa serine/threonine protein kinase that activates the ERK , JNK  and NF-κB (nuclear factor-κB) pathways The common variants rs889312 and rs16886165 lie in a linkage disequilibrium (LD) block of approximately 280 kb which includes MAP3K1 were associated with increased breast cancer susceptibility. There are a number of meta-analyses that have been performed to elucidate the associations between SNPs and breast cancer risk in recent years; however, only 21.7% of those significant associations were noteworthy This meta-analysis demonstrated that the rs889312 and rs16886165 SNPs in When stratified by ethnicity, the rs889312-C allele showed to be a risk factor for the development of breast cancer in European and Asian ancestry populations, but not in Africans. Different frequencies of mutant alleles in different ethnic groups may contribute to different susceptibilities to cancer MAP3K1 are similar in ER-positive and ER-negative tumors.The prognosis of breast cancer is affected by ER status. Previous studies suggested that rs889312 was related to ER-positive breast cancers, which was confirmed by our stratified analysis by ER status. For ER-negative tumors, the results of previous studies were contradictory, but this meta-analysis showed rs889312 might also confer risk. Furthermore, the frequencies of the rs889312-C allele in MAP3K1 and breast cancer in African descendants. Second, we performed the analyses under heterozygote codominant model, homozygote codominant model and the subgroup analysis by ER status on a fraction of all data, the selection bias might therefore have occurred. Third, the controls were not uniformly defined, for those based on hospital population might have had benign disease and had different risks for developing breast cancer. Therefore, non-differential misclassification bias might be possible. Finally, due to the lack of individual-level data, the results were based on unadjusted published estimates. We were unable to examine the interactions of possible confounders including age, menopausal status, obesity, smoking, alcohol consumption and environmental factors.Despite the strengths of this study, such as the large sample size, no significant heterogeneity and high quality of the qualified studies, there are several limitations that should be addressed. First, the sample size of Africans was relatively small, thus the analyses might have insufficient statistical power to detect an association. The trial sequential analysis (TSA) can be used to reveal insufficient information size and potentially false positive results in meta-analyses MAP3K1 polymorphisms rs889312 and rs16886165 in breast cancer predisposition.In summary, this meta-analysis indicated that the polymorphism rs889312 was associated with breast cancer risk in Europeans and Asians, while rs16886165 was a risk factor for breast cancer in Asian and African women, and both could be served as markers predisposition to breast cancer. Larger sample studies by using homogeneous patients, unbiased genotyping methods, as well as well-matched controls will provide further supporting information on association of Checklist S1PRISMA checklist for this meta-analysis.(DOC)Click here for additional data file.


There is increasing evidence that breast cancer is a heterogeneous disease presented by different phenotypes and that white women have a higher breast cancer incidence rate, whereas black women have a higher mortality rate. It is also well known that white women have lower incidence rates than black women until approximately age 40, when rate curves cross over and white women have higher rates. The goal of this study was to validate the risk of white and black women to breast cancer phenotypes, stratified by statuses of the estrogen (ER) and progesterone (PR) receptors.SEER17 data were fractioned by receptor status into , , , and  phenotypes. It was shown that in black women compared to white women, cumulative age-specific incidence rates are: (i) smaller for the  phenotype; (ii) larger for the  and  phenotypes; and (iii) almost equal for the  phenotype. Clemmesen's Hook, an undulation unique to women's breast cancer age-specific incidence rate curves, is shown here to exist in both races only for the  phenotype. It was also shown that for all phenotypes, rate curves have additional undulations and that age-specific incidence rates are nearly proportional in all age intervals.For black and white women, risk for the ,  and  phenotypes are race dependent, while risk for the  phenotype is almost independent of race. The processes of carcinogenesis in aging, leading to the development of each of the considered breast cancer phenotypes, are similar in these racial groups. Undulations exhibited on the curves of age-specific incidence rates of the considered breast cancer phenotypes point to the presence of several subtypes (to be determined) of each of these phenotypes. Breast cancer (BC) is the most common malignancy diagnosed in women in the United States with about 40,000 women dying of this disease annually Age is a common risk factor for majority of cancers, and it is widely accepted that carcinogenesis in aging is coded in the pattern of the age-specific incidence rates However, in contrast to other types of cancer, the curve of the breast cancer age-specific incidence rate for women has a unique undulation occurring near the age of 50, called Clemmesen's Hook In oncology, the idea of heterogeneity of breast cancer population is not new. For years, clinicians have divided breast cancer patients into two groups by age at diagnosis, as having two different diseases Separation of breast cancer population into two fractions by a cut-point age, however, may reflect only an overall tendency of the breast cancer phenotypes to be prevalent at extreme ages The existence of this so-called black-to-white ethnic crossover In this work, we assumed that to better understand the nature of the black-to-white crossover, as well as to perform a robust separation of the breast cancer population on fractions with distinct breast cancer phenotypes, there is a need to stratify breast cancer subtypes by biological markers, such as estrogen receptor (ER) status and progesterone receptor (PR) status, which have been shown to be associated with breast cancer development Overall goal of this study was to validate the risk of white and black women to breast cancer phenotypes, stratified by the ER and PR statuses.i) the population of white and black women diagnosed with breast cancer between 1979 and 2008 and documented in the SEER9 registry subset; and (ii) the population of white and black women diagnosed with breast cancer between 2004 and 2008 and documented in SEER17. The SEER9 registries contain information on cancer cases collected from the following nine geographical areas: Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, Utah. The SEER17 registries include the SEER9 registries and information on cancer cases collected in eight additional areas: Los Angeles, San Jose-Monterey, Rural Georgia, Greater California, Kentucky, Louisiana, New Jersey, and Alaska.  We studied cases only for women known to be black or white, which account for 91.5% of all female breast cancer patients in the SEER database. To determine race, SEER requires participating centers to use all resources, including medical records, face sheets or photographs, and physician or nursing notes. In order to minimize the number of patients classified as unknown race, if race remains unclear, place of birth, nationality, and surname are permitted to ascertain race, but only if these data are accordant and reveal race unambiguously. The remaining 8.5% of cases were for women whose race was coded by SEER as “unknown”  or whose race that was not white or black (which includes Native Americans and Asian Americans/Pacific Islanders). These cases were not studied because they were not available in sufficient quantities to achieve statistical significance.In this study we utilized the SEER registries that accumulate population-based data on patients (cases) diagnosed with different types of cancer during distinct time periods and U.S. Census Bureau data (supplied by SEER) that provide information on the population at risk of getting cancer. From SEER we used data on two breast cancer populations:  effects on breast cancer occurrence in populations of white and black women, we used data obtained from the SEER9 registries. This is because the longitudinal nature of the APC analysis required utilization of data from much earlier time periods, when only nine registries were available three decades ago. Of 903,804 SEER9 cases of breast cancer in white and black women of known age, we excluded 148,106 cases that were not the first primary cancer. In accordance with the SEER Survival Monograph I(it) .The obtained breast cancer cases and the corresponding population at risk (determined from U.S. Census Bureau data that is provided with the SEER database) were grouped in 5-year cross-sectional time-period groups between 1979–2008; 5-year age groups between 20–84 years; and 5-year groups corresponding to the birth cohorts between 1894-1988. For each age interval, incidence rates were age-adjusted by the direct method The breast cancer populations of black and white women presented in SEER17 registries for the time-period of 2004–2008 were fractioned by (positive and/or negative) ER and PR status. We utilized the SEER database fields named “Collaborative Staging Site Specific Factor (CSSSF) 1” and “CSSSF 2,” for ER status and PR status, correspondingly, which are specifically defined for breast cancer starting with the year 2004. Of 289,739 SEER17 cases of breast cancer in white and black women of known age, we excluded 15,113 cases for individuals aged greater than 84 years, 26 cases for individuals aged less than 20 years, 49,499 cases that were not first primary breast cancer, 499 cases diagnosed by death certificate only or at autopsy, 4,336 cases lacking follow-up information, 42,610 cases of in situ breast cancer, 950 cases that were not microscopically confirmed, and 15,500 cases that had indefinite ER or PR status, leaving 161,206 cases for analysis. Receptor status was assumed to be indefinite, when in the case records, it was marked as: “Borderline; undetermined whether positive or negative,” or “Ordered, but results not in chart,” or “Unknown or no information,” or “Not Performed.” The obtained four fractions