The most cited barrier was the complexity of preparation for colonoscopy.Breast cancer survivors are at risk of developing a second primary cancer. Colorectal cancer (CRC) is one of the leading second primary cancers, and it is often preventable. We developed a multi-component educational tool to inform and encourage women breast cancer survivors to engage in CRC screening. To assess the strengths and weakness of the tool and to improve the relevancy to the target audience, we convened four focus groups of women breast cancer survivors in Missouri. We also assessed the potential impact of the tool on the knowledge, attitudes, and beliefs regarding CRC and collected information on the barriers to CRC screening through pre- and post-focus groups’ questionnaires. A total of 43 women breast cancer survivors participated and provided very valuable suggestions on design and content to update the tool. Through the process and comparing pre- and post-focus group assessments, a significantly higher proportion of breast cancer survivors strongly agreed or agreed that CRC is preventable (78.6%  The literature review found statistically significant increased risks in 11 studies ranging from 9% to 40% [et al. found approximately 12.3% of female breast cancer survivors experience a second primary cancer and this risk varied by age (11.7% diagnosed with breast cancer before age 50 and 17% diagnosed at or after age 50) and cancer type [Breast cancer survivors, at almost 3 million, comprise the largest group of cancer survivors recorded in surveillance databases in the United States . There hcer type ,14,15,16Colorectal cancer is one of the three most commonly occurring cancers for women (after breast cancer and lung cancer) and men (after prostate cancer and lung cancer) in the United States . It is ai.e., precursor lesions to cancer) and reducing colon cancer incidence and mortality [A review of the evidence from well conducted clinical trials and other studies support the effectiveness of the different screening modalities in detecting polyps  with colonoscopy being the most commonly used screening test (61.7%) [In 2012, about two-thirds (65.1%) of the U.S. adult population 50 to 75 years of age met the U.S. Preventive Services Task Force (USPSTF) guideline for colorectal cancer (CRC) screening ( (61.7%) . In 2013 (61.7%) . Several (61.7%) ,38,39,40 (61.7%) . In addi (61.7%) . The priPower of Prevention, includes: targeted physician recommendation letter, evidence-based decision aid booklet with stage-of-change assessment, and DVD video. A physician letter was drafted to include CRC burden statistics, the benefits of screening, the problem of the lack of adherence to screening guidelines, and recommendation for colonoscopy. The decision aid booklet presents an overview of colorectal cancer, information on colonoscopy, the various CRC screening modalities, and overall health improvement. It also addresses identified barriers to CRC screening, including lack of knowledge, perception of good health, fear of the test, embarrassment, and unpleasantness of preparing for a colonoscopy. The “Get Tested for Colon Cancer. Here’s How” DVD is included with permission from the American Cancer Society (ACS).Through the collaborative efforts of a multi-disciplinary group of researchers and scientists and a systematic literature review, the CRC educational intervention concept was formed to focus on female breast cancer survivors. A review for effective strategies to improve CRC screening showed that a physician recommendation is a strong predictor of CRC screening. In addition, when developing a multi-level intervention, including such elements as video, targeted brochure, provider reminder, and small media/decision aids also increase CRC screening . The edui.e., susceptibility and severity) together with the perceived benefits of the proposed behavior (pros), barriers (cons), self-efficacy, and cues to action will predict the likelihood of that behavior. The Health Belief Model provided the basis for the risk-benefit assessment. The Transtheoretical Model premise is that people are at different stages of motivational readiness for engaging in health behaviors and this framework serves as the basis for assessing and evaluating the impact of the intervention on increasing readiness to complete a colonoscopy. For this study the definitions of stage of screening are defined as: precontemplation, never had an FOBT/fecal immunochemical test (FIT), sigmoidoscopy/air contrast barium enema (ACBE) or colonoscopy or last FOBT/FIT was more than a year ago, last sigmoidoscopy/ACBE more than five years ago, or last colonoscopy more than 10 years ago; Contemplation, never had or last colonoscopy was more than 10 years ago but giving considerable thought to having a colonoscopy; Action: FOBT/FIT was within the last year, sigmoidoscopy/ACBE within the past five years or colonoscopy was within the past 10 years. While colonoscopy is the primary endpoint for the main study, completion of any CRC-recommended screening modality will contribute to increasing the CRC screening rate and provides the opportunity for early detection.There are many psychosocial aspects involved in the potential diagnosis of CRC and screening that vary by individual, can be test-specific, and long-term or transient. This study explored the psychosocial aspects of CRC and screening based on theoretical constructs. Theories help explain the health preventive patterns of people  through the psychosocial aspects of attitudes ; beliefs ; and barriers  among other social, demographic, and cost factors . The HeaPower of Prevention for breast cancer survivors, a series of four focus groups were held in Missouri, one in each of four cities—Columbia, Jefferson City, Kansas City, and Chesterfield (St. Louis County). The focus group participants were recruited from breast cancer support groups in the four areas and conducted between 13 April and 4 August 2011. A mixed-method design was used to gather information from breast cancer survivors. The focus groups were conducted using a standardized discussion protocol. The discussion protocol included a welcome and introduction with information on the process for the focus group, conveyed the goal of improving the educational tool and assessment questions. The protocol assessed four areas pertaining to the tool: content, packaging, barriers and overall assessment of increased understanding of colorectal cancer screening and motivation to complete colonoscopy. Participants were encouraged to share any other comments or suggestions at the conclusion of the structured questions. The participants were also asked to complete seven-item pre- and post-focus group discussion surveys regarding attitudes, beliefs and practices regarding CRC screening and a 10-point Likert scale on deciding to have a colonoscopy, and a five-item feedback assessment regarding the overall focus group meeting. The survey instruments were comprised of validated questions from previous research on CRC screening [Five breast cancer survivorship groups were identified via internet searches and referrals from colleagues and the local office of the ACS. All five groups were invited to participate through telephone contact with the group coordinators or presenting the study to the group, and four groups accepted (80%). To target the creening , behaviocreening , and expData were analyzed using IBM SPSS Statistics v20  and Qualitative Data Analysis (QDA) Minor v3.2 . Fisher’s Exact test and the Chi Square test were used to compare the changes in knowledge, attitudes, and beliefs before and after the process. The qualitative analysis framework was designed in collaboration with the Alliance oncology nursing committee and included in the protocol. The analysis was conducted with word and themes coded from the meeting notes to align with the protocol categories. The Missouri Department of Health and Senior Services Institutional Review Board reviewed and determined the study to be exempt.i.e., some college or college graduate) (69.8%), and were covered by health insurance (93.0%). The largest proportion of participants were from Columbia  followed by Jefferson City , Kansas City , and St. Louis .The focus groups included a total of 43 women breast cancer survivors including 10 (23.3%) African-American women . The majreal” women on the cover; that the language and tone were appropriate, but there were some terms that should be defined. Three groups also stated the length of the booklet was “just about right”. One group felt the length was “a little long”. However, many participants indicated or provided additional information to be added. The ACS DVD resonated well with the focus groups and three groups suggested connecting the tool to the ACS theme of more “birthdays”. Two of the groups thought the DVD should include younger-looking “50ish” people or include people at varying ages.Overall, all four of the groups liked the multi-component feature of the tool, the color scheme , the pink ribbon logo, the layout, and spiral binding . All foup = 0.02) . In terms of the health beliefs, perceived susceptibility or perceived risk of developing CRC increased with the majority of breast cancer survivors believing they had a slightly higher chance of getting CRC. There was also a significant increase in knowledge that CRC is preventable. A large proportion of the breast cancer survivors reported having had a colonoscopy in the past 10 years (76.7%), FOBT/FIT in the past year (18.6%), and sigmoidoscopy/ACBE in the past five years (9.3%) and were in the action phase according to the Transtheoretical Model; however, there were some women who had not had any CRC screening (18.6%) and were considered in the precontemplation or contemplation phase of CRC screening. The main reasons cited for wanting to have a colonoscopy or perceived benefits was to find polyps early and to detect colon cancer. The primary reason for not wanting to have a colonoscopy or perceived barriers on both the pre- and post-assessments was the involvedness of the preparation . Not being recommended by a doctor, financial considerations, and concern about discomfort were also cited as barriers. There was an increase in the stage-of-change scale on deciding to have a colonoscopy from a mean pre-score of 8.13 to a mean post-score of 8.52 indicating many were between contemplation and action in deciding to have a colonoscopy, but this change was not significant (p = 0.713). The psychosocial aspect of fear declined following the focus group discussion on the post-assessment.All of the female breast cancer survivors (N = 43) returned the pre-assessment questionnaire prior to the focus group; however, due to the short timeframe, fewer women (N = 29) returned the post-assessment questionnaire. Nevertheless, a significantly higher proportion of female breast cancer survivors on the post-assessment strongly agreed or agreed that colon cancer is preventable   and becaLearning about increased risk for colon cancer with breast cancer”; “Booklet and DVD compliment”; “Missouri is taking action about this issue”; and “You are convincing people not to be afraid of a colonoscopy”. Most women thought the content was “very easy” (70%) or “fairly easy” (27.5%) to understand  responded that the discussion was useful  and