Genetic Susceptibility For Breast Cancer Research Articles

Abstract B111: A needs assessment of genetic and hereditary breast cancer awareness in Southern California women diagnosed with a genetic mutation

Abstract Background: Breast cancer is a global public health dilemma, considering the public awareness the issue has garnered over the years it continues to be diagnosed in advanced stages. Genetic mutations can increase the risk of developing breast cancer. Literature findings have identified the lack of knowledge surrounding genetic breast cancer susceptibility. Methods: In partnership with Southern California Chapter of The Breasties (SoCal Breasties), an all inclusive nonprofit organization that creates a community for survivors, previvors, thrivers, and caregivers impacted by breast and gynecological cancers, 20 women with a breast cancer related genetic mutation diagnosis were surveyed in a cross-sectional study to determine the need for health education on breast cancer genetic susceptibility. Of the 20 women surveyed, the racial/ethnic identities of the respondents is as follows: 10% identified as Asian American/Pacific Islander; 5% identified as Black; 35% identified as Hispanic/Latinx; 5% identified as “Mixed Race: Black, White”; 40% identified as White; and 5% identified as Ashkenazi Jewish, White. Results: 70% of survey respondents identified not having adequate knowledge of genetic breast cancer susceptibility prior to diagnosis. When looking at racial and ethnic groups, Black, Hispanic/Latinx, and Asian American/Pacific Islander women made up 71% of the population that lacked proper knowledge of the topic when compared to their white counterparts. 75% identified health education as the most needed resource for genetic breast cancer susceptibility. When asked to share one piece of insight, the most common sentiment expressed was “Knowledge is Power.”Conclusions: There is a need for greater health education on genetic breast cancer susceptibility, especially in racial and ethnic minority populations. Health educators and public health professionals should consider generating awareness campaigns and partnering with community based organizations to disseminate proper knowledge. In addition, resources and awareness campaigns should be culturally tailored and linguistically appropriate to meet the needs of all racial and ethnic groups. Citation Format: Dayanara Ruiz. A needs assessment of genetic and hereditary breast cancer awareness in Southern California women diagnosed with a genetic mutation [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B111.

173P Diet, genetic predisposition and the risk of breast cancer: A cohort study from the UK biobank

Dietary factors have been consistently associated with breast cancer risk, but evidence for their effects in women with different genetic susceptibility of breast cancer is scarce, and little is known about their interaction with alcohol consumption. We analyzed data from 261,857 female participants in the UK Biobank. Multivariable adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between dietary factors and breast cancer risk. We further assessed its interaction with alcohol consumption and polygenic risk score (PRS) for breast cancer. Only processed meat and beef intake more than once a week were associated with a higher risk of breast cancer, especially in women who took alcohol ≥1/d [HR (95% CI):1.20(1.01, 1.42) and 1.35 (1.06, 1.73), respectively]. Fresh fruit intake was associated with reduced risk of breast cancer [HR (95% CI):0.76 (0.64, 0.89)]. There was an interaction between vegetable and fresh fruit intake and alcohol consumption (P for interaction<0.05). When further stratified by PRS, fresh fruit intake with ≥4 servings/d was associated with risk of breast cancer [HR(95% CI):0.87(0.78-0.96)] in women with the highest quantile of PRS, and additive interaction was found between them.Table: 173PAssociations between diet and any breast cancer, by frequency of alcohol consumptionIn women took alcohol <1/dIn women took alcohol ≥1/dHR(95%CI)HR(95%CI)Processed meatNever1.00 (REF)1.00 (REF)<once/wk1.10(1.01-1.18)1.08(0.91-1.29)≥once/wk1.08(1.01-1.17)1.20(1.01-1.42)BeefNever1.00 (REF)1.00 (REF)<once/wk1.04(0.95-1.14)1.27(0.99-1.63)≥once/wk1.05(0.96-1.16)1.35(1.06-1.73)Fresh fruit<2 servings/d1.00 (REF)1.00 (REF)2.0-2.9 servings/d0.99(0.94-1.06)0.90(0.80-1.02)3.0-3.9 servings/d0.99(0.93-1.05)0.92(0.80-1.05)≥4 servings/d0.89(0.83-0.96)0.76(0.64-0.89) Open table in a new tab . Processed meat, vegetable and fresh fruit were associated with risk of breast cancer, and the effect was stronger in those who took alcohol ≥1/d and with high PRS for breast cancer. A combined intervention by reducing alcohol and processed meat consumption while increasing vegetable and fresh fruit intake might contribute to the prevention of breast cancer in high risk women.