were denoted as: , , , and .The APC analysis was performed by the approach we described previously I(it), over all age intervals, it. Standard errors (SE) of the cumulative incidence rates were calculated as a square root of sum of squares of standard errors of the I(it). For black and white women we estimated cumulative incidence rates (and their SEs) for the , , , and  phenotypes.The cumulative incidence rates (CIR) of the fractions, which indicate risk for breast cancer phenotypes, were calculated as the sum of the age-specific incidence rates W) vs. black (B) women (denoted as WI(it) and BI(it) are the age-specific incidence rates at age interval it, for black and white women correspondingly. The standard error of the relative risk, SE[W|BRR(it)], was estimated by using the SE[WI(it)] and SE[BI(it)] by the standard rules of error propagation. The estimate of the averaged relative risk, In addition, we estimated relative risk of white ]. We calculated the SE of the corresponding estimate using the following variance of the weighted mean:In SEs and 95% confidence intervals of the fractions of standardized populations of black and white women, as well as the relative rates and corresponding SEs and 95% confidence intervals of black women vs. white women, For each considered breast cancer phenotype, we calculated the corresponding CIR, To analyze APC effects on breast cancer presentation in aging, we utilized SEER9 data from breast cancer cases in white and black women diagnosed with breast cancer during 1979–2008. Using our previously developed approach, we estimated time period and birth cohort effects and calculated age-specific incidence rates adjusted for these effects it. These rate curves also exhibit a crossover point near the age of 40: for women younger than 40, Absence of significant birth cohort effects allowed us to reduce our further analysis by utilizing just cross-sectional data for the population of white and black women diagnosed with breast cancer between 2004 and 2008 and documented in SEER17. Age-specific breast cancer incidence rates in white and black women, SE) in white and black women. These rates were denoted I+,+(it), I+,−(it), I−,+(it), and I−,−(it), correspondingly. The obtained rates are exhibited as The robust detection of the Clemmesen's Hook and uncovering differences in the shapes of it, whereas the values of Comparative analysis of amplitude and morphology of the breast cancer age-specific incidence rates, shown on lues of  . For therlapping . Figure z-test, 2-sided, p<0.05; confidence intervals do not overlap) than vs. white women, As can be seen from To better perform visual inspection of proportionality between the age-specific incidence rates of breast cancer phenotypes, stratified by ER and PR status, in black and white women, we adjusted the age-specific incidence rates in black women to the analogous rates in white women by scaling with the corresponding coefficients, I+,+(it), I+,−(it), I−,+(it), and I−,−(it) profiles in white and black women  for the age 45–49 interval , I−,+(it), and I−,−(it)  .The reasons causing Clemmesen's Hook  and the other observed undulations  on the curves of the age-specific incidence rates of the fractions of standardized populations of black and white women at risk for the corresponding breast cancer phenotypes, remain unclear. However, these phenomena point to the presence of several subtypes of each of the considered breast cancer phenotypes, and contribute to the growing body of evidence to the heterogeneity of breast cancer. The widely-publicized reports from Perou and colleagues Because our data has shown that there is no statistically significant black-to-white crossover after stratifying by ER and PR status, we now know that black women have higher rates of  disease regardless of age, and lower rates of  disease regardless of age. Researchers may now focus their energies on explaining these race-specific disparities without concern that the disparities reverse themselves in younger ages.There are several potential limitations of this study. Our study has similar limitations as many other SEER-based studies, which assume that SEER cases represent the United States as a whole and that there is little regional variation in diagnostic and reporting standards for breast cancer case data. In addition, SEER data lacks information on other breast cancer biomarkers, most notably, HER2. These biomarkers could account for unexplained features of breast cancer incidence rate curves, and may exhibit differential presentation when stratified by race. Another concern is that we included  in our study, despite there being considerable doubt in the field of the true existence of this phenotype Nevertheless, the use of SEER data allowed us to study breast cancer incidences from a population-based perspective, with numbers of cases that are several orders of magnitude higher than many other breast cancer studies. Large numbers of cases provide not only statistical power, but enable use of novel analytical methods, such the age-period-cohort analysis that we utilized to demonstrate lack of birth cohort effects in breast cancer incidences during 1979–2008. Another elegant technique allowed us to quantitatively compare sizes of fractions of age-standardized subpopulations of black and white women diagnosed with breast cancer by utilizing cumulative incidence rates and their standard errors. Also, using qualitative methods, we demonstrated Clemmesen's Hook is only present in the  phenotype and the black-to-white crossover depend on ER and PR status. Thus, our findings do not support an assertion made in the recently published work In this work, we analyzed how race, as a non-modifiable categorical factor, influences on heterogeneity of sizes of fractions in black and white women at risk for breast cancer phenotypes, stratified by the positive and/or negative statuses of the ER and PR receptors and how race can influence carcinogenesis leading to the development of these breast cancer phenotypes.We used breast cancer data from the SEER17 registries during the years 2004–2008 and showed that these cross-sectional data are not confounded by birth cohort effects. This was done using APC analysis of longitudinal data collected during the years 1978–2008 in the SEER9 registries. We showed that within this 30 year period birth cohort effects have very little influence on breast cancer age-specific incidence rates. Thus we conclude that birth cohort effects cannot perturb results of this study in which cross-sectional data were utilized.Using SEER17 breast cancer cases in black and white women for the years 2004–2008, we showed that in these racial groups, sizes of fractions at risk for the considered breast cancer phenotypes are disproportional. In both racial groups, the  was the most prevalent breast cancer phenotype. However, for cumulative incidence rates in the fraction of population within the standardized population  at risk for this phenotype in white women, Analysis of age-specific incidence rates of the considered breast cancer phenotypes in black and white women showed that in all age intervals, the morphology of the curves of the rates of the corresponding breast cancer phenotypes are similar and that, in most of the age intervals, the rates of a given breast cancer phenotype in black women can be well-adjusted to the corresponding rates in white women by multiplication by corresponding constants, which were also determined in this work.We have shown that black women have lower risk for the  phenotype compared to white women, but higher risk for the  and  phenotypes. In these racial groups, the risk for the breast cancer with the  phenotype was almost the same. It is likely that risks for the breast cancer phenotypes, stratified by ER and PR status, are derived from both hereditary and environmental factors. The obtained results also suggest that carcinogenesis in aging, leading to the development of each of the considered breast cancer phenotypes, is similar in white and black women.Clemmesen's Hook  and other undulations  observed on the corresponding age-specific incidence rates indicate that each of the considered breast cancer phenotypes is also a heterogeneous disease and suggests the existence of several subtypes of each of these phenotypes. For instance, such subtypes could differ by the status of HER2, which is known to play an important role in breast cancer carcinogenesis


There is a paucity of data on familial risk of developing esophageal adenocarcinoma, gastric cardia adenocarcinoma and distal gastric adenocarcinoma from population-based studies.A population-based case–control study of newly diagnosed gastroesophageal adenocarcinoma was conducted in Los Angeles County. This analysis included data of case-patients whom we were able to interview directly  and 1,309 control participants. Multivariate polytomous logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the three cancer types.Risk of esophageal adenocarcinoma was positively associated with a family history of prostate cancer  and a family history of hiatal hernia . Risk of gastric cardia adenocarcinoma was strongly associated with a family history of esophageal cancer  and a family history of hiatal hernia . Risk of distal gastric adenocarcinoma was positively associated with a family history of gastric cancer , particularly early-onset (before age 50) gastric cancer .This study provides evidence that family history of hiatal hernia is a risk factor for esophageal adenocarcinoma and gastric cardia adenocarcinoma and that cancer in specific sites is associated with risk of esophageal adenocarcinoma, gastric cardia adenocarcinoma, and distal gastric adenocarcinoma. It is important to determine the extent to which shared environmental and genetic factors explain these familial associations. There are also some reports of stable or declining incidence of GCA in more recent years. A 2012 study [Esophageal and gastric cancers are one of the most common cancers in the world, with an estimated 482,300 new esophageal cancer cases and 989,600 new gastric cancer cases diagnosed in 2008 worldwide. However, incidence rates at these two cancer sites vary substantially internationally . In the 12 study  reported12 study , which i12 study . However12 study -12 that The details of the study population and design have been described previously -20. BrieThe study was approved by the Institutional Review