include: FOBT or FIT every year; or stool deoxyribonucleic acid (DNA) test every 3 years; or flexible sigmoidoscopy (FSIG) or double-contrast barium enema (DCBE), or computed tomographic colonography (CTC) every 5 years; or colonoscopy every 10 years . SeveralSmoking, excessive alcohol intake, obesity, physical inactivity and not eating healthy also increase the risk for CRC ,57,58,59i.e., those that stress the benefits of the activity for promoting screening); (2) having a colonoscopy is very or extremely important; and (3) the majority agreed or strongly agreed that colon cancer is preventable. Many breast cancer survivors indicated that they had previously or would engage in CRC screening with increased knowledge and support from their health care provider. The most frequent barrier cited to having a colonoscopy was the preparation required and this suggested the need for alternative methods for preparing for the test or other non-invasive screening tests that meet or exceed the standards set by colonoscopy. Based on the information from these focus groups, the educational tool has been updated and redesigned to increase the relevance to target female breast cancer survivors. While the findings of this study were used to enhance this specific tool, these findings have broader primary and secondary prevention implications and provide insights for future behavioral interventions for this population.Overall, the focus group participants were receptive to education on CRC screening and liked the multi-dimensional components of the educational tool. The participants provided invaluable information and suggestions to make the intervention more relevant to breast cancer survivors such as expressing recognition for being a cancer survivor early in the material. Over-arching themes included: (1) the preference for gain-framed messages (


RECQL2 lead to Werner syndrome, a rare autosomal disease associated with premature aging and an increased susceptibility to multiple cancer types. We analyzed the association of two coding single-nucleotide polymorphisms in WRN, Cys1367Arg (rs1346044), and Arg834Cys (rs3087425), with the risk, age at onset, and clinical subclasses of breast cancer in a hospital-based case-control study of an Austrian population of 272 breast cancer patients and 254 controls. Here we report that the rare homozygous CC genotype of rs1346044 was associated with an approximately two-fold elevated breast cancer risk. Moreover, patients with the CC genotype exhibited a significantly increased risk of developing breast cancer under the age of 55 in both recessive and log-additive genetic models. CC patients developed breast cancer at a mean age of 55.2 ± 13.3 years and TT patients at 60.2 ± 14.7 years. Consistently, the risk of breast cancer was increased in pre-menopausal patients in the recessive model. These findings suggest that the CC genotype of WRN rs1346044 may contribute to an increased risk and a premature onset of breast cancer.Like other RECQ helicases, WRN/RECQL2 plays a crucial role in DNA replication and the maintenance of genome stability. Inactivating mutations in  RECQL2 gene product might play a role in cancer, including breast cancer [Breast cancer is the most common cancer of women and the exploration of its causes and the biological complexity of this disease is an issue of public health importance ,2. Takint cancer .RECQL2 belongs to the RECQ helicase gene family and plays a key role in DNA replication, recombination, telomere preservation, and repair [d repair ,5,6,7. Td repair . Therefod repair .RECQL2 give rise to Werner syndrome , a rare autosomal recessive genetic disorder [RECQL2 with missense mutations being extremely rare [RECQL2, was shown to be associated with a reduced WRN helicase activity, while two common SNPs of RECQL2, Leu1074Phe, and Cys1367Arg, exhibited essentially wild-type-level helicase and exonuclease activities [Mutations in human disorder ,11. WS idisorder ,11,12,13disorder . WS is tely rare , perhapsely rare . The rartivities .In cancer research, rs1346044 leading to the non-conservative Cys1367Arg substitution has been a focus of attention ,19,20. IRECQL2, the common rs1346044 (Cys1367Arg) and the rare rs3087425 (Arg834Cys) are associated with the risk, age at onset, and clinical subclasses of breast cancer in Austrian women in a hospital-based case-control study. Our data suggest a critical impact of rs1346044 on breast cancer biology in the investigated Austrian population.We were therefore interested to determine whether two coding polymorphisms in RECQL2 were investigated in a hospital-based case-control study. SNP rs3087425 (Arg834Cys) located in the helicase domain was successfully genotyped in 269 breast cancer patients and 249 female controls, which all exhibited the common homozygote genotype . This SNP was thus non-polymorphic in our study population, precluding any further analyses. SNP rs1346044 (Cys1367Arg) in exon 34 was successfully genotyped in 526 individuals (272 patients and 254 controls). The minor allele frequency was 28.1% in patients and 24.6% in control subjects. Both the controls (p = 0.18) and the patients (p = 0.96) were in Hardy-Weinberg equilibrium. p = 0.005; see also p = 0.084; see next section results, below). The lymph node status was equally distributed for all genotypes (Two single nucleotide polymorphisms (SNPs) in enotypes .Next, odds ratios and 95% confidence intervals were determined to assess the breast cancer risk associated with the different rs1346044 genotypes, and with the C and T alleles. These comparisons showed non-significantly increased odds ratios between 1.08 and 1.91 . Since op = 0.116), whereas the odds ratio adjusted for age was 2.26  compared to the common homozygotes (TT), 2.05  compared to the heterozygote (TC), and 2.18  compared to TT and TC combined  under a dominant genetic model, 2.76  under a recessive genetic model, and 1.58  under a log-additive genetic model. Thus, rs1346044 was significantly associated with an increased breast cancer risk in patients under 55 years based on recessive and log-additive genetic models and almost reached statistical significance based on a dominant model  based on a dominant genetic model, and almost reached statistical significance based on a log-additive model  under a recessive model , which may, at least in part, be due to the small number of CC patients. TC patients exhibited an intermediate mean age at onset  in recessive and log-additive inheritance models . MoreoveRECQL2 gene with breast cancer risk. The Arg834Cys SNP is located in the helicase domain of WRN, and the rare Cys variant was shown to exhibit a dramatic reduction of both helicase and exonuclease activities [i.e., Western European) ancestry (269 breast cancer patients and 249 controls), and did not find a single Cys allele.Here we explored the potential association of two single-nucleotide polymorphisms of the tivities . The Cystivities . In the p = 0.116), whereas the odds ratio adjusted for age was 2.26 . Moreover, we show for the first time an association of the C allele with an increased fraction of patients developing breast cancer at an age younger than 55. Consistently, pre-menopausal patients had a 3.21-fold increased risk of breast cancer in the recessive inheritance model . Since the age at onset this seems to affect the odds ratios associated with Cys1367Arg, we calculated odds ratios adjusted for age in addition to the crude (unadjusted) odds ratios, which increased the magnitude of the observed effects . For exaRECQL2 gene is situated in chromosomal region 8p11–12, which contains one or more breast cancer tumor-suppressor genes [RECQL2 is a RECQ DNA helicase that plays a key role in the maintenance of genome stability . Germlinor genes . RECQL2 or genes .RECQL2 Cys1367Arg appears to be associated with an increased risk of several age-associated disorders, such as myocardial infarction, diabetes mellitus type-2, and osteoporosis [RECQL2 polymorphisms with breast cancer. A significant association of the minor allele of Cys1367Arg with familial breast cancer  and high-risk familial breast cancer  was found in a German study [Epidemiological and functional and analyses have focused on Cys1367Arg, which is located in the COOH-terminal binding domain for TP53 and BRCA1 ,24,25. Roporosis ,27,28, ian study . Howeveran study . TogetheRECQL2 Cys1367Arg and breast cancer, we performed a study in Austrian women of exclusively European ancestry. Our findings add a new yet unidentified potential role of this variant in breast cancer. We found that Cys1367Arg was significantly associated with an increased risk of developing breast cancer at an age younger than 55 years, based on recessive  and log-additive  genetic models  under a recessive model. These patients overlap to a large extent with the patients under the age of 55. In addition, we identified a significant association of the 1367Arg variant with pT2–pT4 tumors (tumor diameter >2 cm).To further evaluate a possible association between c models . Moreovec models . HoweverIt has been suggested that the tumorigenic contribution of variant WRN in breast cancer could be increased due to accelerated cell growth caused by estrogen . HoweverRECQL2 could function as a tumor suppressor gene and polymorphisms in RECQL2 may disrupt this function in breast cancer. In line with this, we observed in our study an approximately twofold risk of breast cancer associated with the CC genotype of rs1346044, which was more pronounced when odds ratios adjusted for age were analyzed  following the manufacturer’s instructions. Genotyping of SNP rs1346044  located in exon 34 near the C-terminus of RECQL2 protein and rs3087425  located in the central helicase domain was performed by TaqMan PCR with allele-specific, fluorescently labeled probes following the manufacturer’s instructions . 40 ng of genomic DNA in a total reaction volume of 10 µL were used.p-values were calculated by the mid-p exact method. Following a previous recommendation, we did not adjust the results of our subgroup analyses in p-values shown are two-sided. p < 0.05 was considered significant.Statistical analyses were performed with R version 2.15.1 . Chi-squEpidemiological analyses of the RECQL2 Cys1367Arg are hampered by the rarity of the disease-associated homozygous CC (Arg/Arg) genotype representing only 4.3% of the controls in the present study. Accordingly, many of our findings in the present study attained only borderline significance. However, despite minor limitations in the present study, such as a hospital-based study design, restriction to a limited population, and limited statistical power, our results provide new support for an impact of Cys1367Arg on the putative function of RECQL2 as a breast cancer tumor suppressor. Our results suggest that the rare homozygous CC (Arg/Arg) genotype is associated with an increased risk and early onset of breast cancer. In contrast, this substitution was not significantly associated with breast cancer risk in subpopulations other than premenopausal patients and patients younger than 55 years at onset. Further epidemiological studies and/or meta-analyses with larger, ethnically-diverse populations as well as functional evaluation of the RECQL2 Cys1367Arg polymorphism are warranted to further address these questions.