Abstract 5900: Integrating prior knowledge of transcription factor occupied elements with transcriptome-wide association analysis identifies 153 breast cancer susceptibility genes

Abstract Transcriptome-wide association studies (TWAS) have been successful in uncovering large numbers of putative disease susceptibility genes. TWAS approaches such as S-PrediXcan, FUSION and TIGAR, show comparable overall performance for susceptibility gene discovery; however, integrating prior disease-specific regulatory information is lacking. To improve accuracy of gene expression prediction by integrating information on susceptible transcription factor (sTF) occupancy in target cells and tissues, we developed an analytical framework, called sTF-TWAS. We evaluated six sets of putative regulatory variants selected from sTF-occupied sites, and performed generalized Berk-Jones (GBJ) analysis to combine sets and quantify overall associations. We demonstrated that sTF-TWAS outperforms S-PrediXcan in both simulation and real data analyses. Using summary statistics data from the Breast Cancer Association Consortium (BCAC), we also incorporated alternative splicing (sp) data in TF-TWAS and identified 76 and 88 significant genes for breast cancer risk at a Bonferroni-corrected P &amp;lt;0.05 from sTF-TWAS and sp-sTF-TWAS, respectively. Of 153 putative susceptibility genes from both sTF-TWAS and sp-sTF-TWAS, 14 genes in 12 loci had novel associations with breast cancer risk and 90 genes were previously unreported by breast cancer GWAS. We also provide strong evidence for 15 previously unreported genes, including 11 essential for breast cell proliferation and five suggested cancer predisposition or driver genes: RAD50, IGHMBP2, ATXN3, KANSL1, and IL6ST. Overall, we demonstrated that our approach has significant advantages over regular TWAS and our findings provide additional insights into the genetic susceptibility of breast cancer. Citation Format: Xingyi Guo, Jingni He, Alicia Beeghly-Fadiel, Zhishan Chen, Chen Cao, Xiao-ou Shu, Wei Zheng, Quan Long. Integrating prior knowledge of transcription factor occupied elements with transcriptome-wide association analysis identifies 153 breast cancer susceptibility genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5900.

Associations of genetic susceptibility to 16 cancers with risk of breast cancer overall and by intrinsic subtypes.

SummaryCertain genetic variants are associated with risks of multiple cancers. We investigated breast cancer risk with overall genetic susceptibility to each of 16 other cancers. We constructed polygenic risk scores (PRS) for 16 cancers using risk variants identified by genome-wide association studies. We evaluated the associations of these PRSs with breast cancer risk (overall and by subtypes) using Breast Cancer Association Consortium data, including 106,278 cases and 91,477 controls of European ancestry. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated to measure the association of each PRS with breast cancer risk. Data from the UK Biobank, including 4,337 cases and 209,983 non-cases, were used to replicate the findings. A 5%–8% significantly elevated risk of overall breast cancer was associated with per unit increase of the PRS for glioma and cancers of the corpus uteri, stomach, or colorectum. Analyses by subtype revealed that the PRS for corpus uteri cancer (OR = 1.09; 95% CI, 1.03–1.15) and stomach cancer (OR = 1.07; 95% CI, 1.03–1.12) were associated with estrogen receptor-positive breast cancer, while ovarian cancer PRS was associated with triple-negative breast cancer (OR = 1.25; 95% CI, 1.01–1.55). UK Biobank data supported the positive associations of overall breast cancer risk with PRS for melanoma and cancers of the stomach, colorectum, and ovary. Our study provides strong evidence for shared genetic susceptibility of breast cancer with several other cancers. Results from our study help uncover the genetic basis for breast and other cancers and identify individuals at high risk for multiple cancers.