Board of the Keck School of Medicine of the University of Southern California and all study procedures adhered to the recommendations of the Declaration of Helsinki. Written informed consent was obtained from each study participant before interview.In-person structured interviews were conducted with participants. Next-of-kin (NOK) were interviewed when case patients were unable to be interviewed due to death or illness. Although it was not feasible to blind interviewers to case (or NOK) or control status, interviewers and study participants were not aware of the study hypotheses. A total of 947 case patients were interviewed, representing 77% of the 1230 eligible patients who were approached . Among them, 528 were matched to one control participant, 382 were matched to two or more control participants, and 37 had no eligible control participant identified. For the current analysis, data from 271 NOK case-patient interviews  were excluded to reduce misclassification of family history. We also excluded 62 case patients and 47 control participants because of extreme caloric intake  or missing information on key covariates . A total of 614 case patients  and 1,309 control participants were included in the statistical analyses.Cases and their matching controls were interviewed by the same interviewer in almost all instances. A reference date was defined as one year before the date of diagnosis of the case patient; this same reference date was used for each case patient’s matched control subject(s). A structured questionnaire designed specifically for this study was administered during the in-person interview, obtaining data up to the reference date. The interview queried demographic information, smoking history, lifetime use of all types of alcoholic beverages, usual diet, weight at ages 20 and 40 years and on the reference date (referred to as current weight), and height. To assess a participant’s medical history of a list of diseases, we asked if the participant had any of the conditions diagnosed by a physician before the reference date. Conditions of the upper gastrointestinal tract that were asked included gastric ulcer, duodenal ulcer, gastritis, hiatal or diaphragmatic hernia, esophagitis, Barrett’s esophagus, gastresophageal reflux disease, excess acid, and gastric hyperacidity.th version (ICD-9) code: any gastrointestinal (ICD-9: 150–159), esophageal (ICD-9: 150), gastric (ICD-9: 151), colorectal (ICD-9: 153–154), hepatic (ICD-9: 155), pancreas (ICD-9: 157), lung (ICD-9: 162), breast (ICD-9: 174), bone/skin/connective tissue (ICD-9: 170–173), oral/upper respiratory organ , prostate (ICD-9: 185), female reproductive organ (ICD-9: 179–184), lymphatic/hematopoietic  cancer, and cancer of unknown primary site (ICD-9: 199). Numbers of other cancers reported in these relatives were insufficient for reliable analyses. If the participant did not have any siblings, only the parents’ history was counted.In addition, we asked detailed questions regarding history of conditions of esophagus and gastrointestinal tract and history of any cancer among participants’ first-degree relatives. Specifically, each participant was asked about the vital status of his/her natural mother and father, the number of full-brothers and full-sisters, and if any of these immediate family members was ever diagnosed by a physician for gastritis, hiatal hernia, Barrett’s esophagus, any type of ulcer or cancer. If the response was yes for any of the non-malignant conditions, participants were then asked at what age was the relative first diagnosed for the condition. Age at diagnosis was unknown for 15 participants’ father, 13 participants’ mother, and 17 participants’ siblings. If the response was yes for cancer, participants were further asked about the cancer site and age at cancer diagnosis. Cancer sites were coded according to the International Classification of Diseases 9A participant was classified as having a family history of a condition if they reported at least one first-degree relative  with the condition and as having a family history of an early-onset condition if they reported at least one first-degree relative with the condition who was diagnosed before age 50 years. A family history of cancer with unknown age at diagnosis was treated as a family history of late-onset cancer, given that most cancers are diagnosed after age 50. Results were essentially unchanged with or without including subjects with a family history of cancer of unknown age at diagnosis.Odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated for associations of family history with risk of EA, GCA, and DGA. To maximize our statistical power, we report results from polytomous logistic regression with adjustment for the matching variables  includinSignificance of the interaction between family and personal history of hiatal hernia was evaluated using one degree of freedom likelihood ratio test of a product term between the two variables. We conducted these analyses separately for each type of cancer using unconditional logistic regression.All reported P values are two-sided. All statistical analyses were performed using the SAS 9.2 statistical software .Demographic characteristics of the cases and controls have been described in detail previously . ControlTable We also investigated whether family history of gastroesophageal disorders including any ulcer, gastritis, hiatal hernia, or Barrett’s esophagus was associated with risk of adenocarcinomas at the three sites, with adjustment for matching factors as well as other known risk factors of these adenocarcinomas Table . ResultsTable In this large population-based case–control study, we found site-specific associations between family history of cancer or gastroesophageal disorders and risk of EA, GCA, and DGA. Family history of cancer in the prostate was associated with an increased risk of EA; family history of esophageal cancer was associated with an increased risk of GCA; and family history of gastrointestinal cancer and particularly gastric cancer was associated with an increased risk of DGA. In addition, family history of hiatal hernia was associated with an increased risk of both EA and GCA, an effect that was more pronounced among individuals with a personal history of hiatal hernia. To our knowledge, this is the first report of an association between family history of hiatal hernia and risk of EA and GCA.The rapid increase in the incidence of EA over the past few decades in Western countries may indicate a strong contribution of environmental factors to the etiology of EA , but genWe also found an increased risk of EA among individuals with a family history of prostate cancer but lower risk among those with a family history of breast cancer and these associations did not substantially change after controlling for gender-specific sibship size. Such results were unexpected and require confirmation. Reports of associations between family history of breast or prostate cancer and risk of gastroesophageal cancer are sparse and have been inconsistent ,12,14. AEA and GCA display some similar descriptive epidemiological features  and riskH. pylori infection [H. pylori may explain the positive associations of GCA risk with family history of gastric cancer and family history of other gastrointestinal cancers, as H. pylori infection has been shown to increase the risk of not only gastric cancer, but also pancreatic cancer [H. pylori infection was not available for majority of our study participants; therefore we were unable to investigate whether history of H. pylori infection was a potential effect modifier of the association between family history of gastric cancer and risk of GCA. However, the associations between family history of these gastrointestinal cancers and increased risk of GCA may also be mediated by shared genetic susceptibilities [The observed association between family history of a gastrointestinal cancer or of gastric cancer and an increased risk of DGA could be explained by shared susceptibility to both genetic and environmental factors. Family studies ,34 have nfection . Common c cancer . Data onbilities . For exabilities ,39.Helicobacter pylori (H. pylori) infection in multivariate analyses, because serum IgG antibodies to H. pylori whole-cell antigens (Helico-G) and CagA were not measured for majority of study participants [The strengths of this study include the population-based design, relatively large sample size, separation of gastroesophageal adenocarcinoma by anatomical sites, and data on family history of cancer and non-malignant gastroesophageal disorders. Results from our study are compatible with the limited evidence to date and known etiological mechanisms of EA, GCA, and DGA. Our study also has a number of limitations. First, even though we excluded NOK interview data from our analyses, our data on family history were reported by study participants rather than by family member themselves; therefore they may be subject to recall bias, under-ascertainment of family history, and misclassification of the primary tumor site. The lack of excessive reporting of family history of esophageal cancer by cases with EA indicates that our results were most likely not affected by selective recall bias. In addition, misclassification of the primary tumor site of a relative was lessened by only collecting data on first-degree relatives . Neverthicipants . FurtherIn summary, our data suggest that family history of cancers at specific sites may be associated with risk of EA, GCA, and DGA. These associations may be mediated by shared environmental factors as well as by genetic factors. Our limited sample size warrants cautious interpretation of the observed null associations. Pooled analyses of individual studies are required for more precise quantification and more thorough investigation of the associations of family history of cancer or gastroesophageal disorders with the development of EA, GCA, and DGA.th version code; ICD-O: The international classification of disease for oncology code; NOK: Next of kin; OR: Odds ratio; SEER: Surveillance, epidemiology, and end results program.BMI: Body mass index; CI: Confidence interval; DGA: Distal gastric adenocarcinoma; EA: Esophageal adenocarcinoma; GCA: Gastric cardiac adenocarcinoma; ICD-9: The international classification of diseases 9All authors declare that they have no competing interests.XJ analyzed data, interpreted results, and drafted the manuscript; CCT provided data management support; LB was involved in obtaining funding, data acquisition, and providing critical revision of the manuscript, and AHW was involved in obtaining funding, data collection, and initiated and supervised analysis of this paper. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/60/prepubTable S2. Family history of gastroesophageal disorders and risk of esophageal and gastric adenocarcinoma adjusted for matching factors only.Family history of cancer and risk of esophageal and gastric adenocarcinoma adjusted for matching factors only. Click here for file