FGFR2) as a candidate gene for breast cancer with single nucleotide polymorphisms (SNPs) located in intron 2 region as the susceptibility loci strongly associated with the risk. However, replicate studies have often failed to extrapolate the association to diverse ethnic regions. This hints towards the existing heterogeneity among different populations, arising due to differential linkage disequilibrium (LD) structures and frequencies of SNPs within the associated regions of the genome. It is therefore important to revisit the previously linked candidates in varied population groups to unravel the extent of heterogeneity. In an attempt to investigate the role of FGFR2 polymorphisms in susceptibility to the risk of breast cancer among North Indian women, we genotyped rs2981582, rs1219648, rs2981578 and rs7895676 polymorphisms in 368 breast cancer patients and 484 healthy controls by Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) assay. We observed a statistically significant association with breast cancer risk for all the four genetic variants (P<0.05). In per-allele model for rs2981582, rs1219648, rs7895676 and in dominant model for rs2981578, association remained significant after bonferroni correction (P<0.0125). On performing stratified analysis, significant correlations with various clinicopathological as well as environmental and lifestyle characteristics were observed. It was evident that rs1219648 and rs2981578 interacted with exogenous hormone use and advanced clinical stage III , respectively. Furthermore, combined analysis on these four loci revealed that compared to women with 0–1 risk loci, those with 2–4 risk loci had increased risk . In haplotype analysis, for rs2981578, rs2981582 and rs1219648, risk haplotype (GTG) was associated with a significantly increased risk compared to the common (ACA) haplotype . Our results suggest that intron 2 SNPs of FGFR2 may contribute to genetic susceptibility of breast cancer in North India population.Genome-Wide Association Studies (GWAS) have identified Fibroblast growth factor receptor 2 ( Worldwide, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality among women BRCA1, BRCA2) account for less than 25% of the familial breast cancer risk, and less than 5% of the overall risk Breast carcinogenesis involves a complex combination of genetic, environmental as well as lifestyle factors. Inherited susceptibility makes an important contribution to breast cancer development and the risk is around two times more in first degree relatives of women with the disease FGFR2 gene, is located at chromosome 10q26, and contains 22 exons FGFR2 to be associated with breast cancer risk, rs2981582 and rs1219648 were the most strongly associated marker SNPs in the two studies respectively FGFR2Fibroblast Growth Factor Receptor 2 (FGFR2) belongs to the FGFR family of tyrosine kinase receptors and contributes to the process of tumorigenesis through cell growth, invasiveness, motility and angiogenesis FGFR2 intron 2 polymorphisms  on sporadic breast cancer and determined their association with the risk for North Indian women in a case control approach, including combined effect of these variants, LD structure measurement, haplotype analysis, as well as relation with patients' clinical, environmental and lifestyle characteristics. We observed significant association of these variants with breast cancer susceptibility for North Indian women.Wide variations in genetic architecture, including differential allele frequencies of SNPs and differently evolved LD structure for the GWAS-identified genetic variants reflect differences among ethnicities and may contribute to disparities in the incidence and characteristics of breast cancer. Thus, variants identified in one study may not have the same impact on risk in other populations. Therefore, there is a need to replicate previously associated loci in multiple populations worldwide. This will help in determining the genetic heterogeneity among different population groups for these loci, particularly in India, which witnesses a rapidly rising breast cancer burden but relatively fewer studies to identify the common breast cancer associated variations. Such studies will assist in evaluating the generalizability of initial findings and to identify the causal variants. Therefore, we tried to assess the impact of The study was approved by Institution Ethics Committee of All India Institute of Medical Sciences (AIIMS), New Delhi and the Institutional Human Ethical Committee of Jamia Millia Islamia, New Delhi. All the participants provided their written informed consent to be included in the study.This hospital-based case control study included a total of 852 genetically unrelated women subjects of North Indian ethnicity comprising 368 sporadic breast cancer cases and 484 healthy controls. Controls were frequency- matched to cases on age (±2 years) and geographical location. The study participation response rates for cases and controls were 88.46% and 81.07%, respectively. All breast cancer cases (aged 24–80 years) were newly diagnosed, histopathologically confirmed with primary breast cancer and were recruited from the Department of Surgical Oncology, AIIMS. Classification of breast cancer has been done according to TNM staging system by American Joint Committee on Cancer (AJCC) and Nottingham grading system for histological grading. Exclusion criteria included in the study were reported previous cancer history, metastasized cancer from other organs and previous exposure to radiotherapy or chemotherapy.2), geographical location, education level and economic independence (employed/unemployed)].Detailed information on clinical profiles for cases and controls were collected from their medical records and are presented in Participating women provided 3–5 ml of venous blood samples used for isolating genomic DNA based on standard phenol–chloroform extraction method FGFR2 SNPs showing association with breast cancer in one or more GWAS and candidate gene studies including the two proposed functional variants  Previously reported P<0.05 was considered statistically significant. Further, all P-values were corrected for multiple comparisons according to Bonferroni method. LD pattern and population haplotype frequencies for the SNPs were estimated using HaploView v4.2 To compare the overall distribution of genotypes between patients and healthy controls 3×2 Chi-square (χ2) test was performed. Hardy–Weinberg equilibrium (HWE) was evaluated by a goodness-of-fit χ2 test. For estimating associations between individual genotypes and breast cancer risk, and for cumulative risk analysis, odds ratios (ORs) and their 95% confidence intervals (CIs) were computed using unconditional logistic regression analysis with adjustment for age. One-way ANOVA  was carried out for estimating the contribution of different number of risk loci to breast cancer risk. These statistical analysis were performed using Statistical Package for the Social Sciences, version 17  and FGFR2 intronic variants  were available from 368 breast cancer cases/484 healthy controls and a notably significant association with breast cancer susceptibility was observed.Results of genotype analysis on the four selected P>0.05) with Hardy–Weinberg equilibrium in both cases  and controls  for the SNPs rs2981582, rs1219648, rs2981578 and rs7895676 respectively.The observed genotype frequencies were found to be in agreement . Logistic regression analysis (age adjusted) further confirmed this association which remained significant in per-allele model for rs2981582/T, rs1219648/G, rs7895676/C and in dominant model for rs2981578 (AG+GG) even after Bonferroni correction (P<0.0125).Distribution of genotype and allele frequencies of the four P = 0.006) compared to those with 0–1 risk loci. Further a progressively increased risk was noted from 1 risk loci  to 2 risk loci  to 3–4 risk loci  in comparison to 0 risk loci (P<0.05) differences in the contribution of various risk loci to diseased condition for the four SNPs taken together as well as in different combinations , and BCD . On conducting multiple comparison analysis in ANOVA, similar trends were observed (P = 0.026) and 4 risk loci (P = 0.002) compared to 0 risk loci. Also for the four different SNP combinations, significant P values for all the risk loci were observed for combination BCD . For determining the contribution of different risk loci overall as well as in four different trio combinations of these SNPs, logistic regression and one-way ANOVA tests were performed . Logistiisk loci . ANOVA dobserved . SignifiP value cut-off after bonferroni correction was set as (P<0.000694).Further we analyzed association of these variants with various clinicopathological characteristics including several reproductive and environmental risk factors of breast cancer in a stratified analytical approach  The corrrs2981582(C/T)/FGFR2, genotype CT vs. CC (vs.  =  in comparison to) and combined CT+TT vs. CC significantly correlated with premenopausal status . T allele displayed stronger association with ER-positive women  and with PR-positive women . Association with histologically less malignant grade I+II , early age at menarche  and employed status  was also observed.For rs1219648 (A/G)/FGFR2, AG genotype presented a significantly higher distribution in premenopausal patients exhibiting higher risk . Furthermore, G-carriers were more significantly linked to tumors with ER-positive status , LN positive status , and more malignant histological grade III . Also, interaction of the risk allele with positive breastfeeding status  and strongly with exogenous hormone exposure  was noted.For rs2981578 (A/G)/FGFR2, G allele carriers were more likely to bear tumors of greater aggressiveness with advanced clinical stage III+IV  and LN metastasis . Association with late age at menarche  and parous status  was also observed.For rs7895676 (T/C)/FGFR2, TC genotype exhibited significantly greater risk in PR-positive women . Further association of the risk allele with LN-positive status , pathologically less malignant grade I+II tumors  and with negative breastfeeding status  was evidenced.For 2 ≥0.80, D′ = 1, in control group of our study population, the four studied SNPs were found to be in moderate to weak LD . However, contrary to the combined risk analysis, predominant contribution towards the risk in terms of higher odds ratio was observed for trio combinations ABC  and ACD . However, SNP combination BCD , seems to be relevant as pair wise D′>0.80 for these three SNPs (P = 0.008). While among duo SNP combinations, AC (rs7895676 and rs2981582) displayed highest odds ratio , Setting measure of high LD between two genetic markers cut off to a value rree SNPs  and carrFGFR2 were all significantly associated with increased breast cancer risk. Recent identification of these intron 2 SNPs FGFR2 as a candidate gene for breast cancer. At present, much effort is focussed into targeting additional genetic alterations that drive breast cancer and FGFR2 which has been implicated in different types of human malignancies, including breast cancer In this case–control study of sporadic breast cancer in North Indian women we found that the variant genotypes rs2981582C/T, rs1219648A/G, rs2981578A/G and rs7895676T/C of FGFR2 variant with breast cancer, as was observed in Europeans and other Asian populations Since a previous report from South India FGFR2 and it has been shown that haplotype marked by this allele associates with a higher level of FGFR2 transcription both in breast cancer cell lines and tumors FGFR2 variants contribute to breast cancer and confer their effect primarily in ER-positive and PR-positive tumor subtypes Present study reports significant association of rs2981582 and rs1219648 with breast cancer, consistent with previous observations from two Asian studies by Liang et al. For rs1219648, we observed