A polygenic-score-based approach for identification of gene-drug interactions stratifying breast cancer risk

An individual's genetics can dramatically influence breast cancer (BC) risk. Although clinical measures for prevention do exist, non-invasive personalized measures for reducing BC risk are limited. Commonly used medications are a promising set of modifiable factors, but no previous study has explored whether a range of widely taken approved drugs modulate BC genetics. In this study, we describe a quantitative framework for exploring the interaction between the genetic susceptibility of BC and medication usage among UK Biobank women. We computed BC polygenic scores (PGSs) that summarize BC genetic risk and find that the PGS explains nearly three-times greater variation in disease risk within corticosteroid users compared to non-users. We map 35 genes significantly interacting with corticosteroid use (FDR < 0.1), highlighting the transcription factor NRF2 as a common regulator of gene-corticosteroid interactions in BC. Finally, we discover a regulatory variant strongly stratifying BC risk according to corticosteroid use. Within risk allele carriers, 18.2% of women taking corticosteroids developed BC, compared to 5.1% of the non-users (with an HR = 3.41 per-allele within corticosteroid users). In comparison, there are no differences in BC risk within the reference allele homozygotes. Overall, this work highlights the clinical relevance of gene-drug interactions in disease risk and provides a roadmap for repurposing biobanks in drug repositioning and precision medicine.

Relationship between HLA-DRB1 gene polymorphism and breast cancer: A protocol for systematic review and meta-analysis.

Background:Breast cancer is one of the common malignant tumors in women, which seriously affects women's physical and mental health and even life-threatening. The occurrence and development of breast cancer are closely related to genetic factors. Many studies have shown that human leukocyte antigen DRB1 is associated with the development of breast cancer, but lack evidence. This study aims to systematically evaluate the relationship between HLA-DRB1 gene polymorphism and breast cancer.Methods:The retrieval time of this study was from the establishment of the database to February 2021. The retrieval databases included CNKI, Wanfang, VIP and China Biomedical Database, PubMed, Embase, Web of Science, and the Cochrane Library. The retrieval objects were observational studies on the relationship between HLA-DRB1 gene polymorphism and breast cancer (including case--control studies, cross-sectional studies, and cohort studies). The language restrictions were English and Chinese. Two researchers independently extracted the data and assessed the quality of the included studies, and Stata 16.0 software was used for statistical analysis.Results:This study will systematically evaluate the relationship between HLA-DRB1 gene polymorphism and breast cancer based on existing studies.Conclusion:This study will explore the early warning signal of breast cancer genetic susceptibility, and provide evidence-based medical evidence for clarifying the role of HLA-DRB1 gene polymorphism in breast cancer.OSF Registration number:DOI 10.17605/OSF.IO/847FQ

Abstract PS8-02: Influence of a breast cancer polygenic risk score on adherence to preventive endocrine therapy in high risk women at 1 and 2 year follow-up: The genetic risk estimate (GENRE) trial