A recent genome-wide association study (GWAS) has identified three new breast cancer susceptibility loci at 12p11, 12q24 and 21q21 in populations of European descent. However, because of the genetic heterogeneity, it is largely unknown for the role of these loci in the breast cancer susceptibility in the populations of non-European descent.P = 0.010) and 0.84 , respectively, which was consistent with those reported in populations of European descent. Similar effects were observed between ER/PR positive and negative breast cancer for both loci. However, we did not found significant association between rs2823093 and breast cancer risk .Here, we genotyped three variants  in an independent case–control study with a total of 1792 breast cancer cases and 1867 cancer-free controls in a Chinese population. We found that rs10771399 and rs1292011 were significantly associated with risk of breast cancer with per-allele odds ratios (ORs) of 0.85 : 0.76–0.96; Our results indicate that genetic variants at 12p11 and 12q24 may also play an important role in breast cancer development in Chinese women. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women around the world, accounting for 23% of the new cancer cases and 14% of the cancer deaths in 2008 et al. carried out a large-scale genome-wide association analysis of breast cancer and further evaluated 72 promising associations in ∼70 000 cases and ∼68 000 controls from 41 case-control studies and 9 breast cancer GWAS. Three new breast cancer susceptibility loci, rs10771399 (12p11), rs1292011 (12q24) and rs2823093 (21q21), were identified in European women, and rs10771399 was also associated with breast cancer risk in Asian women et al. genotyped rs10771399 and rs1292011 in 12 599 BRCA1 and 7132 BRCA2 mutation carriers, and found that rs10771399 near PTHLH was also associated with breast cancer risk for BRCA1 mutation carriers Recently, Maya This study was approved by the institutional review board of Nanjing Medical University. The design and performance of current study involving human subjects were clearly described in a research protocol. All participants were voluntary and would complete the informed consent in written before taking part in this research.A total of 1792 breast cancer cases and 1867 cancer-free controls were included in the current study, which has been described previously Genotyping was performed using the TaqMan allelic discrimination assay on the platform of 7900HT Real-time PCR System  without knowing the subjects’ status (case or control). Two negative controls included in each 384-well reaction plate were used for quality control and the genotyping results were determined by using SDS 2.3 Allelic Discrimination Software (Applied Biosystems).2 test by comparing the observed genotype frequencies with the expected ones among the controls. Differences between the cases and the controls on the demographic characteristics, selected variables and frequencies of the genotypes were analyzed by using the Student’s t test (for continuous variables) and χ2 test . Logistic regression analyses were employed to evaluate the associations between SNPs and the risk of breast cancer and to estimate the odds ratios (ORs) and their 95% confidence intervals (CIs) with adjustment for age, age at menarche and menopausal status. The heterogeneity of associations between subgroups was assessed using the χ2-based Q-test. All of the statistical analyses were performed with Statistical Analysis System software .Hardy–Weinberg equilibrium for the distribution of each single nucleotide polymorphism (SNP) was evaluated using the goodness-of-fit χP>0.05). The breast cancer cases showed an earlier age at menarche (P<0.05), a later age at first live birth (P<0.05) and different distribution of menopausal status (P<0.05) when compared with the controls. Among the 1,792 breast cancer subjects, 803 (55.5%) cases were ER positive while 810 (56.1%) cases were PR positive.Characteristics of the 1792 breast cancer cases and the 1867 cancer-free controls are presented in P>0.05 for all SNPs). Significant associations were observed between rs10771399 at 12p11 and rs1292011 at 12q24 and breast cancer risk . The G allele of rs10771399 and the G allele of rs1292011 were associated with a decreased risk of breast cancer , which are consistent with those reported by Maya et al.The genotype distributions of the 3 SNPs in cases and controls and their associations with breast cancer risk were summarized in P for heterogeneity >0.05). Similar per-allele ORs were observed between ER/PR positive and negative breast cancer for both SNPs.We further evaluated the associations of rs10771399 and rs1292011 on breast cancer risk in subgroups stratified by age, age at menarche and first live birth, and menopausal status . As shown in et al. (OR = 0.85) et al. (OR = 0.87) et al. (OR = 0.92). These findings provided new evidence for the usefulness of the breast cancer susceptibility loci at 12p11 and 12q24 in multiple populations with various descents.In this study, we evaluated the associations of genetic variants at 12p11 (rs10771399), 12q24 (rs1292011) and 21q21 (rs2823093) with breast cancer susceptibility in an independent case–control study with 1792 breast cancer cases and 1867 controls in a Chinese population. We found that rs10771399 and rs1292011 but not rs2823093 were significantly associated with altered risk of breast cancer in our population. The OR of 0.85 for rs10771399 in this Chinese population was similar to those observed in European populations initially reported by Maya PTHLH encodes a protein that regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands, whose receptor is responsible for most cases of humoral hypercalcemia of malignancy 2>0.8) with rs10771399 based on CHB/JPT data of 1000 Genome pilot (2 = 1.0) with rs10771399. Analyses of DNase Footprinting and Position-Weight Matrix (PWM) suggest that rs788463 is in the binding sites of transcriptional factors Osf2, C/EBP and C/EBPalpha. ChIP-seq data suggests this variant located at sites of multiple histone modification marks, including H3k27me3, H3k4me1 and H3k4me2. Taken together, these evidences indicate that genetic variants at 12p11 (such as rs788463) may affect the binding sites of transcriptional factors (such as C/EBP), modify the function of regulatory elements and finally involve in the development of breast cancer. However, the potential target genes are unclear and the above statements also need to be experimentally validated in the future.Since rs10771399 was a proxy of 12p11 region, we further functionally annotated the linkage disequilibrium (LD) block containing rs10771399 using the UCSC genome browser, and found that none of known genes overlapped with this region . The neame pilot , and pre2>0.8) (2 = 0.96), implies a functional potential in effecting the combination between transcription factors and their binding site. This variant falls on a position within a footprint containing an Evi-1 and GATA-1/2/3 motifs in MCF-7 cell line and substantially affect footprinting of these motifs, resulting in allelic imbalance in chromatin accessibility. Again, these evidences are kind of bioinformatics prediction and functional experiments are warranted to validate these insights.Similarly, we also functionally annotated the LD block containing rs1292011 at 12q24  and perf2>0.8) . There aet al.et al.P<0.05 in a direction consistent with that reported previously. In terms of the inconsistence of rs2823093 in this study, one of the explanations is the genetic heterogeneity between populations that the identified SNP rs2823093 may be a good proxy of causal variants at 21q21 in population of European descent but poor in Asians. Moreover, as shown in We did not observe a significant evidence of association between rs2823093 and breast cancer risk in our study. In the study of Maya In summary, our study evaluated three new breast cancer loci in a Chinese population that were identified in populations of European descent. Our results suggest that genetic variants at 12p11 and 12q24, tagged by rs10771399 and rs1292011, respectively, may also play an important role in the susceptibility of breast cancer in Chinese women. Further studies are warranted to clarify the biological mechanisms of these two loci with breast cancer risk and determine the causal variants in breast carcinogenesis.Figure S1Overview of the LD block containing rs10771399 at 12p11 from the UCSC browser (NCBI36/hg18). A 250-kb window within upstream and downstream of the proxy SNP rs10771399 at 12p11 was annotated. Linkage disequilibrium (LD) region was generated using the HaploView 4.2 software according to HapMap II+III CHB data.(DOC)Click here for additional data file.Figure S2Overview of the LD block containing rs1292011 at 12q24 from the UCSC browser (NCBI36/hg18). A 250-kb window within upstream and downstream of the proxy SNP rs1292011 at 12q24 was annotated. Linkage disequilibrium (LD) region was generated using the HaploView 4.2 software according to HapMap II+III CHB data.(DOC)Click here for additional data file.Table S12>0.8) with rs10771399 at 12p11 based on 1000 Genome pilot CHB/JPT data and biological function scores predicted by RegulomeDB.SNPs in strong LD (r(DOC)Click here for additional data file.Table S2SNPs in strong LD (r2>0.8) with rs1292011 at 12q24 based on 1000 Genome pilot CHB/JPT data and biological function scores predicted by RegulomeDB.(DOC)Click here for additional data file.