a strong association of G allele with more invasive tumors with higher chance of LN metastasis, consistent with a previous report from China FGFR2 variants to ER-positive and PR-positive tumors suggests that these SNPs affect the reproductive hormone-related pathway in the development of breast cancer in North Indian women. But these observations need to be confirmed in larger sample size studies from our population.Breast cancer tends to be diagnosed at an earlier age in developing countries than in European and American populations and a rapid rate of increase in incidence has been observed before menopause FGFR2 SNPs rs2981578 and rs7895676 within intron 2 region alter the DNA binding affinity of transcription factors octamer-binding transcription factor 1 (Oct-1)/runt-related transcription factor 2 (Runx2) and CCAAT/enhancer binding protein β (C/EBPβ) respectively, resulting in an increased FGFR2 gene expression both in cell lines and in breast tissues in patients homozygous for the risk allele as compared to those homozygous for the wild type allele Recently done analysis by Meyer et al. have shown that two P<0.000694), while other clinical features lost statistical significance, suggesting the importance of these SNPs in sub-categorized breast cancers in our population. But these observations need to be confirmed in further studies with larger sample size, to rule out false positive results and to establish intron 2 FGFR2 SNPs as breast cancer susceptibility loci.Association with exogenous hormone exposure and higher stage for SNPs rs1219648 and rs2981578 respectively, achieved statistical significance even after Bonferroni correction . Moreover a progressively augmented risk with increasing number of risk loci was also noted demonstrating that a combination of these variants cumulatively increases risk . In haplFGFR2 variants taken together along with LD measurement, haplotype analysis and stratified analysis for possible correlation with patients' clinical parameters in susceptibility to breast cancer.To the best of our knowledge, we are reporting for the first time, a case control study on these four intronic FGFR2 variants in intronic region suggests the probable explanation for their association with the risk through differential expression. Aberrant expression of alternatively spliced isoforms of FGFR2 has been shown to activate signal transduction leading to transformation in breast cancer cells FGFR2 in relation to intron 2 SNPs has been supported by the analysis carried out by Meyer et al. FGFR2 intron 2 shows a high degree of conservation in mammals, and number of conserved putative transcription-factor binding sites have been identified in it FGFR2 upregulation remains unclear.Location of these FGFR2 could be targeted in search for newer and efficient biomarkers in the future. Several altered FGFR2 characteristics have been linked with breast tumorigenesis and have shown promising results in studies on breast cancer cell lines and tumors, like amplification and overexpression, mutations, alternative splicing and isoform switching Besides SNPs, other features of FGFR2 intron 2 SNPs with breast cancer risk, as well as their interaction with various clinical parameters revealing their contribution to breast cancer susceptibility among North Indian women. Although, findings of the present study by themselves are unlikely to have any immediate clinical implications, however, such studies may play a key role in elucidating the biological mechanism that underline breast tumor heterogeneity, which may ultimately lead to improved treatment and prevention. These findings suggest that genetic variants of FGFR2 might be used as candidate potential biomarkers for breast cancer risk. Further epidemiological and experimental studies of larger data sets along with sub-categorization by clinical parameters and expression studies are warranted to explore and confirm the role of these variants in increasing breast cancer risk, particularly from India, that will help us better understand the genetic heterogeneity in complex diseases like breast cancer.In conclusion, our study revealed a significant association of Figure S12 value} of the four intronic Linkage disequilibrium analysis {a) D′ value and b) rFGFR2 SNPs in the studied population of North India.(TIF)Click here for additional data file.Table S1Clinical, lifestyle and other demographic details of cases (N = 368) and controls (N = 484) in the present study.(DOC)Click here for additional data file.Table S2Details of the SNPs selected for present study.(DOC)Click here for additional data file.Table S3Distribution of risk loci for the studied FGFR2 SNPs  in cases and controls of North India.(DOC)Click here for additional data file.Table S4One Way ANOVA for relative risk assessment of different number of risk loci for the studied FGFR2 SNP combinations.(DOC)Click here for additional data file.Table S5Frequencies of inferred haplotypes of various FGFR2 SNPs combinations taken two at a time in breast cancer cases and controls.(DOC)Click here for additional data file.


We aimed to estimate the effect of alcohol consumption on breast cancer risk and to test whether overweight and obesity modifies this association.We included in the analysis 45,233 women enrolled in the Swedish Women’s Lifestyle and Health study between 1991 and 1992. Participants were followed for occurrence of breast cancer and death until December 2009. Poisson regression models were used, and analyses were done for overall breast cancer and for estrogen receptor positive or negative  and progesterone receptor positive and negative  tumors separately.A total of 1,385 breast cancer cases were ascertained during the follow-up period. Overall, we found no statistically significant association between alcohol intake and breast cancer risk after adjustment for confounding, with an estimated relative risk (RR) of 1.01 (95 % CI: 0.98–1.04) for an increment in alcohol consumption of 5 g/day. A statistically significant elevated breast cancer risk associated with higher alcohol consumption was found only among women with BMI ≤25 .2.An increase in breast cancer risk with higher alcohol consumption was found for breast cancers in women with a BMI ≤25 kg/m The International Agency for Research on Cancer (IARC) has classified alcohol as a human carcinogen  which inSeveral mechanisms have been proposed to explain this association  increasiWe hypothesized that if alcohol and obesity compete via a similar mechanism to increase risk of postmenopausal breast cancer, then these two exposures may not be additive. We further hypothesized that the possible association between these exposures and breast cancer may pertain chiefly or exclusively to hormone receptor positive cancers. We tested our hypotheses in a large prospective study in Sweden.http://ki.se/en/meb/womens-lifestyle-and-health). Details of the study design have been described elsewhere [n = 68), emigration without re-immigration (n = 67), previous breast cancer diagnosis (n = 273), and uninterpretable answers to questionnaire (n = 2). We further excluded 3,652 women with any missing value on selected key covariates . The final analytic cohort consisted of 45,233 women. Participants were asked to report the number of glasses of beer, wine, and spirits that she currently drank per week, per month, or per year on the baseline questionnaire. On the follow-up questionnaire, consumption frequency and the amount of consumption on one occasion for low alcohol beer, beer, white wine, red wine, dessert wine, and spirits were asked. Body mass index was calculated by using the present height and weight reported on the baseline questionnaire.The study cohort comprised participants of the Swedish Women’s Lifestyle and Health (WLH) study  and progesterone receptor (PR) status of breast tumor was obtained from the regional register. Incident invasive breast cancer (ICD7 170) was ascertained from the Swedish cancer register from 1st September 1992 when the regional breast cancer register in Uppsala was set up, up to 31st December 2009. The Swedish Data Inspection Board and the regional Ethical Committee, Uppsala University, Uppsala, Sweden and the Ethical Committee of the Karolinska Institutet in Stockholm, Sweden approved the study protocol. All participants signed an informed consent form.We analyzed breast cancer risk associated with alcohol consumption using Poisson regression. This was done with alcohol intake modeled without any predefined shape, with step-function using alcohol categories and also as linear continuous form. To evaluate the functional form between alcohol intake and breast cancer incidence, we estimated the relative risk (RR) using splines, i.e. log (cancer rate) = h  where h  is an arbitrarily shaped curve. We fitted all models adjusting for age and for other possible confounding variables. Poisson regression is commonly used in survival analysis and gives approximately the same parameter estimates and likelihood ratios as Cox proportional hazards regression when the length of follow-up is split into finer intervals  , 13.The details for the calculation of total alcohol intake have been described previously . Briefly2 and >25 kg/m2). Age at menopause and the use of hormone replacement therapy (HRT) were both analyzed as time varying variables using the combined 1991 and 2003 follow-up data. Thus, women’s menopausal status and HRT use could change along the follow-up period. Participants were censored when death or immigration occurred after entry into the cohort, or at 31st December 2009, whichever came first. The RR of breast cancer comparing different groups of exposure and change in RR by level of modifying covariates was estimated together with associated two-sided 95 % confidence intervals.We assessed the following potential confounding covariates: educational attainment , history of breast cancer in mother and/or sister(s) (Yes/No), smoking habits , physical activity at enrollment with five grade scale, age at menarche (years), menopausal status (Yes/No), time varying parity at baseline , age at the first child birth (years), breast feeding duration (month), and oral contraceptive use (current/former/never). Age at the first birth was modeled using, for nulliparous women, zero and for parous women extracting the average age at the first birth from the age at the first birth. Self-reported BMI was categorized into two groups  and alcohol intake . We calculated RR for breast cancer comparing each combination of alcohol and BMI versus low BMI and an alcohol intake of 0 g/day. In the same model we tested the statistical hypothesis of no interaction using a likelihood ratio test.All statistical tests were two-sided with α= 0.05. All models for overall breast cancer were repeated for ER+/PR+, ER+/PR-, and ER-/PR- breast cancers separately. We did not separately analyze the ER-/PR+ tumors owing to the small number.2 was highest among non-drinking women. In addition, the alcohol intake was higher among women with BMI ≤25 kg/m2 . During the follow-up period, a total of 1,385 breast cancer cases were ascertained. Among them, 718 tumors were ER+/ and PR +, 196 were ER+/PR-, 187 were ER -/PR- and 37 were ER-/PR+. Table Baseline characteristics of study participants are presented in Table 2 , but not among women with BMI over 25 kg/m2. Similar patterns were observed for all subtypes of breast cancer, but statistical tests for interaction were significant only for ER-/PR- breast cancer (p = 0.04) .2. It suggests that alcohol and obesity may not act as an additive manner on the breast cancer risk among pre-menopausal women. We also observed statistically significant effect modification of alcohol by body mass index on ER-/PR- breast cancer risk.After multivariable adjustment we did not observe a statistically significant risk of breast cancer in the combined group of lean and