Abstract Background: Preventive endocrine therapy (ET) has been proven extensively to decrease breast cancer (BC) risk by 50-65%. Despite this significant reduction, a small proportion of high risk women take ET, due to attitudes toward medications, inaccurate risk perception and drug side-effects. The addition of a polygenic risk score (PRS), comprised of 77 BC genetic susceptibility loci (Single Nucleotide Polymorphisms (SNP)), to the standard risk calculator estimates, can be used to improve BC risk estimation. We previously reported on the influence of the PRS-adjusted BC risk estimates on the intent to use ET (Abstract, SABCS, 2019). Here we report on the influence of PRS-adjusted BC risk estimates on ET adherence at 1 and 2 year follow –up. We also report on ET side effects over this same time period. Methods: Women older than age 35 were eligible if they were deemed at high risk for BC by either a 5 year Gail Model risk of ≥3% or 10 year Tyrer-Cuzick risk (IBIS) of ≥5%. We excluded women with a personal history of BC or hereditary BC syndromes. At baseline, participants were counseled on their BC risk using standard risk calculators: Gail and IBIS risk scores (5 yr, 10 yr, &amp; lifetime) and ET options were discussed, including benefits and risks. Blood samples were obtained and genotyped for 77 SNPs, and an updated BC -PRS risk report was shared with study participants that reflected the IBIS and Gail risk predictions for 5 yr, 10 yr, &amp; lifetime BC risk with and without the PRS. A baseline self-reported questionnaire assessed understanding of BC risk and decision to take ET. Follow-up questionnaires at 1 and 2 years assessed self-reported ET adherence and ET side effects (vasomotor symptoms, vaginal symptoms, sexual dysfunction, weight gain, GI symptoms, headaches, breast sensitivity, mood changes, and joint pain). Adherence to ET at 1 and 2 year follow-up was stratified by three categories of lifetime PRS-BC risk: 0-20%; 20-40%; 40-100%. Results: 151 women at Mayo Clinic Rochester and CancerCare Manitoba were enrolled in the study from 2016 to 2017. Of the 149 participants with evaluable data at 1 and 2 year follow-up, 57 (38%) started on ET therapy, all within 1 year of the baseline visit; 43 (29%) were taking ET at 1 year and 33 (22%) were taking ET at 2 year follow-up, representing a discontinuation rate of 26% at 1 year and 42% at 2 year follow-up. Adherence to ET use at 1 year and 2 year follow-ups correlated significantly with the category of PRS-BC risk estimation: at 1 year follow up, 17% of those in the lowest PRS-IBIS risk category, 23% in the middle risk category and 50% of those in the highest risk category were taking ET (p=0.001). At 2 year follow up, 12% of those in the lowest PRS-IBIS risk category, 18% in the middle risk category and 38% of those in the highest risk category were taking ET (p=0.008). At 1 year follow up, participants taking ET reported significantly more bothersome symptoms of vaginal itching (p=0.010), weight gain (p=0.015) and joint pain (p=0.044), compared with those not on ET. There was a trend towards increased irritability and mood swings on those taking ET (p=0.059). At year 2 there was no significant difference in side effects between those taking and not taking ET. Conclusion: Adherence to ET in a population of women at high risk for BC decreased overtime and strongly correlated with the level of risk, with 38% of those at highest risk of breast cancer taking ET at 2 year follow up. Side effects of vaginal itching, weight gain and body aches were more common on those taking ET versus not taking ET at the 1 year follow-up, but did not differ at 2 year follow-up, possibly due to the fact that those with the most bothersome symptoms have discontinued ET by the 2 year follow up. Citation Format: Daniela Stan, Julian Kim, Daniel Schaid, Erin Carlson, Andrew Cooke, Christina A. Kim, Benjamin Goldenberg, Jason Sinnwell, Debjani Grenier, Amy Degnim, Fergus Couch, Celine Vachon, Sandhya Pruthi. Influence of a breast cancer polygenic risk score on adherence to preventive endocrine therapy in high risk women at 1 and 2 year follow-up: The genetic risk estimate (GENRE) trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-02.

Impact of Personalized Genetic Breast Cancer Risk Estimation With Polygenic Risk Scores on Preventive Endocrine Therapy Intention and Uptake.

Endocrine therapy is underutilized to reduce breast cancer incidence among women at increased risk. Polygenic risk scores (PRSs) assessing 77 breast cancer genetic susceptibility loci personalizes risk estimates. We examined effect of personalized PRS breast cancer risk prediction on intention to take and endocrine therapy uptake among women at increased risk. Eligible participants had a 10-year breast cancer risk ≥5% by Tyrer-Cuzick model [International Breast Cancer Intervention Study (IBIS)] or ≥3.0 % 5-year Gail Model risk with no breast cancer history or hereditary breast cancer syndrome. Breast cancer risk was estimated, endocrine therapy options were discussed, and endocrine therapy intent was assessed at baseline. After genotyping, PRS-updated breast cancer risk estimates, endocrine therapy options, and intent to take endocrine therapy were reassessed; endocrine therapy uptake was assessed during follow-up. From March 2016 to October 2017, 151 patients were enrolled [median (range) age, 56.1 (36.0-76.4 years)]. Median 10-year and lifetime IBIS risks were 7.9% and 25.3%. Inclusion of PRS increased lifetime IBIS breast cancer risk estimates for 81 patients (53.6%) and reduced risk for 70 (46.4%). Of participants with increased breast cancer risk by PRS, 39 (41.9%) had greater intent to take endocrine therapy; of those with decreased breast cancer risk by PRS, 28 (46.7%) had less intent to take endocrine therapy (P < 0.001). On multivariable regression, increased breast cancer risk by PRS was associated with greater intent to take endocrine therapy (P < 0.001). Endocrine therapy uptake was greater among participants with increased breast cancer risk by PRS (53.4%) than with decreased risk (20.9%; P < 0.001). PRS testing influenced intent to take and endocrine therapy uptake. Assessing PRS effect on endocrine therapy adherence is needed.Prevention Relevance: Counseling women at increased breast cancer risk using polygenic risk score (PRS) risk estimates can significantly impact preventive endocrine therapy uptake. Further development of PRS testing to personalize breast cancer risk assessments and endocrine therapy counselling may serve to potentially reduce the incidence of breast cancer in the future.