MUC16 (CA125) and MUC1 (CA15.3) in relation to ovarian cancer risk and survival.To examine single nucleotide polymorphism (SNPs) in MUC16  and MUC1  using samples collected from 758 ovarian cancer cases and 788 controls enrolled in the New England Case-Control Study between 2003 and 2008. We calculated age-adjusted odds ratios (OR) and 95% confidence intervals (CIs) for disease risk using unconditional and polytomous logistic regression and hazard ratios (HR) for survival using Cox proportional hazard ratios. In a subset of cases, we compared log-normalized CA125 values by genotype using generalized linear models.We genotyped germline variants of MUC16 SNP, rs12984471, had poorer overall survival (log-rank p = 0.03) and higher CA125 levels, especially cases over age 65 (p = 0.01). For MUC1 SNP, rs4072037, women homozygous for the G variant had a non-significantly decreased risk for serous invasive types but elevated risk for serous borderline tumors, mucinous borderline and invasive tumors, and endometrioid tumors. Women with the variant allele of MUC16 SNP, rs2547065, especially those who were homozygous had an elevated risk for ovarian cancer; but this association was not confirmed in an independent dataset.Cases homozygous for the variant allele of MUC16 and MUC1 genes failed to identify and confirm effects on ovarian cancer risk overall. However, there may be effects of MUC16 rs12984471 on survival and MUC1 rs4072037 on risk for histologic types of ovarian cancer other than invasive serous. Further study is warranted.This targeted screen of seven polymorphisms of  The tethered human mucins (MUC) are a family of large, heavily glycosylated transmembrane proteins that have a diverse range of functions MUC16 or MUC1 and their association with ovarian cancer risk or survival. Therefore, we examined the association between a targeted set of single nucleotide polymorphisms (SNPs) in MUC16  and MUC1  in relation to ovarian cancer risk and survival.Several studies have examined genetic variation in genes involved in glycosylation of CA125 and CA15.3 and ovarian cancer risk, observing overall null associations Institutional Review Boards at Brigham and Women’s Hospital, Dana Farber Cancer Institute, and Dartmouth Medical School approved the studies and all study participants signed informed consent.Data and specimens come from the last enrollment phase of the New England Case Control Study of ovarian cancer from 2003–2008 (NECC). Details regarding case and control enrollment for this study are described elsewhere After written informed consent, demographic information, reproductive and medical history, and lifestyle factors were assessed by in-person interviews and heparinized blood samples were collected.MUC16  and MUC1  was performed using 5′ nuclease assays (Taqman®) on the Applied Biosystems Prism 7900HT Sequence Detection System . Primers, probes, and conditions for genotyping assays are available upon request. Replicates of 10% of the samples were included for quality control. Laboratory personnel were blinded to case control status and the location of quality controls.DNA was extracted and genotyping was performed at the Dana-Farber/Harvard Cancer Center (DF/HCC) High Throughput Polymorphism Core, an affiliate of the Partners Healthcare Center for Personalized Genetic Medicine. DNA was extracted from buffy coat samples using QIAmp . Genotyping of Based on preliminary data, we sought to validate one of the SNPs in an independent dataset. We used samples from 534 cases and 1513 controls from the Nurses’ Health Study cohorts (NHS/NHSII) We reviewed all medical records and computerized laboratory reports for cases who received care at Brigham and Women’s Hospital or Massachusetts General Hospital (n = 809) We used chi-square tests to assess Hardy–Weinberg Equilibrium (HWE) for each SNP among controls. Unconditional logistic regression was used to calculate overall odds ratios (OR) and 95% confidence intervals (95% CI) of ovarian cancer risk adjusted for age (continuous), study center (Massachusetts or New Hampshire), and race (white or non-white). The more common allele for each SNP served as the reference group in the regression models. Co-dominant (heterozygous vs. wild type or homozygous variant vs. wild type), recessive (homozygous variant vs. heterozygous and wild type), and per allele (trend test) models were computed. Multivariate regression models were additionally adjusted for family history of ovarian or early onset breast cancer and a personal history of breast cancer.Polytomous logistic regression was used to calculate OR (95%CI) for risk of various histological subtypes adjusted for age, study center, and race. Likelihood ratio tests were used to test for heterogeneity across histologic categories  comparing a model that allows the estimate of the association to vary by histologic type to a model that restricts to one estimate of the association for all histologic types.Cox proportional hazard models (HR) were used to examine the association between each polymorphism and survival, adjusting for study center and race and in a secondary model for stage (I-IV) and histology . Co-dominant, recessive, and per allele models were used as described in supplemental methods . The KapMUC16 polymorphism. Statistical analyses used general linear regression, adjusted for age, race, and time between CA125 measurement and diagnosis , using continuous log transformed CA125 levels and a variable that represents increasing variant alleles for each polymorphism . CA125 levels can vary during the menstrual cycle, and levels vary between pre and postmenopausal women Geometric mean CA125 values by genotype were calculated for each A total of 758 women with ovarian cancer and 788 controls were included in the final analytic sample . For botMUC16 polymorphisms was associated with ovarian cancer risk (MUC16 polymorphisms.All seven polymorphisms were in Hardy-Weinberg equilibrium and had genotyping success greater than 95% except for rs2547065 (93%). In general the minor allele frequencies (MAF) we found for our controls were comparable to that of the Caucasian European (CEU) HapMap populations (data not shown). In the NECC study, one of the four cer risk . For polMUC1, none of the polymorphisms we tested were significantly associated with overall ovarian cancer risk in the per allele model. Women carrying two copies of the MUC1 polymorphism rs2070803 variant had an increased risk of serous invasive cancer of borderline statistical significance  in the recessive model. Although we observed no significant risk associated with MUC1 polymorphism rs4072037 overall, significant heterogeneity by histology was observed when evaluating the recessive model for this polymorphism (p-heterogeneity = 0.02). Women homozygous for the G variant of rs4072023 had a non-significantly decreased risk for invasive serous cancers but elevated risks for serous borderline tumors , mucinous borderline and invasive , and endometrioid tumors . Adjusting for family history of ovarian or early onset breast cancer and personal history of breast cancer did not change estimates for any of the MUC1 or MUC16 polymorphisms.For MUC16 polymorphism rs12984471  and lowest for homozygous variants (110.0) (p = 0.03). Among elderly postmenopausal women, increasing variant alleles of polymorphism rs12984471 were significantly associated with increasing levels of CA125 (p = 0.02).Finally, we evaluated the association between ratively . Among aMUC1 gene is located on 1q21–22, which is a region frequently altered in both neoplastic and non-neoplastic disorders. MUC1 gene amplification due to increased gene copy number has been observed in ovarian, breast, papillary thyroid, and gastric cancers MUC1 SNPs we studied were selected based on previous publications that studied associations between MUC1 polymorphisms and gastrointestinal cancers MUC1 gene in a large LD block, and polymorphism rs1045253 was previously identified as a tagSNP representative of the MUC1 region The MUC16 gene is located at 19p13, which is altered in a variety of cancers, especially ovarian. In ovarian carcinoma, 19p13 has been identified as the chromosome band most frequently involved in structural rearrangement MUC16 gene. The minor alleles of rs12984471 and rs1559168 introduce missense mutations while rs2121133 is within an intron MUC16 polymorphisms studied, we observed associations between rs2547065 and ovarian cancer risk and between rs12984471 and survival.The MUC16 variants including rs2547065, Bouanene et al. observed that the CC genotype was more frequent in cases (49%) than in controls (34%), similar in direction to what we observed but not significant in their study which included only 41 cases and 76 controls In a small study that examined two MUC16 polymorphism rs12984471 was the only SNP associated with survival. The variant allele, which conferred poorer survival among all cases, also was correlated with high CA125 serum levels in postmenopausal women, especially those over the age of 65. The possibility that the association between rs12984471 and survival may have a biologic basis is suggested by possible functional consequences on MUC16 protein. Polymorphism rs12984471 is located in the largely uncharacterized extracellular subunit where the C variant is responsible for a conservative missense mutation changing a glutamate to an aspartate MUC16 gene product as suggested by its effects on CA125 levels in cases.MUC16 (CA125) and three SNPs in MUC1 (CA15.3) in relation to ovarian cancer risk and survival in the New England Case-Control study. One of four MUC16 SNPs, rs2547065, was associated with increased risk for ovarian cancer. A different MUC16 SNP, rs12984471, was associated with survival and also correlated with serum levels of CA125. Of the three MUC1 SNPs studied, we found one, rs4072037, which displayed significant heterogeneity by histologic type. We had the opportunity to examine one of these findings, rs2547065 with increased risk, in data from the Nurse’s Health Study. The finding was not validated raising the issue of chance in explaining our findings. However, the association of rs12984471 in MUC16 with survival has some biologic support in that it is also correlated with CA125 levels. Since our study population is composed of primarily Caucasian women, we were not able to generalize our results to other ethnicities. Our study should not be considered definitive because we targeted SNPs as opposed to conducting a comprehensive gene or genome wide investigation. Evaluation of a broader set of tagging SNPs is planned in the Ovarian Cancer Association Consortium.In conclusion, our study examined four SNPs in Methods S1Supplementary methods on age and histologic type classification, statistical models, and SNP selection and genotyping.(DOCX)Click here for additional data file.