overweight women. However, we found that high intake of alcohol was associated with an increase in overall breast cancer risk only among women with BMI ≤25 kg/m2 in EPIC and <22.5 kg/m2 in NHANES). In the California Teachers Study Cohort, normal weight or marginally overweight women (BMI < 27.3 kg/m2) whose alcohol consumption level was ≥ 20 g/day showed 40 % higher risk for breast cancer compared with nondrinking normal weight or marginally overweight women (95 % CI 1.10–1.80) [Three cohort studies reported similar results –17. In b10–1.80) . The RR 10–1.80) , 19. In 10–1.80) .2 vs. 31.7 nmol/L for >27.5 kg/m2) than by alcohol consumption level (51.1 nmol/L for non-drinker vs. 43.7 nmol/L for ≥ 16 g/day). We postulate that obese women whose SHBG level is already decreased may be less affected by alcohol intake.Alcohol and obesity probably share common biological mechanisms in breast carcinogenesis through circulating sex hormone levels. Both alcohol consumption and obesity measures (BMI and waist-hip ratio) were associated with circulating hormones, especially SHBG in a cross-sectional study . The varPrevious epidemiological studies reported associations between alcohol consumption and ER+ breast tumors, whereas weak or null associations were observed for ER- tumors . The strStrengths of our study include its prospective design, which minimizes potential for recall bias. Potential confounders of the association between alcohol consumption and breast cancer risk, such as family history of breast cancer, were adjusted for in the multivariate model. Breast cancer ascertainment by linkage to the registries ensures virtually complete follow-up. In addition, information on hormone receptor status was available for most of breast cancer patients with relatively high completeness. Another strength is the age structure of the cohort, since few cohort studies aimed to include predominantly premenopausal women .Limitation of the study includes that information on alcohol consumption was assessed at baseline and follow-up surveys and may not accurately reflect long- term consumption habit. Analysis by hormone receptor status may lack statistical power due to small numbers of cases in each exposure groups.2. The competing effects of obesity and alcohol consumption on circulating sex hormone levels may explain the results.In conclusion, an increase in breast cancer risk with higher alcohol consumption was found for all breast cancers only among women with a BMI ≤25 kg/m


Studies suggest that higher breast cancer rates in urban areas persist after accounting for the prevalence of known risk factors, leading to speculation that urban environmental exposures, such as air pollution, may play a role in the etiology of breast cancer. Combining modeled ambient air concentrations with data from a large prospective cohort of California women with over 15 years of follow-up, we examined the relationship between breast cancer incidence and modeled concentrations of air pollutants shown to be mammary gland carcinogens (MGCs).The study population of 112,378 California Teachers Study participants included 5,676 women diagnosed with invasive breast cancer. Modeled annual average ambient air concentrations of 24 MGCs from the U.S. Environmental Protection Agency were linked to participants’ addresses. Cox proportional hazards models were used to estimate hazard rate ratios and 95% confidence intervals associated with residential MGC levels. MGCs were examined individually and as a combined summary variable for all participants, in selected subsets, and by tumor hormone responsiveness.Initial models yielded some evidence for increased risk for several compounds, including acrylamide, carbon tetrachloride, chloroprene, 4,4'-methylene bis(2-chloroaniline), propylene oxide, and vinyl chloride, but after adjustment for multiple comparisons, only results for propylene oxide and vinyl chloride remained statistically significant. In subset analyses, estrogen-receptor positive or progesterone-receptor positive (ER+/PR+) tumors were associated with higher ambient levels of acrylamide, benzidine, carbon tetrachloride, ethylidene dichloride, and vinyl chloride, while ER-/PR- tumors were associated with higher ambient levels of benzene. Interesting results for different compounds were observed within certain subsets of the population.While our initial models yielded several elevated risk estimates, after adjusting for multiple comparisons and breast cancer risk factors, most hazard ratios were no longer statistically significant. Our subset analyses, however, suggest that elevated risk may be associated with some compounds for certain subgroups of interest. A summary variable for all 24 MGCs did not offer any advantage over the models for individual compounds. Results must be interpreted cautiously, as estimated exposure was limited to modeled annual average ambient air concentrations, and could not account for other sources or routes other than inhalation.The online version of this article (doi:10.1186/1476-069X-14-14) contains supplementary material, which is available to authorized users. Breast cancer is the leading cancer diagnosed among women in United States . An estiFew studies have examined ambient air pollution exposure and risk of breast cancer incidence in human populations. Two case–control studies examined breast cancer risk and proxies of exposure , and found suggestive evidence for an association, but these studies used crude estimates of exposure, and did not evaluate specific compounds or classes of compounds , 18. An The United States Environmental Protection Agency (EPA) has produced modeled ambient concentrations for hazardous air pollutants at the census tract level for the entire United States for select years since 1996 . CombiniThe California Teacher Study (CTS) is a large on-going prospective cohort established in 1995–1996 when 133,479 active and retired female teachers and administrators enrolled in the California State Teachers Retirement System returned a completed baseline questionnaire. A full description of the CTS cohort is available elsewhere . For theUse of human subjects data in this study was reviewed by the Human Subjects Research Committees of the Cancer Prevention Institute of California, the City of Hope, the University of Southern California, the University of California at Irvine, and the California Health and Human Services Agency and found to be in compliance with their ethical standards as well as with the U.S. Code of Federal Regulations, Title 45, Part 46 on the Protection of Humans Subjects.The CTS cohort is followed annually for cancer diagnosis, death, and change of address. Annual linkage between the California Cancer Registry (CCR) and cohort membership is used to identify incident cancer cases. Modeled after the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program, the CCR maintains high standards for data quality and completeness and is estimated to be 99% complete . MortaliThe baseline questionnaire collected information on personal breast cancer risk factors. These include: age , race/ethnicity, family history of breast cancer in a first degree relative, age at menarche, age at first full-term pregnancy, total lifetime breastfeeding months, menopausal status and hormone therapy use at baseline, physical activity (defined as the average number of hours per week of strenuous activity over lifetime), body mass index (BMI), current alcohol consumption, smoking status, and total pack-years of smoking. Menopausal status was derived at the time of the baseline questionnaire from responses to questions about menstrual periods, duration and timing of both estrogen and progestin therapy, age of respondent, and ages at reported surgeries, if relevant.Address at the time of the baseline questionnaire (1995–1996) was used to derive neighborhood socioeconomic status (SES). Using 2000 U.S. Census block group, data were obtained on a variety of SES variables including: percentage of adults over age 25 years having completed a college degree or higher; percentage of adults without a high school degree; median family income, percentage of adults employed in managerial/professional occupations; and percentage of population below the poverty line. A principal components analysis was conducted to create a composite variable of SES based on the five individual variables described above. The loading of the first principal component, categorized into quintiles, was then used in the Cox regression models. This metric was originally developed for covariate adjustment in a prior study of breast cancer in the CTS in which it was found to be predictive .Estimated ambient concentrations of hazardous air pollutants (HAPs) were assigned to CTS participants using data from the United States Environmental Protection Agency (EPA). The EPA produces the National-Scale Air Toxics Assessment (NATA) to identify and prioritize air toxics with respect to their potential population health risks . The firWe determined the census tracts participants resided in by using a geographic information system  to geocode their addresses at the time of the baseline questionnaire to a 2000 U.S. Census tract. We then assigned to participants the corresponding modeled annual average ambient concentrations for the HAPs available in NATA for that census tract to create a proxy of inhalation exposure to outdoor air contaminants of interest.Because the NATA concentration estimates were not specifically designed for use in health studies, we previously evaluated the agreement between the NATA modeled data and available monitored data for 12 compounds in the state of California . These aTo choose a set of HAPs to focus on for these analyses we relied upon the work of Rudel et al. , which iFollow-up time was calculated as the number of months (rounded to the nearest full month) between joining the cohort  and either the date of invasive breast cancer diagnosis, the date of in situ breast cancer diagnosis, the date of death, the date the woman moved out of California for a period longer than four consecutive months, or December 31, 2011, whichever came first. In situ breast cancer cases were not included with invasive cases and were instead censored at the time of diagnosis.3 for a compound (estimates of no exposure) were replaced by the minimum non-zero value observed for that compound, divided by two, 2) given the skewed distributions of these compounds, concentrations were transformed using log base 10, 3) for each compound, the log-transformed values were standardized across all participants by (i) subtracting the mean of the compound from each value and then (ii) dividing the values by the standard deviation, thus producing a standardized concentration for each compound, and 4) a summary variable for each participant was calculated by summing the participant’s standardized concentrations across all compounds of interest.  