Abstract PD3-03: Impact of the breast cancer polygenic risk score on preventive endocrine therapy adherence and endocrine therapy usage on quality of life - The Genetic Risk Estimate (GENRE) trial

Abstract Background: Studies demonstrate breast cancer risk reduction of 50-65% with the use of endocrine therapy (ET) and yet drug uptake and adherence in this setting is suboptimal even among high risk women. A Polygenic Risk Score (PRS) comprised of 77 BC genetic susceptibility loci (Single Nucleotide Polymorphisms (SNP)) can provide a personalized risk assessment and potentially influence ET adherence. We assessed ET adherence at 1 year comparing women whose risk estimate increased due to PRS versus women whose risk estimate decreased due to PRS. The effect of ET use on quality of life (hot flashes, night sweats, vaginal dryness, weight gain, joint pain) was evaluated. Methods: Eligible women required either a 5 year Gail Model risk of ≥3% or 10 year IBIS ( International Breast Intervention Study or Tyrer-Cuzick model) of ≥5%. Women with a history of breast cancer (BC) or hereditary BC syndrome were excluded. High risk women were counseled at baseline using their Gail and IBIS risk scores and ET options were discussed including benefits and risks. Participants completed a self-reported questionnaire at baseline to assess their understanding of breast cancer risk and decision to take preventive ET. Blood samples were obtained and genotyped for 77 SNPs, and the odds ratio from the SNPs were used to modify the IBIS and Gail risk estimates. The BC -PRS risk estimate information was shared with study participants that reflected the IBIS and Gail risk estimates for 5 year, 10 year, &amp; lifetime BC risk with and without the PRS. Follow up questionnaires at year 1 were administered to assess drug adherence and ET usage on quality of life. Results: 151 women were enrolled at Mayo Clinic Rochester and CancerCare Manitoba from 2016 to 2017. The median age was 56.1 (range 36-76.4), 35.6% were premenopausal, 98.7% were Caucasian and 64.7% had&amp;gt;1 family member with BC. Median 5yr, 10yr, &amp; lifetime IBIS- PRS risk estimates were 3.8% (2.0-11.5), 7.9% (5.0-23.1), and 25.3% (5.5 to 92.2). At year 1 (n=112 women) 46 % of those with an increase in risk when considering the BC-PRS score and 16 % with a decrease in risk were taking ET ( p&amp;lt; 0.001). Types of ET taken: tamoxifen-18, raloxifene- 3, exemestane -14 and missing-1. Women taking ET reported weight gain ( 19.4% vs 6.7%, p=0.04) and more joint pain ( 27.8 % vs 12%, p=0.04) when compared to women not taking ET. Conclusion: In high risk women, BC-PRS risk estimates in addition to standard BC risk calculators had a significant impact on preventive ET adherence. ET use was associated with weight gain and joint pain. Citation Format: Sandhya Pruthi, Julian O Kim, Daniel Schaid, Andrew Cooke, Christina Kim, Benjamin Goldenberg, Jason Sinnwell, Debjani Grenier, Fergus Couch, Celine Vachon. Impact of the breast cancer polygenic risk score on preventive endocrine therapy adherence and endocrine therapy usage on quality of life - The Genetic Risk Estimate (GENRE) trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-03.