MPO). Association of the low transcription activity variant allele A in the G463A polymorphism has been investigated for its association with breast cancer risk, considering the modifying effects of menopausal status and antioxidant intake levels of cases and controls.Breast cancer susceptibility may be modulated partly through polymorphisms in oxidative enzymes, one of which is myeloperoxidase  in contrast to their post-menopausal counterparts which showed non-significant increased risk . High intake of antioxidants  and carotenoids  conferred significant protection in the women. Stratified by menopausal status, this effect was observed in pre-menopausal women especially those whose antioxidant intake was high . In post-menopausal women, effect of low intake elicited susceptibility  to breast cancer.To obtain a more precise estimate of association using the odds ratio (OR), we performed a meta-analysis of 2,975 cases and 3,427 controls from three published articles of Caucasian populations living in the United States. Heterogeneity among studies was tested and sensitivity analysis was applied. The lower transcriptional activity MPO G463A polymorphism places post-menopausal women at risk for breast cancer, where this effect is modified by diet.Based on a homogeneous Caucasian population, the  MPO-containing neutrophils are elevated in breast secretions as well as breast tissue with and without cancer MPO is involved in DNA adduct formation through activation of heterocyclic amines to form chemically-reactive reactive oxygen species (ROS) in mammary epithelial cells MPO activity who consumes low antioxidants sources are likely to have increased levels of oxidative stress Myeloperoxidase (MPO) is a microbicidal enzyme secreted by reactive neutrophils at the sites of inflamed organs and tissues during the phagocytosis. Upon activation MPO catalyze the formation of powerful oxidants such as hypochlorous acid, which kills microbes. Levels of G) to adenosine (A) nucleotide substitution, −G463A (rs2333227), located 463 bp upstream of transcription start site of MPO is found to have impact on the consensus transcription factor binding sites −463G allele (frequency: ∼77%) were found to elevate MPO transcriptional activity, via promoting SP1 transcription factor binding whereas the minor −463A allele (frequency: ∼23%) was shown to confer ∼25 times lower transcriptional activation, leading to less inflammatory potential −463G allele has been associated with increased MPO activity in several diseases A allele which is associated with lower levels of polycyclic aromatic hydrocarbons MPO-G463A with breast cancer development although discrepancies exist.A guanosine  polymorphism was also included given its 100% genotype concordance in Caucasians (http://snp500cancer.nci.nih.gov) with G463A polymorphism. Thus, the final number of studies included in the meta-analysis was three MPO G463A polymorphism.MPO-G463A polymorphism in pre-menopausal and post-menopausal women. There were three subgroups in our meta-analysis that involved the diet variable. One, genotypic data from the antioxidant subgroup were based on consumption of the combination of fruits and vegetables which were categorized as low and high. Two, genotypic data from the vitamin/carotenoid subgroup were based on low and high intake of vitamins C, E and carotenoids. Three, we investigated the level of antioxidant consumption patterns in menopausal women. In all analyses, the probability of differential risk associations between pre-menopausal and post-menopausal women as well as high and low consumption levels warranted testing for presence of interactions.In the main analysis, we sought effects of the 2 test, we evaluated deviation of the genotypic frequencies of control subjects from the Hardy-Weinberg equilibrium (HWE). While controls in Ahn et alet alUsing the χhttp://www.psycho.uni-dueldorf.de/aap/projects/gpower), Review Manager  and SigmaStat 2.03.All three studies AA versus GG). We also examined the heterozygous genotype with low versus medium+high activity (AA versus GA+GG) as well as low+medium versus high activity (AA+GA versus GG). These contrasts correspond to recessive and dominant effects of the variant A allele, respectively. Finally, we estimated OR of the variant A allele frequency assuming the risk could differ across all three genotypes (co-dominant genetic model) We estimated OR and 95% CI of breast cancer associated with variant low activity compared with common high activity using the homozygous model  and pre-menopausal  groups came from three MPO activity [AA] genotype were at non-significantly increased risk under homozygous and recessive models   (Here we investigated the breast cancer risk associated with  = 0.35) . Under t = 0.03) .et al study Removing the Ahn AA genotype women  who consumed high levels of fruits-vegetables . Separate analyses of fruits only and vegetables only yielded similar results (data not shown). Likewise, similar results were seen in such women with high levels of carotenoid intake . Separate analyses of vitamins C and E yielded similar but non-significant results (data not shown).AA genotype were protected from breast cancer risk, non-significant in post-menopausal  but significant in pre-menopausal  women. The pre-menopausal findings, however, came from just one study with a sample size of 350 AA genotype were associated with increased risk in all genetic models . Increased risk, however, was not evident in pre-menopausal women with low antioxidant intake.2 = 0%). However, none of the tests of interaction between pre-menopausal and post-menopausal women as well as between low and high consumption in the subgroup analyses were significant after the Bonferroni correction treatment  had none (Ireatment .AA genotype were associated with non-significantly increased breast cancer risk (up to 1.1-fold) whereas the risk associated with pre-menopausal women who carried the low activity AA genotype was significantly protective (up to 44%). The altered breast cancer risk observed by menopausal status may be partly explained by the differences in age and levels of estrogen production between pre-menopausal and post-menopausal women MPO activity levels by influencing gene expression, monocyte number, or degree of MPO release, potentially altering serum levels MPO levels during the menstrual cycle MPO expression according to genotype Our analysis has demonstrated that post-menopausal women carrying the low activity MPO-G463A polymorphism regardless of the menopausal status and ethnic background heterogeneity = 0.10–0.78) and (c) a substantial number of cases and controls were pooled from the studies, which significantly increased the statistical power of the analysis.A recent meta-analysis MPO genotype and breast cancer risk is consumption of fruits and vegetables. It has been shown that post-menopausal women with reduced levels of MPO activity who consume low antioxidants are likely to have increased levels of oxidative stress MPO genotype were found to be associated with statistically significant protective risk when they consumed high level of antioxidants. The analysis of antioxidant effects in pre-menopausal women have shown statistically significant protective effects  in all genetic models with high consumption of antioxidants, although these findings are based on one study. The relatively small sample size, particularly in the pre-menopausal group, may increase the likelihood of Type I error meriting caution regarding interpretation of its outcomes. The antioxidant intake data from two studies An important modifier in the relationship between MPO-G463A polymorphism in concert with the variants of other antioxidant enzymes, including catechol-O-methyltransferase (COMT) NOS3) heme-oxygenase-1 (HO-1) and catalase (CAT) COMT and MPO was marginally protective . In addition, the CAT-MPO combination may greatly decrease the hazard of death from breast cancer The modifying influences of diet, age and menopausal status are best considered in context of other genes in the oxidative stress pathway. Two studies in our analysis investigated the AA genotype of MPO-G463A polymorphism. The non-significantly increased risk associated with post-menopausal women became highly significant when they consumed low levels of antioxidants. On the other hand, pre-menopausal women with the same lower activity genotype were at protective risk, which became more protective when they used high levels of antioxidants. Our findings suggest the role of estrogens which were shown to impact on the MPO activity. Future studies with larger sample sizes particularly among pre-menopausal women may shed light on complexities of the many pathways involved in oxidative stress and breast cancer development, providing hypotheses for future functional studies.Our meta-analysis implicates that menopausal status and intake of antioxidants modified the risk associated with breast cancer risk of women who carried the low activity


The benefit of mammography is overestimated among UK women, although the National Health Service (NHS) offers comprehensive information about breast screening with its official pamphlet. This study examined how women in the UK construct their views of mammography and how they interpret the information in the NHS pamphlets and newspaper articles about breast screening.Focus groups and individual interviews with 11 female participants aged 26–58 were conducted using a baseline questionnaire.Many participants possessed knowledge about mammography, which differed from the medical consensus. Various factors, including self-beliefs, experience of breast cancer or being screened with a mammogram and stories from friends and relatives, could influence the participant’s view about breast screening with a mammogram. Sceptical attitudes towards the media description of breast screening issues were revealed. The participants felt that the NHS pamphlets offered enough information about breast screening.The women in this study showed that people may not be surrounded by the practical information sources to know about mammogram efficacy until they are invited to the breast screening. In order to achieve democratic discussion over breast screening, including mammography, the NHS and mass media have room for further cooperation to provide the full picture of breast screening to the public. The NHS Breast Screening Programme (NHS BSP), which invites women aged between 50 and 70 to breast screening three yearly, has improved its breast cancer detection rate since foundation . It has et al [Many countries where a breast screening programme is organized offer official pamphlets covering a range of information about mammography . Neverthet al  shows thet al . This iset al .The 2003 report of the House of Lords Select Committee on Science and Technology, while admitting the importance of the media role in communicating science to the public, noted scientists’ dissatisfaction with media portrayal of scientific issues . One recThe UK Chief Medical Officer (CMO) stresses that members of the public are encouraged to be committed to the debate of health care issues rather than just consume what the authorities have decided . A qualiThe purpose of this study was to explore how members of the public in the UK, especially in the Cardiff area, construct their views of mammography, in order to address whether they are surrounded by practical information sources. Furthermore, this study sought to look in to how the participants perceive the information about mammography from both the NHS and the media, as they are important information bases for public engagement in the breast screening debate.This study used a qualitative research method in order to explore how the participants had constructed their perception of mammography. A focus group method was adopted as the main strategy as this method allows participants to feel more comfortable and express their real perspectives . Two groWomen over the age of 20 were recruited in the Cardiff area by distributing handouts at some shops and cancer charity offices as well as by using the electronic notice board system of Cardiff University computer network. Seventeen women were contacted through the University’s notice board, and 11 women aged between 26 and 58 actually participated in either focus groups or individual interviews at Cardiff University during November and December 2007. For women who had not been screened with a mammogram, one focus group with three participants and three individual interviews were carried out. Another focus group and three individual interviews were conducted for women who had been screened with a mammogram before.There was one participant who had a family history of breast cancer in each group. Three women who did not have a mammogram experience, and one woman who had a mammogram experience, had friends affected by breast cancer. There were two participants who had had breast cancer in the group of women with a mammogram experience. One participant had not been screened with a mammogram