Finally, the summary variable was categorized into quintiles of standardized concentration across all participants and a quintile assigned to each participant. Associated risks were then assessed using this overall estimate of MGC exposure. This method for summarizing exposure to the 24 MGC was chosen over a simple summation because the range of concentrations among these compounds varied dramatically and because the potency factor for each unit concentration was not assumed to be similar across the compounds. Among compounds with cancer slope factors, these range from 500 (mg/kg-day)−1 for benzidine to 0.0035 (mg/kg-day)−1 for methylene chloride underscoring the incomparability of risk for a unit concentration of exposure [Because the analysis examined the relationship between risk of breast cancer and numerous compounds of interest, we used two different methods for parameterizing exposure in our models. First we examined each compound individually, categorized into quintiles of concentration, without including exposure from any other compound in the model. Second, we created a summary variable of exposure to all compounds of interest for each participant to assess exposure to multiple pollutants. This was done as follows: 1) all concentrations of zero μg/mBreast cancer is thought to be a hormonally mediated and multifactorial disease in which the effects of a risk factor may be strongly influenced by the endogenous hormonal milieu of the host . ConsequCox proportional hazard models were used to estimate hazard rate ratios (HR) and 95% confidence intervals (95% CI) associated with concentration estimates for the MGCs using age at start and end of follow-up (in days) to define time on study. No apparent violation of the underlying assumption of proportional hazards was detected. All models were stratified by age at baseline and adjusted either for race alone or for race and personal risk factors of interest . Tests for trend were conducted by parameterizing exposure into quintiles, setting the value to the median for each quintile, modeling exposure as a continuous variable, and testing for non-zero slope using a likelihood ratio test. Lastly, for each compound, the p-values for each non-degenerative quintile HR were adjusted for multiple testing across the ten subsets using False Discovery Rates . All analyses were performed in SAS 9.3 .Table 3 for benzene to 1.07 × 10−8 μg/m3 for benzidine. Additionally, there was some variability in the range of concentrations within compounds, from the smallest range of 1.22 ×10−7 μg/m3 for benzidine to the largest range of 50.0 μg/m3 for styrene. While most compounds had no zero values, of the eight compounds that did, the percentage of zero values ranged from 13% to 73%.The distribution of the 24 MGC concentrations among the CTS participants included in this study are presented in Figure Results of the age-stratified and race-adjusted breast cancer incidence risk analysis for the individual compounds are shown in Table Select results by tumor hormone responsiveness and for subset populations are presented in Table There were a number of statistically significant results for different compounds within certain subsets of the population Table . For subFor those 18 compounds with tobacco smoke as a potential source, analyses among non-smokers were generally similar to the initial analyses (data not shown). The only large change observed was among o-toluidine exposure, for which the HR in the third quintile increased to 1.17 (95% CI: 1.05-1.31) compared to the main analysis.Among the subset of participants who were not known to have moved during the follow-up period, we found that results were generally similar to the initial analysis (data not shown). Only one of the two initially significant sets of results in the main analysis remained statistically significant among the non-mover subpopulation. For propylene oxide, the pattern of the exposure-response relation was similar, though slightly more elevated, in non-movers compared to the main analysis, and there was a statistically significant HR of 1.16 among women in the third quintile (95% CI: 1.05-1.29).Results using the summary MGC variable as the exposure metric displayed a positive trend with participants in the highest quintile having a HR of 1.05 for breast cancer incidence compared with those in the in the lowest quintile Table . None ofOverall, we observed little evidence of risk associated with ambient exposure to MGC HAPs. While our initial models yielded some elevated risk estimates, after adjusting for multiple comparisons and breast cancer risk factors, confidence intervals were broader, as would be expected, and tended to include one. Our subset analyses, however, suggest there may be interesting elevations in risk associated with some compounds for certain subpopulations of women and/or types of breast cancer tumors.The subset analyses were designed to assess the degree to which risk associations might be evident for breast cancer subtypes and risk groups in which there traditionally has been evidence for differential effects for personal and lifestyle risk factors , 37. It Despite the many comparisons in this study, there appear to be a few compounds for which the results are compelling in the context of the existing toxicological and epidemiologic literature, and considering the consistency of observed patterns in risk, as well as the likely relative contribution of ambient exposures to total exposures in human populations. These are discussed in detail below.Our results showed that those women in the top quintile of exposure for carbon tetrachloride had the highest risk for breast cancer incidence and the exposure-response had a generally positive trend. This was consistent when examining risk among the different subsets and for all subset analyses presented in Table Although there are a number of sources, the majority of carbon tetrachloride in the environment is due to direct release to the atmosphere during production, disposal, or use of the compound . It is vWhile carbon tetrachloride has been associated with mammary gland tumors in laboratory animals, few studies exist examining this association in humans. A previous case control study that relied upon qualitative measures of exposure found an association between breast cancer mortality and level of carbon tetrachloride exposure . The higThe exposure-response patterns for ethylidene dichloride and vinyl chloride were similar for initial and subset models, and exposure concentrations for these two chemicals were highly correlated among our study participants (Pearson correlation coefficient: 0.99). In the initial and some of the subset models, the exposure-response was an inverse-U shape, with peak risk associated with one or both middle quintiles of estimated exposure. Only for those in the past/never HT use subset was the risk consistently high for all three top quintiles of exposure, although peak risk was observed for the fourth quintile of exposure, rather than the fifth quintile. This non-monotonic risk relationship may be due to a number of reasons. First, this could be due to exposure misclassification. If there were truly a monotonic exposure-response relationship, and those who were truly in the highest exposure level were misclassified as being in the middle exposure levels, it would appear that those in the middle exposure levels had the greatest risk of breast cancer risk. Alternatively, there may be a biological explanation for this pattern. Several mechanisms have been proposed for non-monotonic dose–response curves, including cytotoxicity (cell death at high doses), receptor selectivity (differences in receptor affinity at low vs. high doses), receptor down-regulation and desensitization, and receptor competition , 41. ToxThe concordance of results and high correlation between these two chemicals is not unexpected given that ethylidene dichloride is an intermediate in the production of vinyl chloride, which, in the U.S., is almost exclusively produced to make polyvinyl chloride (PVC). Anthropogenic sources are responsible for all of the ethylidene dichloride and vinyl chloride found in the environment, most of which is released from industrial processes almost entirely to the atmosphere , 43. BotThere are no published epidemiologic studies specifically examining exposure to either ethylidene dichloride or vinyl chloride and risk of breast cancer incidence or mortality. There have been, however, two reports on workers in PVC manufacturing. A cross-sectional mortality study among employees of 17 PVC fabricators found a statistically significantly elevated risk of breast cancer mortality among white female workers  , consistOur results suggest that exposure to benzene may only increase breast cancer risk for ER-/PR- breast tumors. Benzene is widely used and ranks among the top 20 for production volume for chemicals produced in the United States. Industrial processes are the main sources of benzene in the environment, and ambient air concentrations can also be elevated by emissions from burning coal and oil, motor vehicle exhaust, and benzene waste and gasoline storage operations . BecauseIn our study we examined risk from modeled ambient concentrations for a large number of MGC compounds. We conducted analyses based upon individual compounds, but we also attempted to account for exposure to multiple pollutants by using a summary MGC variable. The results showed that the overall summary variable was not statistically significantly associated with increased risk. There may be a number of reasons for this. First, including compounds with no risk association in the summary variable may dilute the effect of those compounds with an association. Second, if total concentration is important, scaling each compound to a standard distribution (mean set to zero and standard deviation to one) before summing across compounds would dilute the summary effect. Finally, the individual compound models may have been more likely to detect signals in exposure data than the summary variable models because the latter summed across multiple distributions of compounds, producing an exposure with a lower signal-to-noise ratio. While we have examined only one type of summary measure, other summary measures using different summation methods remain worth exploring.There were some limitations in this study. Perhaps foremost is the potential for exposure misclassification. Residential addresses at the baseline survey (1995–96) were linked with census tract level estimates of annual average ambient concentrations for the year 2002. We assumed that the relative concentrations were representative of the entire follow-up period. Our selection of the 2002 concentration estimates were based on a previous study examining agreement over time between NATA estimates and monitored data in California . AlthougSecond, our analyses are predicated on the assumption that these modeled ambient concentrations can serve as reasonable proxies for inhalational exposure to these compounds, which may not be the case. The estimated concentrations provided by the EPA are based on complex modeling of emissions data, subject to the constraints of the data and the assumptions underlying the predictive models. The EPA provides an overall confidence in exposure assessment rating for each compound whose concentration they estimated . Of the Third, we could not consider indoor inhalation exposures or ambient exposures outside of the census tract of baseline residence. While the majority of the chemicals examined do not have major indoor sources, the few exceptions include benzene, 2,4-toluene diisocyanate, propylene oxide, and styrene which are likely indoor air contaminants for the general public primarily through vehicle exhaust from an attached garage or through consumer products –53. If fLastly, this study examined the risk associated only with inhalational exposure; other routes of exposure may be as, or more, important for certain chemicals. Ingestion from dietary sources is thought to be the primary or one of the major routes of exposure among the general population for acrylamide, ethyl carbamate, o-toluidine, and vinylidene chloride –58. IngeDespite these limitations, this study offers a number of advances over previous research on air pollution and breast cancer risk. First, these analyses use data from a large prospective cohort of women with the opportunity to account for covariate information on individual breast cancer risk factors. While the individual SES of study participants was not assessed, it is likely to be fairly homogeneous within this study population by virtue of the CTS being an occupational cohort of professional women, all of whom have at least a 4-year college degree. Furthermore, the incorporation of adjustment for a summary measure of neighborhood SES further