Breast cancer genetic susceptibility: With focus in Saudi Arabia

Abstract In recent years there have been important advances in molecular genetics and linkage analysis of the breast cancer. Beside germline BRCA1 or BRAC2 mutations, and somatic genetic alterations, epigenetic alterations in numerous genes play an essential role in the tumorigenesis of breast cancer. TP53, STK11, PTEN, CDH1, NF1 or NBN mutations are associated with high breast cancer associated syndromes. Mutations in DNA repair associated genes (ATM, CHEK2, BRIP1, PALB2 and RAD50) are associated with increased breast cancer risk. Moreover, several single nucleotide polymorphisms (SNPs) were considered as breast cancer susceptibility polymorphisms within genes (FGFR2, TOX3, LSP1, MAP3K1, and TGFB1). This review discusses breast cancer genetic susceptibility, highlights recent advances in breast cancer genetics, with a particular focus in Saudi women.

Abstract IA05: Modeling genetic susceptibility to breast cancer

Abstract Several breast cancer genetic susceptibility variants have been identified to date. These include mutations in the high risk BRCA1 and BRCA2 genes, other rare genetic variants conferring intermediate to high risks (e.g. PALB2, CHEK2, ATM and others) and &amp;gt;150 common alleles (SNPs) conferring low risks. The presentation will provide an overview of the latest developments and challenges in understanding the penetrance of mutations in BRCA1, BRCA2 and PALB2. Genetic counseling of women with BRCA1 and BRCA2 mutations currently relies on average cancer risk estimates obtained from retrospective penetrance studies. The talk will present penetrance estimates from ongoing prospective analyses, based on data from the International BRCA1/2 Carrier Cohort Study, the largest prospective cohort of BRCA1/2 mutation carriers that includes ~10,000 BRCA1/2 mutation carriers with follow-up information. The talk will also review the latest efforts and results from the Consortium of Investigators of Modifiers of BRCA1/2 to identify and characterise genetic modifiers of cancer risks for BRCA1 and BRCA2 mutation carriers and to provide individualized cancer risks for women with BRCA1 and BRCA2 mutations. Finally, the presentation will describe the efforts to develop a comprehensive risk prediction model for breast cancer, specifically the BOADICEA model that includes the explicit effects of mutations in BRCA1, BRCA2, PALB2, CHEK2, ATM, and of the common breast cancer susceptibility variants identified through genome-wide association studies. Citation Format: Antonis C. Antoniou. Modeling genetic susceptibility to breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr IA05.

An association study between CHEK2 gene mutations and susceptibility to breast cancer

CHEK2 gene is known as a tumor suppressor gene in breast cancer (BC), which plays a role in DNA repair. The germ line mutations in CEHK2 have been associated with different types of cancer. The present study was aimed at studying the association between CHEK2 mutations and BC. Peripheral blood was collected from patients into a test tube containing EDTA, and DNA was extracted from blood samples. Then, we analyzed mutations including 1100delc, IVS2+1>A, del5395bp, and I157T within CHEK2 gene in patients with BC and 100 normal healthy controls according to PCR-RFLP, allelic specific PCR, and multiplex-PCR. Although IVS2+1G>A mutation within CHEK2 gene was found in two BC patients, other defined mutants were not detected. For the first time, we identified CHEK2 IVS2+1G>A mutation, one out of four different CHEK2 alterations in two Iranian BC patients (2%). Also, our results showed that CHEK2 1100elC, del5395bp, and I157T mutations are not associated with genetic susceptibility for BC among Iranian population.

Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast.

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per-allele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.

Genetic and Epigenetic Regulation of TOX3 Expression in Breast Cancer.