although her age was over 50.et al [At the beginning of the focus group or individual interview, participants were asked to fill out a baseline questionnaire. This questionnaire aimed to assess participants’ basic awareness of breast screening with a mammogram. et al .The actual interviews started by asking the following introductory questions: (1) What do you think about breast cancer? (2) What do you consider as risk factors of contracting breast cancer? and (3) What is mammography to you? After these introductory questions, the participants were asked about: (4) influential factors or information sources in constructing their views of mammography or in deciding to take a mammogram. On interviewing the participants, the influential factors or information sources were divided into the following four categories: (a) media coverage, (b) friends and relatives, (c) medical experts and (d) other factors or information sources. The participants were also asked to give the information content they obtained from those sources.Daily Mail [Daily Telegraph and contained an article headlined ‘Breast screening for under-50s questioned’ [In the last part of each session, the participants were asked to express their views on reading the information on mammography from the following two sources: (5) the NHS BSP pamphlets, and (6) two types of newspaper coverage. One of the pamphlets was named ‘Breast Screening: A Pocket Guide’, and the other was entitled ‘Breast Screening: The Facts’ , which wily Mail . The secstioned’  and one stioned’ .Each conversation from focus groups and individual interviews was transcribed and analysed carefully along with the questionnaire results and the field notes created through the sessions.A.For Question 1, asking ‘Who do you think the NHS Breast Screening Programme invites to the screening?’, all the participants answered that women over the age of 50 are invited to the NHS BSP.Question 2—‘Why do you think the NHS set the standard as you stated?’—saw eight participants suggest that women aver the age of 50 were most at risk of contracting breast cancer so the NHS invited this age group. Two women with a mammogram experience answered that cost-effectiveness was also attributable to the age criteria that NHS had set. One participant did not know the reason.Answers to Questions 3–6 are summarized in For the outcome of Question 3, four women without a mammogram experience answered ‘don’t know’. In the group of women with a mammogram experience, two participants chose the answer ‘don’t know’ and the other three participants selected overestimated answers.With regard to Question 4, three women without a mammogram experience answered ‘don’t know’, and two women in this group selected the correct answer. Four women with a mammogram experience picked overestimated answers.As to Question 5, no participants chose the answer ‘don’t know’. Three participants of each group gave overestimated answers. Three women without a mammogram experience and two women with a mammogram experience selected the correct answer.For the answers to Question 6, five participants mentioned self-examination as an important breast examination method. Three participants answered that they did not know whether mammography is most effective. One participant confided that mammography was the most effective breast screening method.B.(1)Five participants conceptualized breast cancer as a terrifying disease. Three participants answered that if tumours are caught early enough, there may be various treatments available. The other three participants were not worried about contracting breast cancer.(2)All the participants gave genetics as a risk factor of contracting breast cancer. Diet was also suggested by six participants. Being post-menopausal was given by two women with a mammogram experience. Four women associated smoking as one risk factor of contracting breast cancer.(3)In a group of women who had not been screened with a mammogram, four participants insisted how uncomfortable a mammogram procedure would be. Of a group of women who had been screened with a mammogram, three participants expressed that the benefit of mammography outweighed the discomfort of the procedure.(4)(a)No participants could recall any specific media coverage of mammography. Two women without a mammogram experience had seen the coverage about the NHS BSP, but the report was not specifically about mammography. One woman stated that she possibly had been influenced by the media coverage from ‘Let’s go for the screening’ point of view. Four women expressed doubt as to whether the mass media could be a reliable source for information about mammography.‘I would get an idea, but I would look at it further, I wouldn’t take it as a face value’. (Participant no. 8)‘(Media coverage) is a short term thing’. (Participant no. 11)(b)Six women possessed experience of having conversations about mammography with their friends or relatives. Four of them without a mammogram experience stated that the conversation was about the feeling of those friends or relatives on taking their mammogram. Another participant stated that her friend whose tumour was found by a mammogram, had strongly influenced on her view that mammography is very important. One woman over the age of 50, who had not been to the NHS BSP before, denied her friend’s influence over her, as she herself believed that the mammogram procedure is not friendly to women.‘I’m assured when I speak to someone who agrees with me, but most people don’t agree with me, so I could hardly be influenced’. (Participant no. 4)(c)There was only one participant who had an experience of having conversation about mammography with her general practitioner (GP) before being invited or having any breast problem. Three women took a mammogram because their symptoms were found by their GPs. In addition, two participants implied people’s dependence on GPs or medical experts to find out abnormalities in their bodies. Also, two women stated that they would visit their GPs if they had any concern about breast cancer.(d)As to other useful sources of information about mammography, four women suggested the internet as available in their daily lives, and three participants considered medical journals as practical. The other three participants regarded cancer charities as useful since those charities offered members of the public the information about breast cancer or detecting methods in a more familiar way. Two women with a mammogram experience stated that they had referred to pamphlets of the NHS BSP on taking their mammograms.During the interviews, many participants revealed that they had not considered mammography until the time of this study’s sessions, an invitation to the NHS BSP, or an encounter with breast cancer.‘I wouldn’t have thought anything about it (mammography) at all until the letter came inviting me for the screening’. (Participant no. 8)(5)Participants revealed their own impression on reading two types of NHS pamphlets. Most participants admitted that the NHS pamphlets offered enough information. They also suggested that there was an appropriate amount of figures in the pamphlets.‘It’s not patronising. It’s not offensive. It’s not frightening. It’s just all the facts. It’s clearly explained’. (Participant no. 2)‘It is informative. There’s not a lot in there that it’s missed’. (Participant no.9)Some participants appreciated that the NHS offered a subsidiary booklet explaining about the NHS BSP without scientific figures.‘That (the Facts) is very good one for someone who isn’t gonna read a lot of stuff’. (Participant no.11)However, one woman without a mammogram experience considered that the pamphlets did not cover enough information about the method of mammography itself. In addition, some women gave comments that the pamphlet portrayal of the information could be more reassuring and less confusing.‘Lots of statistics. I’d like to see a pie chart rather than all these figures’. (Participant no. 4)‘Ninety-five per cent as normal of those we (the NHS) called. It would be better if they said 5% or the numbers about these abnormalities. Don’t fudge it up’. (Participant no. 8)(6)Daily Mail, seven participants showed their confusion or dissatisfaction regarding what was described in the article.Reading an article from the ‘Scaremongering. They can’t get the facts right from one single article’. (Participant no. 1)‘I’ve got the impression that mammography is bad’. (Participant no. 5)‘I really don’t know what to think about’. (Participant no. 6)Two women without a mammogram experience stated that people would consider the words ‘breast scans’ of the title as ‘mammograms’.‘I tend to flick through papers. If I read “breast scans may cause cancer in high-risk women”, I would equate that mammograms cause cancer in high-risk women’. (Participant no. 3)Daily Telegraph coverage also left the participants with some confusion and dissatisfaction. Especially, one sentence: ‘Even though screening at a younger age caused 17% drop in breast cancer mortality, the result was not statistically significant’ seemed to catch the attention of many participants.The ‘I would have to read the Lancet or whatever to get the real picture’. (Participant no. 4)‘Who wrote this? Who is questioning the significant 17% drop in mortality?’ (Participant no. 6)Most participants showed a sceptical attitude about news media itself.‘The papers, they always take a negative view and blow it up’. (Participant no. 4)‘I certainly don’t believe everything I read in the newspaper’. (Participant no. 9)It has been suggested that women tend to overvalue how effective mammography would be ,6,12. ByOver half of participants accepted the idea that mammography could prevent or reduce the risk of contracting breast cancer, despite the fact that mammography could be only a method of breast cancer screening. In addition, most participants persisted that self-awareness is significant as a method of breast screening. It is ironic that although they were aware of the importance of self-awareness to screen breast cancer, they did not understand the true sense of mammography as a breast cancer screening method.The interview sessions explored what kind of factors had influenced the participant’s view of mammography. The participants remembered media coverage of breast screening or conversations about mammography with their friends, but neither information sources were practical for the participants to know about mammogram efficacy. Women with a mammogram experience tended to have had an interaction with their GP in the process of finding their breast problems. Nevertheless, these interactions happened in order only to make a referral for screening with a mammogram so that those participants never talked about the efficacy of mammography with their GP at that time.Members of the public basically possess high trust in health authorities to have the best knowledge of medicine . Many paOnly women being invited to the NHS BSP had had an opportunity to read the official pamphlet about breast screening. Furthermore, some participants stated that mammography was not an issue they would consider unless they were faced with a particular occasion, such as having breast problems or being invited to the NHS BSP. It might be suggested that women in this study were not surrounded by enough opportunities, unless they had been invited to the breast screening, to know about the efficacy of mammography.Achieving a clear understanding of breast screening among the general public is a common issue faced by all health organizations . Most woMass media, when dealing with health issues, can exaggerate risk in order to make profit . In factIn this study, both the results from the questionnaire and interviews may indicate that there was not enough information provided for the participants to understand the efficacy of mammography. Considering the CMO’s suggestion that the public should be committed to health care debates , the parIn this study, there were two participants who had a strong personal opinion about either mammography itself or her taking a mammogram. In these cases, those two women tended to have been persistent in their own opinions over any information about mammography. Further research could explore the influence of those personal beliefs on participants’ attitudes towards obtaining the information about mammogram efficacy. Therefore, it would be able to suggest how and to what extent health authorities should intervene with those people to increase their understanding about the efficacy of mammography.In this study, it was not possible to assess whether holding a science degree led to the participants’ appropriate knowledge about the efficacy of mammography. Furthermore, 11 participants had limited demographic and sociodemographic backgrounds, including the fact that they were from Cardiff University, an academic institution. Quantitative research with participants from various demographic and/or sociodemographic backgrounds may offer different outcomes or further support to generalize this study result.


