Research Findings

Genetic Studies - Breast Cancer

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus (2016)
 In a pooled analysis of breast cancer cases (63,337) and comparison subjects from 96 international studies participating in the Breast Cancer Association Consortium and the Consortium of Investigators of Modifiers, fine-scale mapping of a locus on chromosome 12 (12p11) identified four independent association signals for breast cancer risk among women of European origin. Multiple candidate causal variants were identified at each signal and several putative functional variants were also identified.
Prediction of breast cancer risk based on profiling with common genetic variants (2015)
 Genomic profiling based on 77 currently established single nucleotide polymorphisms was found to improve breast cancer risk prediction in women with and without a family history of breast cancer.
Analysis of heritability and shared heritability based on genome-wide association studies for thirteen cancer types (2015)
 Findings from an analysis of more than 80,000 individuals revealed a large heritable component to most cancers, but most of the cancer heritability could not be attributed to known susceptibility loci, marker SNPs were not consistently present across cancers, and genetic correlations between most pairs of cancer sites were not strong.
Sunlight, polymorphisms in vitamin D-related genes and risk of breast cancer (2013)
 In a study of 1,329 radiologic technologists, including 484 women with breast cancer and 845 control subjects, breast cancer risks were evaluated in relation to 8 single nucleotide polymorphisms (SNPs) in vitamin D-related genes. Two of six SNPs in the CYP24A1 gene were associated with increased, and one with reduced breast cancer risk, while one of two SNPs in the VDR gene was related to decreased risk. Measures of sunlight exposure were not linked to breast cancer risk.
Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors (2013)
 Using data from 24 studies participating in the Breast Cancer Association Consortium, including 34,793 breast cancer cases and 41,099 controls of European ancestry, the authors examined whether risks associated with 23 single nucleotide polymorphisms (SNPs) were modified by 10 established breast cancer risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity). Risks associated with two SNPs varied by parity status and risk related to one SNP varied by alcohol consumption.
A role for XRCC2 gene polymorphisms in breast cancer risk and survival (2011)
 In a study involving discovery (Sheffield Breast Cancer Study), replication (Utah Breast Cancer Study), and survival analysis (USRT and 5 other cohorts), 12 XRCC2 tagging SNPs were evaluated. The most significant associations observed were increased breast cancer risk with the XRCC2 (rs3218408) SNP and poor breast cancer survival with the XRCC2 coding R188H SNP (rs3218536).
Novel breast cancer risk alleles and interaction with ionizing radiation among U.S. radiologic technologists (2010)
 In an effort to understand the underlying genetic mechanisms that influence breast cancer risk, we evaluated variation in risk by genotype based on exposure to radiation, which is a known carcinogen. We examined interaction between 27 newly identified breast cancer risk alleles and occupational and medical diagnostic radiation exposure among 859 cases and 1083 controls. We did not find significant variation in the radiation-related breast cancer risk for a variant in RAD51L1 as hypothesized; however, we found that radiation-associated breast cancer risk varied significantly by several linked markers in the MRPS30 gene.
Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the Breast Cancer Association Consortium: a combined case-control study (2010)
 In a study of 26,349 invasive breast cancer cases and 32,308 comparison subjects from 21 case-control studies included in the Breast Cancer Association Consortium, researchers evaluated 12 recently identified breast cancer genetic susceptibility variants (10Q26-RS2981582 [FGFR2], 8q24-rs13281615, 11p15-rs3817198 [LSP1], 5q11-rs889312 [MAP3K1], 16q12-rs3803662 [TOX3], 2q35-rs13387042, 5p12-rs10941679 [MRPS30], 17q23-rs6504950 [COX11], 3p24-rs4973768 [SLC4A7], CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314) in combination with other cancer risk factors, including age at menarche, parity, number of live births, age at first birth, and body mass index. The breast cancer risks associated with these genetic polymorphisms did not differ significantly according to BMI or reproductive history.