reduces the likelihood that our results are merely a reflection of residual confounding due to SES, although we cannot fully dismiss that possibility. Additionally, because of the longitudinal nature of this study misclassification of menopausal status is a concern for women who reported being pre-/peri-menopausal at baseline (43%). This misclassification would have affected primarily the stratified analyses among pre-/peri-menopausal women, pooling together women who were still pre-/peri-menopausal with those who had become menopausal. If pre-/peri-menopausal women where truly more susceptible to the effects of these exposure than menopausal women, results would have been biased towards null due to this misclassification. Previous studies have relied on cancer registry data  or on ocUsing pre-existing EPA data on annual average ambient concentrations of MGC hazardous air pollutants at the census tract level, we found statistically significant associations between increased risk of breast cancer and residence in areas with high estimated ambient concentrations of propylene oxide and vinyl chloride. Suggestive evidence of an association with breast cancer incidence was also seen in certain subpopulations for several MGCs, most notably for carbon tetrachloride, ethylidene dichloride, and vinyl chloride. Stratified by tumor hormone responsiveness, ER+/PR+ tumors were associated with estimated exposure to acrylamide, benzidine, carbon tetrachloride, ethylidene dichloride, and vinyl chloride, while ER-/PR- tumors were associated with estimated benzene exposure. Additionally, we found that using a summary variable for all 24 MGCs of interest was not fruitful and did not offer any advantage over the individual compound models. This is the first study to quantitatively examine the relationship between ambient residential exposures to select hazardous air pollutants and risk of breast cancer incidence among women using individual-level data. Risk relationships for exposures to these MGCs should be further examined.Participants of this study are all members of the CTS cohort who provided written informed consent at the time they joined the cohort. This consent included consent to be contacted in the future for follow-up data collection, consent to allow their data to be linked to the California Cancer Registry and consent for their data to be used for research purposes.Additional file 1: Table S1: Select information for 24 Mammary Gland Carcinogens. (PDF 21 KB)


Results from this study suggest that diet-associated inflammation may increase the risk of colorectal cancer, and this effect may differ by certain factors, such as anatomical site, age, sex, and lifestyle.The role of diet-associated inflammation in colorectal cancer is of interest. Accordingly, we aimed to examine whether the dietary inflammatory index (DII) was associated with the risk of colorectal cancer in a case-control study conducted in Korea. The DII was based on dietary intake, which was determined by a 106-item semi-quantitative food frequency questionnaire completed by 923 colorectal cancer cases and 1846 controls. Logistic regression was used to estimate odd ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by the anatomical site of the cancer, sex, and other risk factors. Higher DII scores were associated with an increased incidence of colorectal cancer (OR (95% CI) = 2.16  for highest vs. lowest tertile). The magnitude differed by anatomical site and sex. This association was slightly weaker in subjects with proximal colon cancer ) and was stronger in women ). Additionally, stronger associations were observed in subjects who were older than 50 years ( Chronic inflammation is known to play an important role in cancer, particularly in colorectal cancer . EvidencRecently, the dietary inflammatory index (DII) was developed based on an extensive literature review to evaluate the inflammatory potential of an individual’s diet ,10. The The incidence of colorectal cancer in Korea has increased rapidly in recent decades . In addiThe cases were patients newly diagnosed with colorectal cancer between August 2010 and August 2013 at the Center for Colorectal Cancer of the National Cancer Center in Korea. Of the 1070 patients who agreed to participate in the study and provided informed consent, 145 were excluded because of incomplete semi-quantitative food frequency questionnaire (SQFFQ) data, and two were removed because of implausible energy intakes . Therefore, 923 patients were included in the analysis.n = 4779) and other questionnaires (n = 265) and 120 subjects were excluded because of implausible energy intakes. Of the remaining 9037 subjects, two controls per case were frequency-matched by age (within five years) and sex .n-3 fatty acid, n-6 fatty acid, cholesterol, thiamin, riboflavin, niacin, vitamin B6, vitamin B12, vitamin C, folic acid, vitamin A, vitamin D, vitamin E, β-carotene, iron, magnesium, selenium, zinc, ethanol, garlic, ginger, onion, green tea, flavan-3-ols, flavones, flavonols, flavanones, anthocyanidins, and isoflavones. Energy adjustment was performed using the residual method [Information on demographic and lifestyle risk factors of both cases and controls were collected using a structured questionnaire conducted at the initial recruitment, prior to cancer diagnosis. The dietary intake of each participant was assessed using a 106-item SQFFQ. The validity and reproducibility of the questionnaire have been previously reported . Particil method .t-tests for continuous variables. The scores on the DII were categorized into tertiles according to the distribution of the control groups . The differences in demographic and lifestyle factors and the distributions of the intake of specific food groups  were examined across the DII tertiles. ANOVA was used to test for differences.The differences between cases and controls were analyzed according to demographic and lifestyle factors using chi-square tests for categorical variables and Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression for both the crude and multivariable models. The multivariable model was adjusted for age, sex, body mass index, education, family history of colorectal cancer, physical activity, and total caloric intake. A linear test for trend was conducted by including the median value of each DII tertile as a continuous term in the regression model. For the subgroup analyses by anatomical location, polytomous logistic regression model was used. The outcome variables included colorectal cancer overall and subsites . The anatomical subsites were defined based on the International Statistical Classification of Disease and Related Health Problems, 10th revision (ICD-10) .2 and ≥25 kg/m2), physical activity (yes/no), and smoking status (ever/never). The interactions between the DII scores and risk factors were assessed with a likelihood ratio test comparing the model with interaction terms with the model containing only the main effects.Potential effect modification of the association between the DII and colorectal cancer risk was examined by stratifying the data by age group (<50 years old and ≥50 years old), BMI . A two-sided p-value less than 0.05 was considered statistically significant.All statistical analyses were performed using SASp < 0.001), were less highly educated (p < 0.001), were less likely to have professional occupations (p < 0.001), had lower incomes (p < 0.001), were less likely to be married (p < 0.001), were less likely to drink alcohol (p < 0.001), and had lower physical activity (p < 0.001) than controls. The total calorie intake was 1689.9 kcal/day among controls and 2026.3 kcal/day among cases (p < 0.001). The mean DII value was 1.07 and 1.80 for controls and cases (p < 0.001), respectively, indicating a more pro-inflammatory diet among the cases. The DII score in the present study ranged from a maximum pro-inflammatory score of 7.26 to a maximum anti-inflammatory score of −6.50, with a standard deviation of 2.18.The distribution of participant characteristics is presented in p < 0.001), were more likely to perform physical labor (p < 0.001), had lower incomes (p = 0.008), and had lower physical activity (p < 0.001) than those with a lower DII score. The distribution of certain food groups across tertiles of the DII was also examined in both controls and cases (Some differences in demographic and lifestyle factors across tertiles of the DII were observed in controls . Those wnd cases . Concernp for trend < 0.001). When the data were stratified by anatomic site, a slightly weaker association was observed with proximal colon cancer (OR (95% CI) = 1.68  for highest vs. lowest tertile, p for trend = 0.02) (p for trend < 0.001) compared with men (OR (95% CI) = 1.72  for highest vs. lowest tertile, p for trend < 0.001) ( = 0.02) . When th< 0.001) .p for interaction = 0.004), physical activity (p for interaction < 0.001), and smoking status (p for interaction = 0.03). Stronger associations were observed among subjects who were 50 years and older (OR (95% CI) = 2.61 for highest vs. lowest tertile), engaged in physical activity (OR (95% CI) = 3.42  for highest vs. lowest tertile) and did not smoke (OR (95% CI) = 2.58  for highest vs. lowest tertile).The potential effect modification of the association between the DII and colorectal cancer by age, BMI, physical activity, and smoking status was investigated . AnalysiThis study found that a more pro-inflammatory diet was associated with an increased risk of colorectal cancer. The magnitude of the risk varied slightly by anatomic location and sex. In addition, the association between colorectal cancer risk and diet-associated inflammation may be modified by factors such as age and physical activity.The DII was developed to assess the inflammatory potential of an entire diet by integrating individual food components . This meThe results of this study were similar to those of previous studies using the DII. Two US cohort studies of postmenopausal women, the Iowa Women’s Health Study  and the n-3 fatty acids), physical activity, and medications [N-nitroso compounds, which can damage DNA [Several mechanisms have been proposed to explain the effect of diet-related inflammation in colorectal carcinogenesis. First, systemic inflammation is responsible for increasing insulin resistance  which maications . Moreovemage DNA . Diets hmage DNA .We observed slightly different effects of diet-associated inflammation by anatomical site. In this study, relatively smaller effects were observed in subjects with proximal colon cancer. Colorectal cancer is a heterogeneous disease, presenting different clinical and molecular characteristics by anatomic location ,36. For Other factors may affect the role played by diet-associated inflammation in colorectal carcinogenesis. In this study, stronger associations were observed among subjects who were older than 50 years and those who engaged in physical activity. The incidence of colorectal cancer increases sharply after the age of 50 , suggestIn conclusion, this study found that consuming a diet with greater pro-inflammatory potential was associated with an increased risk of colorectal cancer in a Korean population, suggesting a role of diet-associated inflammation in colorectal carcinogenesis. This study also suggested that the role of diet-associated inflammation may be affected by several factors, such as anatomical location, age, sex, and lifestyle. These findings may lead to more specific strategies to prevent colorectal cancer in the Korean population that consider both dietary habits and lifestyles. Combined with regular exercise, changing dietary habits by increasing fruit and vegetable consumption, and reducing meat, sweets, and fried foods may help prevent colorectal cancer. The use of this new tool for assessing dietary inflammatory potential could be extended to other inflammation-related diseases.