Few studies have investigated the association between body mass index (BMI) and breast cancer with consideration to estrogen/progesterone/human epidermal growth factor type 2 receptor status (ER/PR/HER2) in the breast tissue among Chinese pre- and post-menopausal women.Four thousand two hundred and eleven breast cancer patients were selected randomly from seven geographic regions of China from 1999 to 2008. Demographic data, risk factors, pathologic features, and biological receptor status of cases were collected from the medical charts. Chi-square test, fisher exact test, rank-correlation analysis, and multivariate logistic regression model were adopted to explore whether BMI differed according to biological receptor status in pre- and post-menopausal women.s BMI, PR+r = 0.867, P = 0.001; s BMI, HER2+r = 0.636, P = 0.048), but the ER+ rates did not vary by increasing BMI. Controlling for confounding factors, multivariate logistic regression models with BMI<24 kg/m2 as the reference group were performed and found that BMI≥24 kg/m2 was only positively correlated with PR+ status among post-menopausal breast cancer cases .Three thousand two hundred and eighty one eligible cases with BMI data were included. No statistically significant differences in demographic characteristics were found between the cases with BMI data and those without. In the rank-correlation analysis, the rates of PR+ and HER2+ were positively correlated with increasing BMI among post-menopausal women (2) have a higher proportion of PR+ breast cancer. In addition to effects mediated via the estrogen metabolism pathway, high BMI might increase the risk of breast cancer by other routes, which should be examined further in future etiological mechanism studies.Post-menopausal women with high BMI (≥24 kg/m Between 2003 and 2007, it was the 6Obesity is a well-known risk factor for breast cancer development The expression of ER, PR, and human epidermal growth factor type 2 receptor (HER2) is considered to be crucial in determining prognosis and therapeutic decision making The aim of the present study is to explore if breast cancer subtypes defined by ER, PR, and HER2 status differ according to BMI, also taking menopausal status into account, among Chinese women, thereby providing clues for further study of the etiological mechanisms of breast cancer. This study is based on the Nationwide Multicenter 10-year (1999–2008) Retrospective Clinical Epidemiological Study of Breast Cancer in China led by the Cancer Institute/Hospital, Chinese Academy of Medical Sciences (CICAMS) The study protocol was approved by the Institutional Review Board of the Cancer Foundation of China. The institutional review board obtained written consent from participating hospitals to access patient medical records. As it was a retrospective design, some data subjects were deceased, and it was impossible to contact with the patients or their relatives, so the Cancer Foundation of China waived the need for written informed consent from the participants.A nationwide multicenter clinical epidemiological study of female breast cancer over 10 years was conducted within China. All proposed data were collected retrospectively from the existing medical charts from year 1999 to 2008.Hospital selection and case sampling procedures have been previously described elsewhere in detail 2); family history of breast cancer was defined as breast cancer occurrence among the first-degree genetic relatives ; positive breastfeeding status indicated the patients had a more than 6-month breastfeeding experience.A case report form was designed to collect information from each enrolled patient’s chart regarding general information, demographic characteristics, breast cancer risk factors, breast clinical examination results, diagnostic imaging, treatment process, and pathological characteristics. Breast cancer risk factors included hormone-mediated factors  and non-hormone-mediated factors (family history of breast cancer), which were measured at or soon after diagnosis of breast cancer. Among them, BMI was calculated as weight (kg) divided by height squared  and PR positivity (PR+) were defined as at least 10% of tumor cells showing positive nuclear staining of any intensity. Samples not meeting this criteria were defined as negative (ER−/PR−) 2 was defined as normal, while BMI≥24 kg/m2 was defined as overweight in the present study.In view of the differences in BMIs among Chinese population, Western populations, and other Asian populations, we classified categories of BMI based on the Chinese adult BMI classification which was made by China Obesity Task Force and was generally accepted. P = 0.05 and P = 0.10) among pre- and post-menopausal women, with BMI<24 as the reference group. All statistical analyses were performed using SPSS 17.0 software with a two-tailed significance level of 0.05.The demographic characteristics of cases with and without BMI information were compared by ANOVA or chi-square test. The differences of the proportion of risk factors  and pathological characteristics  were tested by chi-squared test (or Fisher’s exact test where appropriate) between the BMI<24 group and BMI≥24 group among pre- and post-menopausal women, respectively. The relationships between BMI and ER/PR/HER2 positivity were drawn and tested by rank-correlation analysis in all, pre-, and post-menopausal cases. Taking confounding variables of other risk factors and pathological characteristics into consider, the adjusted odds ratios (ORs) and 95% confidence intervals (CI) for the relationship between BMI and ER/PR/HER2 status were estimated by the forward stepwise multiple logistic regression models  were selected for the original retrospective study from out of 45,200 cases seen at the 7 hospitals from 1999 to 2008. Nine hundred and thirty cases were excluded due to missing information regarding height. Ultimately, 3,281 cases (48.73±10.35 years old) with complete information were included in the analysis. .χ2 = 0.438, P = 0.995). We therefore considered the 3,281 cases with BMI information representative of the Chinese breast cancer population.In our study, the distribution of demographic characteristics for the 3,281 cases with BMI data and the 930 cases missing BMI data were similar. No statistical differences were observed with respect to age at diagnosis, menopausal status, and marital status between the two groups . Though 2 = χ28.606, P<0.001). A greater proportion of women with BMI<24 were nulliparous, did not have a history of breast feeding, or had a family history of breast cancer than women with BMI≥24. Compared with the BMI<24 group, women who delivered their first child at or after 30 years of age accounted for a higher proportion of the BMI≥24 group. Among the pre-menopausal cases, a higher percentage of women with BMI<24 reported late childbirth (first delivery ≥30 years old), nulliparity, and non-lactation than those with BMI≥24. However, no significant difference in rates of breast cancer family history was seen between the BMI<24 group and the BMI≥24 group. By contrast, the results from the post-menopausal cases showed no statistical differences in age at diagnosis and age at menopause between two BMI groups. However, a lower proportion of the cases with BMI<24 reported late childbirth (first delivery≥30 years old) and nulliparity than those with BMI≥24. There was no statistical difference in breast feeding history between the two BMI groups.  than pre-menopausal women (34.7%) . These findings are shown in Among all cases, statistically significant differences were found in the distribution of pathological characteristics including invasive ductal carcinoma (IDC), HER2 status alone, and combined ER&PR&HER2 status between the BMI<24 and BMI≥24 groups. Among the pre-menopausal cases, we did not observe any statistically significant differences between the pathological characteristics of the two BMI groups. However, among the BMI≥24 subgroup of the post-menopausal cases, the proportions of PR+, as well as HER2- cases were significantly higher than among the BMI<24 group. This finding could explain the fact that after combining the status of receptors, the proportions of ER(+/−)&PR+ and ER+/PR+&HER2− cases were also statistically higher in the BMI≥24 group than that in the BMI<24 group. Moreover, there were more cases with PR+ status among the post-menopausal women than among the pre-menopausal women , but the percentage of ER+ and HER2+ cases did not correlate with increasing BMI. Among pre-menopausal women, no relationship was observed between the expression of ER/PR/HER2 and BMI, whereas the percentage of both PR+ and HER2+ cases were positively correlated with BMI among post-menopausal women . The proportion of ER+ cases did not vary with increasing BMI in post-menopausal women. . As well, the proportions of ER+&PR+ and ER−&PR+ cases were higher in the BMI≥24 group compared with the BMI<24 group among post-menopausal women. No relationship was observed between HER2 status and BMI among the entire cohort or among pre- and post-menopausal cases in the multivariate analysis.   According to surveillance data for chronic diseases from 162 areas of 31 provinces in China, 30.6% of the Chinese population has been classified as overweight (BMI≥24 kg/m2) and PR+ status in breast tissue among the post-menopausal cases by both univariate analysis and multivariate analysis. However, elevated BMI was not related to ER+ breast cancer among post-menopausal women nor ER+/PR+ breast cancer among pre-menopausal women. These results are consistent with findings from Japan Multiple studies seeking to evaluate the molecular basis behind these relationships have found that the association between obesity and breast cancer risk varies by menopausal status, and may be attributable to the status of ER and PR in breast tissues With regards to HER2 status, biological studies have suggested that the status of HER2 could antagonize the expression of hormone receptor As the different trends of ER+/PR+/HER2+ breast cancers among heavily obese patients were apparent in Obesity has been shown to be a poor prognostic factor in post-menopausal patients already diagnosed with breast cancer This study has potential limitations. First, due to the original study design, there was no comparison group of normal healthy women with whom to compare the risk factors for developing breast cancer. Case-case analysis was not possible to explore the risk factors for cancer but we were able to describe the difference between breast tumor subtypes. Second, data quality was dependent on the thoroughness of the clinician’s documentation and some cases were missing risk factor information, especially regarding history of smoking, alcohol use, and oral contraceptive use, which could have interactions with BMI. Third, poor accessibility of Fluorescence in situ hybridization (FISH) analysis for HER2 in some of the study hospitals resulted in missing values and may account for the inability to detect significant differences for HER2 expression between different BMI groups in multivariate analysis. Fourth, the Waist-Hip Ratio (WHR) is considered a superior index for evaluating central obesity, which is common among post-menopausal women. However no information was collected regarding waist circumference and hip circumference for the breast cancer patients in the study. Nevertheless, BMI remains a useful tool and recent studies from Japan and America have begun to focus on evaluating the association of BMI gain from a younger age and the risk of breast cancer onset 2), there was an increased proportion of PR+ breast cancer. However, the proportion of ER+ cases did not vary with increasing BMI in post-menopausal women. In addition to effects mediated by the estrogen metabolism pathway, high BMI might also increase the risk of developing breast cancer via other routes, which should be further evaluated in future etiological mechanism studies.In summary, the results of this study showed that among post-menopausal Chinese women with elevated BMI (BMI≥24 kg/m