Polymorphisms in oxidative stress and inflammation pathway genes, low-dose ionizing radiation, and the risk of breast cancer among U.S. radiologic technologists (2010)
 We estimated breast cancer risk for 28 common variants in 16 candidate genes involved in oxidative stress and inflammatory pathways among 859 breast cancer cases and 1,083 controls nested within the U.S. Radiologic Technologists cohort. We also assessed differences in breast cancer dose-response from occupational and personal diagnostic radiation exposures across genotypes. We found suggestive evidence of an interaction between a variant in the PTGS2 gene and radiation-related breast cancer risk (pinteraction= 0.04). The association between radiation and breast cancer was not modified by other SNPs examined. This study suggests that variation in PTGS2 may modify the breast cancer risk from occupational radiation exposure, but replication in other populations is needed to confirm this result.
Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2 (2009)
 More than 800 promising associations from genome-wide association studies (GWAS) of breast cancer were tested in two stages among 37,012 cases and 40,069 controls from 33 studies. Strong evidence for additional susceptibility loci on chromosomes 3p (rs4973768: per-allele OR=1.11, 95% CI=1.08-1.13) and 17q (rs6504950: per-allele OR=0.95, 95% CI=0.92-0.97) were observed. Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.
Association of ESR1 gene tagging SNPs with breast cancer risk (2009)
 A comprehensive SNP-tagging study of the ESR1 gene in more that 55,000 breast cancer cases and controls from the Breast Cancer Association Consortium revealed no large associations of common ESR1 gene variants with breast cancer risk. A marginally significant increase primarily in estrogen-receptor positive breast cancer risk was observed for SNP rs3020314 tagging a region of ESR1 intron 4.
Five polymorphisms and breast cancer risk: results from the Breast Cancer Association Consortium (2009)
 Based on a combined analysis of more than 30,000 breast cancer cases and 30,000 controls from 30 studies in the Breast Cancer Association Consortium, persuasive evidence against an overall association between invasive breast cancer risk and five polymorphisms that were associated inconclusively in previous studies was observed. The polymorphisms studied were ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315.
Polymorphisms in estrogen biosynthesis and metabolism-related genes, ionizing radiation exposure, and risk of breast cancer among US radiologic technologists (2009)
 We evaluated breast cancer risk related to 12 candidate variants in 12 genes involved in steroid metabolism, catabolism, binding, or receptor functions in a case-control study of 859 breast cancer cases and 1083 controls. Using cumulative breast dose estimates from a detailed assessment of occupational and personal medical ionizing radiation exposure, we examined the joint effects of radiation and genotype on breast cancer risk. We found that the minor allele of CYP1b1 V432L significantly increased the dose-response relationship between personal diagnostic x-ray exposure and breast cancer adjusted for occupational radiation exposure, and had a similar joint effect for occupational radiation exposure adjusted for personal diagnostic x-ray exposure.
A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1) (2009)
 The Cancer Genetic Markers of Susceptibility (CGEMS) consortium, in which the U.S. Radiologic Technologists Study participates, undertook a three-stage genome-wide association study of breast cancer in 9,770 cases and 10,799 controls. Strong associations were confirmed for six previously reported genomic regions on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26, and 16q12.1 and new risk alleles were identified at 1p11.2 and 14q24.1.
Breast cancer risk polymorphisms and interaction with ionizing radiation among U.S. radiologic technologists (2008)
 We evaluated the possible modifying effect by radiation on the genotype-associated breast cancer risk of 11 single-nucleotide polymorphisms in a study of 859 cases and 1083 controls. We found that breast cancer risk varied significantly by radiation dose for the rs2107425 variant in the H19 gene.
Polymorphisms in DNA repair genes, ionizing radiation exposure and risk of breast cancer in U.S. radiologic technologists (2008)
 We investigated the potential modification of radiation-related breast cancer risk by 55 candidate single nucleotide polymorphisms in 17 genes involved in base excision or DNA double-strand break repair among 859 cases and 1083 controls. A variant in the WRN gene significantly modified the association between occupational breast dose and breast cancer risk, while one variant in the BRCA1 gene and three variants in the PRKDC gene significantly altered the personal diagnostic radiation exposure-response relationship.
Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics (2008)
 The clinical presentation of breast cancer was evaluated among 23,039 invasive breast cancer cases and 26,272 controls from 20 studies, and survival after diagnosis was evaluated among 13,527 cases from 13 studies, according to common variants in five susceptibility loci (FCFR2, TNRC9, MAP3K1, 8q24, and LSP1) recently identified by the Breast Cancer Association Consortium. Variants in the FCFR2 (fibroblast growth receptor 2) gene and the 8q24 region were more strongly related to estrogen-receptor positive vs. ER-negative and to low-grade vs. high-grade tumors. Survival was not associated with these loci after adjustment for known indicators of prognosis. These findings indicate that pathological subtype of breast cancer is influenced by common genetic variants and supports the theory that ER-positive and ER-negative tumors differ biologically.
Nucleotide excision repair polymorphisms may modify ionizing radiation-related breast cancer risk in US radiologic technologists (2008)
 We evaluated breast cancer risk associated with six candidate variants in four nucleotide excision repair genes in a case-control study of 859 breast cancer cases and 1083 controls. The findings suggested that the C allele variant in ERCC5 (XPG) rs17655 was related to breast cancer risk and may modify the radiation-related breast cancer association. The AA variant in ERCC2 (XPG) rs13181 also modified the radiation-related breast cancer risk.
A common coding variant in CASP8 is associated with breast cancer risk (2007)
 The Breast Cancer Association Consortium (BCAC), which includes the U.S. Radiologic Technologist Study, was established to conduct combined case-control studies to confirm genetic associations with breast cancer. Nine single-nucleotide polymorphisms that were previously associated with breast cancer were studied. BCAC found evidence of an association with a common coding variant in the CASP8 gene.
Genome-wide association study identifies multiple novel breast cancer susceptibility loci (2007)
 The Breast Cancer Association Consortium (BCAC), which includes the U.S. Radiologic Technologist Study, was established to conduct combined case-control studies to confirm genetic associations with breast cancer. To identify additional breast cancer susceptibility alleles, BCAC conducted a two-stage genome-wide association study, followed by a third stage in which 30 single-nucleotide polymorphisms were tested for confirmation in cases and controls from 22 studies.
Polymorphisms in apoptosis- and proliferation-related genes, ionizing radiation exposure, and risk of breast cancer among U.S. radiologic technologists (2007)
 In a case-control study of 859 breast cancer cases and 1083 controls, we assessed breast cancer risk related to 16 candidate variants in eight genes involved in apoptosis, inflammation, and proliferation, and the joint effects of these variants with occupational and personal diagnostic radiation on risk. We found that IL1A A114S significantly modified the radiation dose-response relationship between cumulative personal diagnostic radiation and breast cancer risk, adjusted for occupational radiation dose.
Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Consortium (2006)
 Large sample sizes are needed to detect and confirm, at appropriate levels of statistical significance, genetic variants that are associated with modest increases in cancer risk. We participate in the Breast Cancer Association Consortium, which includes more than 20 international collaborative groups, with a combined sample size in excess of 30,000 breast cancer cases and 30,000 controls. The current study evaluated 16 single-nucleotide polymorphisms that were previously evaluated by at least 3 of the participating centers. Five of the SNPs were found to be associated with breast cancer risk, while 11 were not.
The ATM missense mutation p.Ser49Cys (c.146C>G) and risk of breast cancer (2006)
 In a combined analysis of breast cancer cases and controls from the USRT and Polish Breast Cancer Studies, we found convincing evidence that missense mutations in the ataxia telangiectasia gene (ATM) may be associated with increased breast cancer risk.
CHEK2:1100delC and female breast cancer in the United States (2004)
 A genetic mutation in the CHEK2 gene (1100delC) was evaluated as a possible breast cancer susceptibility allele in two populations: a nested breast cancer case-control study within the USRT cohort and a study of families with breast/ovarian cancer. Investigators concluded that this mutation appears to be a rare allele that approximately doubles a carrier's risk of breast cancer.
Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes (2004)
 A recently developed statistical method called "Kin Cohort" allowed us to evaluate the association of normal genetic variation (called polymorphisms) and breast cancer risk in family members. We analyzed 19 single nucleotide polymorphisms (SNPs) in eight genes related to DNA repair, growth regulation, and protein interaction with BRCA1. We assessed these SNPs and breast cancer risk among first-degree relatives (mothers, sisters, daughters) based on family history information. We found that two SNPs in a DNA repair gene and one SNP in a gene coding a BRCA1 interacting protein (BRIP1) were associated with increased breast cancer risk. However, because we analyzed so many variants at one time, when we adjusted for all of our comparisons none of the associations remained significant. We were surprised to find two polymorphisms (one in a DNA repair gene and another in BRCA2) that were significantly associated with decreased breast cancer risk. We plan to follow-up these interesting findings with additional studies.
Re: Population-Based, Case-Control Study of HER2 Genetic Polymorphism and Breast Cancer Risk (letter) (2003)
 Using the same kin-cohort methodology described above, we also investigated breast cancer risk associated with a polymorphism in the human epidermal growth factor receptor 2 (HER2) protooncogene. We found an increased breast cancer risk up to age 70 associated with the polymorphic variant, but this was not statistically significant. However, the risk estimate was consistent with several previous reports, suggesting that risk may indeed be increased for breast cancer.
Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIP1/BACH1 among BRCA1 and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals (2003)
 We continued our research plan of finding and describing new polymorphisms in genes that associate with BRCA1 and to also try to discover new genes related to breast cancer susceptibility. Using some of the same 58 anonymous samples from radiologic technologists who developed breast cancer before age 35, two newly discovered genes (ZNF350 and BRIP1) were searched for polymorphisms. Several new polymorphisms were found that will be studied further in the US Radiologic Technologist study and likely epidemiologic studies of other populations.
A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers (2001)
 We tried the gene called RAD51 because it associates with BRCA1 and BRCA2 and it is involved in DNA repair. We wanted to see if genetic differences in RAD51 could impact whether someone with a BRCA1 or BRCA2 mutation might or might not get breast cancer. As described above, anonymous samples from 10 radiologic technologists who had multiple cancers (breast cancer and a cancer of another site) were included to discover variations in the RAD51 gene. The variations we searched for are called polymorphisms. Polymorphisms are different from mutations. Polymorphisms are considered to be normal genetic variation because they are common and on their own are not thought to be the cause of any specific disease. However, polymorphisms could be weakly related to disease, often in combination with other genes and environmental factors, but their effect can only be found if large population groups are studied. We discovered two new polymorphisms and tested them to see if they changed the risk of breast or ovarian cancer among several groups of women (not radiologic technologists) with BRCA1 or BRCA2 mutations. The results were mixed and depended on the group studied, but generally suggested an increased breast cancer risk for one of the polymorphisms and BRCA2.
BRCA1 mutations in young women with breast cancer (1996)
 Since breast cancer has been associated with radiation exposure in several studies, including atomic bomb survivors, we are very interested in genes that could change how our cells handle damage caused by radiation. One of the first genes identified that strongly predisposes someone to breast cancer is BRCA1. Because the BRCA1 gene is involved in DNA repair, we thought this gene would be a good place to start. But, the genetic tests for BRCA1 mutations are extremely time consuming and expensive, we thought that picking some of the most common mutations and screening only for those in a high risk group (women who were diagnosed with breast or ovarian cancer at age 35 or younger), would be valuable for our research purposes. After we completely removed any and all information that would link an individual to a particular sample (we made the samples "anonymous"), we found that 3 of 70 had a mutation in BRCA1. We concluded this method would work as a crude screen to establish mutation frequencies in large population groups, but we estimated we would miss about 55% of women who were true carriers of a BRCA1 mutation. This meant that at least 4.3% of women who developed breast or ovarian cancer before age 35 are likely to have a BRCA1 mutation.