Genome wide association studies (GWAS) have identified low penetrance and high frequency single nucleotide polymorphisms (SNPs) that contribute to genetic susceptibility of breast cancer. The SNPs at 16q12, close to the TOX3 and CASC16 genes, represent one of the susceptibility loci identified by GWAS, showing strong evidence for breast cancer association across various populations. To examine molecular mechanisms of TOX3 regulation in breast cancer, we investigated both genetic and epigenetic factors using cell lines and datasets derived from primary breast tumors available through The Cancer Genome Atlas (TCGA). TOX3 expression is highly up-regulated in luminal subtype tumors compared to normal breast tissues or basal-like tumors. Expression quantitative trait loci (eQTL) analyses revealed significant associations of rs3803662 and rs4784227 genotypes with TOX3 expression in breast tumors. Bisulfite sequencing of four CpG islands in the TOX3 promoter showed a clear difference between luminal and basal-like cancer cell lines. 5-Aza-2’-deoxycytidine treatment of a basal-like cancer cell line increased expression of TOX3. TCGA dataset verified significantly lower levels of methylation of the promoter in luminal breast tumors with an inverse correlation between methylation and expression of TOX3. Methylation QTL (mQTL) analyses showed a weak or no correlation of rs3803662 or rs4784227 with TOX3 promoter methylation in breast tumors, indicating an independent relationship between the genetic and epigenetic events. These data suggest a complex system of TOX3 regulation in breast tumors, driven by germline variants and somatic epigenetic modifications in a subtype specific manner.

Association between genetic variants of EGF-containing fibulin-like extracellular matrix protein1 gene and sporadic breast cancer in a Chinese Han population.

Genetic susceptibility of breast cancer has been shown to be modulated by inheritance of polymorphic genes. EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) gene played an important role in many tumors, including lung cancer, hepatic carcinoma, and prostate cancer. In addition, it was importantly downexpressed in breast cancer. The present research aimed to assess the association between genetic variations of EFEMP1 and breast cancer risk. The authors genotyped 11 common tagging SNPs with an array platform including 960 cases and 972 cancer-free controls of Chinese women, according to the HapMap database based on the pairwise linkage disequilibrium (LD) r² threshold of 0.8, minor allele frequency of 0.05. Three SNPs were significant associated with breast cancer (rs3791679, p = 0.016, OR = 1.21, 95% CI = 1.04-1.41; rs1346786, p = 0.005, OR = 1.31, 95% CI = 1.08 -1.59; rs727878, p = 0.002, OR = 1.29, 95%CI = 1.10-1.51). Multivariate logistic regression analysis revealed that, compared with wild-type carriers in a dominant model, a significantly increased breast cancer risk was associated with the three identified risk SNPs. Among the selected tagging SNPs, three haplotype blocks were identified, and the results of haplotype analysis were consistent with the single-locus analysis. The haplotype 'GG' in block 1 and haplotype 'AG' in block 2 were significantly associated with breast cancer, and had a 54% and 28% increased breast cancer risk respectively, compared with their corresponding noncarriers. The present results suggested that the polymorphisms of EFEMP1 gene were associated with breast cancer and might contribute to the susceptibility of the progression of breast cancer in Chinese Han women. Individuals with the risk alleles might increase the risk of breast cancer.

Association between fibroblast growth factor receptor-2 gene polymorphism and risk of breast cancer in Chinese populations: A HuGE review and meta-analysis.

To evaluate the effect of fibroblast growth factor receptor.2. (FGFR2) on genetic susceptibility for breast cancer. (BC) in Chinese populations. A computerized literature search was carried out in PubMed, Chinese Biomedical Database. (CBM), and Chinese National Knowledge Infrastructure. (CNKI) to collect relevant articles. Pooled odds ratio. (OR) and 95% confidence interval. (CI) were used to assess the strength of the associations. A total of 21 articles involving a total of 15 polymorphisms of the FGFR2 gene were included in the meta-analysis. Due to the limited studies for rs17102287, rs2981578, rs3135718, rs3803662, rs3750817, rsl0510097, rsl7542768, rs13387042, and rs1982073; we only pooled the six polymorphisms. (rs11200014, rs1219648, rs2420946, rs2912778, rs2981579, and rs2981582) into this meta. Overall, significantly increased BC risk was associated with five polymorphisms. (rs2981579, rs2981582, rs1219648, rs2420946, and rs2912778) when all studies were pooled into the meta. When stratified by ethnicity and source of controls, similar results were also detected. However, for rs2981579 no significant association was found among Chinese Han in all genetic models. Our meta-analysis suggests that FGFR2 is likely an important genetic marker contributing to susceptibility of BC. We recommend that these single nucleotide polymorphisms to be included in future association studies and functional assays.