IGF1 gene (rs1019731 and rs12821878) were associated with breast cancer risk among European women. Four highly linked IGF1 SNPs  were modified by menopausal status among East Asian women only and associated with postmenopausal breast cancers. The association between rs2288378 and breast cancer risk was also modified by breast tumor subtype among East Asian women. Several IGF1 polymorphisms were found to be associated with breast cancer risk and some of these associations were modified by menopausal status or breast tumor subtype. Such interactions should be considered when assessing the role of these variants in breast cancer etiology.Genetic variants of insulin-like growth factor 1 (IGF1) pathway genes have been shown to be associated with breast density and IGF1 levels and, therefore, may also influence breast cancer risk via pro-survival signaling cascades. The aim of this study was to investigate associations between IGF1 pathway single nucleotide polymorphisms (SNPs) and breast cancer risk among European and East Asian women, and potential interactions with menopausal status and breast tumor subtype. Stratified analyses of 1,037 cases and 1,050 controls from a population-based case–control study were conducted to assess associations with breast cancer for 22 SNPs across 5 IGF1 pathway genes in European and East Asian women. Odds ratios were calculated using logistic regression in additive genetic models. Polytomous logistic regression was used to assess heterogeneity by breast tumor subtype. Two SNPs of the  The insulin-like growth factor 1 (IGF1) signaling pathway has been implicated in normal cell growth, development, and differentiation in the mammary gland and other tissues . StimulaInsulin-like growth factor 1 is suggested to play a role in the progression of many cancers, including prostate , 6, coloIGF1  with risk of breast cancer among women of European and East Asian descent. Potential interactions between IGF-related genes and menopausal status and breast tumor subtype were also assessed.We examined the associations of 22 polymorphisms across five IGF1 pathway genes  were recruited from the BC Cancer Registry and comprised women aged 40–80 newly diagnosed with in situ or invasive breast cancer with no previous history of cancer (except non-melanoma skin cancer). Age frequency-matched cancer-free controls  were recruited from the Screening Mammography Program of BC. In Kingston, both cases (n = 131) and age frequency-matched controls (n = 163) were recruited from the Hotel Dieu Breast Assessment Program. All participants completed a questionnaire, either self-administered or by telephone interview, and provided a biological sample, either blood or saliva. Sufficient DNA for genotyping was extracted from blood and saliva samples for 92% of participants  in the study. Pathologic data concerning tumor ER, progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) expression were obtained for most cases  from both Vancouver and Kingston. Written informed consent was obtained from all participants and ethical approval for this study was obtained from the University of British Columbia – BC Cancer Agency Clinical Research Ethics Board and the Queen’s University Health Sciences Research Ethics Board.To investigate the associations between IGF1 pathway genes and breast cancer risk, data from the Canadian Breast Cancer Study, previously known as the Molecular Epidemiology of Breast Cancer (MEBC) Study as described , were usThe questionnaire completed by participants provided information regarding geographic ancestry; menopausal status; education; health, medical, and reproductive history; family history of cancer; lifestyle characteristics, including lifetime tobacco and alcohol consumption; and lifetime physical activity.IGF1), bioavailability (IGFBP3), and downstream signaling  of IGF1 were selected. Based on suspected relationships with breast cancer risk or disease susceptibility from existing literature and using SNP tagging methods, a set of 28 SNPs were selected for genotyping. Selection of tagSNPs, using the CEU population from HapMap release 28 with a minimum minor allele frequency (MAF) of 0.10 and r2 threshold of 0.8, was conducted for three genes  using Tagger  in European-ancestry controls. Relevant to this analysis, six SNPs were excluded following quality control: two by the genotyping center (rs1520220 and rs2854744), two for poor clustering (rs9672965 and rs693293), one for low call rate (rs10255707), and one for discrepancies in replicate samples (rs2162679). Therefore, final analyses included 22 IGF1 pathway SNPs.Quality control of genotype data was performed in Genome Studio v2011.1 , PLINK v1.07 , GRR 3232, and En = 14); unrelated samples having identical genotypes (n = 6); sex discrepancy, as identified by Y chromosome markers, indicating that the sample was male (n = 1); excess heterozygosity, specifically >3 SDs from the mean of other samples of the same ethnicity (n = 4); discrepancies between self-reported ethnicity and predicted ethnicity from genotype data (n = 5). If participants in the study were related, one was excluded (n = 9). Questionnaire data were used to verify that nine pairs of samples were from relatives. If the pairs were both cases, the individual with the later diagnosis date was excluded; if the pairs were both controls, the individual with the younger age was excluded. To compare self-reported ethnicity to predicted ethnicity, identity-by-state was calculated and multi-dimensional scaling plots  if the IHC results for HER2 were equivocal. Tumors were grouped according to biomarker status, regardless of intensity of expression. Four breast tumor subtypes were identified: ER+ and/or PgR+/HER2−, ER+ and/or PgR+/HER2+, ER−/PgR−/HER2+, and ER−/PgR−/HER2−.ER, PgR, and HER2 status of all invasive tumors was determined using immunohistochemistry (IHC), supplemented by fluorescence p-values. SNPs with a q-value  <0.05 were considered statistically significant. Modification of these relationships by menopausal status was assessed by including an interaction term. Case–case polytomous logistic regression was used to assess heterogeneity of odds ratios between hormone receptor- and HER2-defined tumor subtypes. Assessment for these interactions was restricted to SNPs with p-value <0.1 for an association with breast cancer risk prior to false discovery rate (FDR) adjustment and MAF among controls >0.1 in each respective ethnic subgroup. All analyses were performed using SAS  and PLINK . The Benjamini–Hochberg adjustment  was usednd PLINK .Characteristics of the study participants are presented in Table IGF1 SNPs  was associated with decreased risk of breast cancer, but only two of these SNPs passed adjustment for the FDR: rs1019731  and rs12821878 . Among East Asians, no SNP was associated with breast cancer risk even prior to FDR adjustment.Relationships between SNPs and breast cancer risk among European and East Asian women are presented in Table IRS1 gene , which appeared to decrease the risk of premenopausal, while increasing the risk of postmenopausal breast cancers. Among East Asian women, modification of genetic effect by menopausal status was apparent for four IGF1 SNPs: rs17727841, rs2288378, rs7136446, and rs7956547 , although these SNPs were in high linkage disequilibrium (LD) (r2 = 0.86–0.98). The minor alleles of these SNPs were associated with decreased risk of breast cancer among postmenopausal women.Analyses further stratified by menopausal status are presented in Table TH = 0.04), in which a decreased risk of ER+ and/or PgR+/HER2− tumors, but not other tumor subtypes, was noted.Lastly, heterogeneity in odds ratios between breast tumor subtypes for select IGF1 pathway SNPs among European and East Asian women are presented in Table IGF1 SNPs and breast cancer risk in both European and East Asian women. In Europeans, the minor alleles of two IGF1 SNPs (rs1019731 and rs12821878) were associated with reduced breast cancer risk. In East Asians, the association between four IGF1 SNPs  in high LD and breast cancer risk was modified by menopausal status and the minor alleles of these SNPs were associated with decreased risk of postmenopausal breast cancer. Lastly, heterogeneity by tumor subtype for rs2288378 was observed in East Asian women.In our analyses of European and East Asian women, we observed associations between select IGF1 gene, which encodes the IGF1 protein, are associated with increased circulating IGF1 levels  in high LD among East Asian women. Menopause-associated declines in IGF1 levels have been previously reported  for SNPs with MAFs of 0.50, and OR = 1.80 (or OR = 0.56 if protective) for SNPS with MAFs of 0.05. The small sample sizes in the analyses of East Asian women and of tumor subtypes warrant caution in the interpretations, and further large studies are needed to confirm these findings. Differences in demographic, lifestyle, and reproductive factors between cases and controls of the study may be partly attributed to the recruitment methods used in BC where cases were selected using a population-based cancer registry and controls were recruited from a breast mammography program. If those who elect to participate in screening programs are different than those who do not, there is potential for selection bias to be introduced. However, since the study recruitment strategies are unlikely to be related to individuals’ genetic variants in IGF pathway genes, concerns for selection bias are minimized.IGF1 SNPs and breast cancer risk among European and East Asian women, although evidence of an association for other IGF pathway SNPs was limited. Potential modification of these relationships by menopausal status and breast tumor subtype may warrant further consideration when assessing molecular signaling pathway interactions in the genetic etiology of breast cancer.In conclusion, our study observed associations between some JS was responsible for the analysis and drafting the manuscript. Drs. KA and JJS are the co-principal investigators of the Canadian Breast Cancer Study (CBCS). Drs. AG, IB, CL, SS, AB-W, and HR are investigators of the CBCS. All co-PIs and investigators of the CBCS were involved in designing and conducting the original study. AL is the Research Project Coordinator for the CBCS and was involved in study planning. LK assisted in the analysis of the physical activity-related variables, and Dr. JMS was responsible for the quality control for the genotype data. Dr. HR also played a supervisory role in the preparation of this manuscript. All authors reviewed and contributed to the submitted version of the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.