Evaluation of a newly discovered breast cancer susceptibility locus at 6q25.1 in Iranian Azari-Turkish women.

Aim of the studyA recent breast cancer genome-wide association study (GWAS) identified single-nucleotide polymorphism (SNP) rs2046210 on 6q25.1 showing a strong association with breast cancer risk. Numerous association studies have been conducted to investigate the relationship between this polymorphism and breast cancer risk in various populations. There have been conflicting reports about the association of this locus with breast cancer risk in different ethnic groups. For the first time, this study has investigated the association of rs2046210 SNP with breast cancer risk in Iranian Azari-Turkish women in North West Iran.Material and methodsIn this study 192 breast cancer subjects and 186 healthy controls were genotyped using Taqman SNP genotyping assays for different SNP rs2046210 alleles.ResultsNo significant association between rs2046210 SNP alleles and the risk of breast cancer was detected in Iranian Azari-Turkish women.ConclusionsThe data suggests that rs2046210SNP does not play a role in the aetiology of breast cancer in the Iranian Azari-Turkish population, and it indicates possible genetic differences for breast cancer between different population ancestries. Our result is an important contribution to the literature about genetic susceptibility for breast cancer in Asian populations. Additional studies are required to confirm our findings.

Five COX-2 gene polymorphisms and risk of breast cancer: an updated meta-analysis based on 19 case-control studies.

The correlationship between COX-2 gene polymorphisms and breast cancer has been wildly studied, but the results remain controversial. Hence, the present meta-analysis aimed to investigate the association between COX-2 SNPs (rs5275, rs20417, rs689466, rs5277, rs2206593) and risk of breast cancer. Data were collected from PubMed, Embase and China National Knowledge Infrastructure. Summary odds ratio (OR) with 95% confidence interval (CI) was applied to assess the relationship. Heterogeneity test, sensitivity analysis and publication bias test were also performed. There were 17 articles that contained 19 studies in this research. Fourteen case-control studies with 15,007 breast cancer cases and 20,005 controls were concerning rs5275 polymorphism, and 8 case-control studies with 10,216 cases and 12,839 controls were about rs20417 polymorphism. Other three polymorphisms (rs689466, rs2206593, rs5277) were studied in 5, 3 and 3 studies, respectively. COX-2-rs20417 CC genotype was significantly associated with increased risk of breast cancer when comparing to G allele [ORs were 1.231 (1.050-1.444) for CC vs. GG, P=0.01, 1.223 (1.045-1.432) for CC vs. G carrier, P=0.01]. Furthermore, the results of the subgroup analysis by ethnicity suggested that C allele significantly contributed to the risk of breast cancer for Asians [1.459 (1.182-1.802) for GC vs. GG, 1.472 (1.201-1.805) for C carrier vs. GG]. However, no association was found for rs5275, rs689466, rs5277 and rs2206593 in all comparison modes. This meta-analysis indicated that the COX-2 rs20417 polymorphism contributed to genetic susceptibility of breast cancer. In contrast, COX-2 rs5275, rs689466, rs2206593 and rs5277 polymorphisms might be not associated with the risk of breast cancer.

A study on genetic variants of Fibroblast growth factor receptor 2 (FGFR2) and the risk of breast cancer from North India.

Genome-Wide Association Studies (GWAS) have identified Fibroblast growth factor receptor 2 (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 (after Bonferroni correction, P<0.000694), 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 (OR = 1.645, 95%CI = 1.152–2.347, P = 0.006). In haplotype analysis, for rs2981578, rs2981582 and rs1219648, risk haplotype (GTG) was associated with a significantly increased risk compared to the common (ACA) haplotype (OR = 1.365, 95% CI = 1.086–1.717, P = 0.008). Our results suggest that intron 2 SNPs of FGFR2 may contribute to genetic susceptibility of breast cancer in North India population.

Genetic breast cancer susceptibility variants and prognosis in the prospectively randomized SUCCESS A trial

Genetic breast cancer susceptibility variants and prognosis in the prospectively randomized SUCCESS A trial