Breast Cancer Family Registry Research Articles

Abstract IA42: Genome wide association for breast cancer risk in Latinas: Analysis of known susceptibility loci

Abstract Background: Genome wide association studies have identified over 90 common variants associated with breast cancer risk. The majority of these findings have been made in populations of European ancestry. We have performed a genome wide association study of in ~2400 US Latina and Mexican breast cancer cases and ~7500 controls. Here we report on examination of previously reported loci and fine mapping within those loci. Methods: Cases and controls included women from the San Francisco Bay Area Study, the Northern California Breast Cancer Family Registry, the Multi-Ethnic Cohort and the Kaiser Permanente Research Program on Genes and the Environment on Health all based in California. In addition we included cases and controls from the CAMA study, based in Mexico and recruiting from 4 different states: Mexico City, Veracruz, Monterrey, and Puebla. Each of the samples were genotyped using an array with genome wide coverage (Affymetrix 6.0, Affymetrix Axiom, Illumina 1M, Illumina 2.5M or Illumina Oncoarray). We inferred genetic ancestry using principal components analysis. We imputed each array to the Haplotype Reference Consortium and performed association testing with breast cancer using logistic regression models, adjusting for study, array used, and principal components 1-10. Results: We have identified several signals at 6q25 which are independent of previously reported SNPs in other populations. We have also evaluated the utility of polygenic risk using data from common variants at previously reported loci. We compared a range of algorithms to enhance the predictive power of polygenic risk in Latinas, including ones that utilize fine mapping vs. ones which use the top SNPs from other populations. Conclusion: We demonstrate that a combination of new variants and judicious use of data from the known loci generates useful polygenic risk for breast cancer in Latinas. Citation Format: Joshua Hoffman, Sarah Sawyer, Laura Fejerman, Donglei Hu, Scott Huntsman, Esther John, Gabriela Torres-Mejia, Larry Kushi, Chistopher Haiman, Elad Ziv. Genome wide association for breast cancer risk in Latinas: Analysis of known susceptibility loci. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA42.

Methylation of Breast Cancer Predisposition Genes in Early-Onset Breast Cancer: Australian Breast Cancer Family Registry.

DNA methylation can mimic the effects of both germline and somatic mutations for cancer predisposition genes such as BRCA1 and p16INK4a. Constitutional DNA methylation of the BRCA1 promoter has been well described and is associated with an increased risk of early-onset breast cancers that have BRCA1-mutation associated histological features. The role of methylation in the context of other breast cancer predisposition genes has been less well studied and often with conflicting or ambiguous outcomes. We examined the role of methylation in known breast cancer susceptibility genes in breast cancer predisposition and tumor development. We applied the Infinium HumanMethylation450 Beadchip (HM450K) array to blood and tumor-derived DNA from 43 women diagnosed with breast cancer before the age of 40 years and measured the methylation profiles across promoter regions of BRCA1, BRCA2, ATM, PALB2, CDH1, TP53, FANCM, CHEK2, MLH1, MSH2, MSH6 and PMS2. Prior genetic testing had demonstrated that these women did not carry a germline mutation in BRCA1, ATM, CHEK2, PALB2, TP53, BRCA2, CDH1 or FANCM. In addition to the BRCA1 promoter region, this work identified regions with variable methylation at multiple breast cancer susceptibility genes including PALB2 and MLH1. Methylation at the region of MLH1 in these breast cancers was not associated with microsatellite instability. This work informs future studies of the role of methylation in breast cancer susceptibility gene silencing.

Mismatch Repair Polymorphisms as Markers of Breast Cancer Prevalence in the Breast Cancer Family Registry.

Major breast cancer susceptibility genes involved in DNA repair, including BRCA1 and BRCA2, have been identified. However, mutations in these genes account for only 5-10% of identified breast cancer cases. Additional DNA repair pathway genes may also contribute to susceptibility. We investigated the association between 12 single nucleotide polymorphisms (SNPs) in mismatch repair (MMR) genes and breast cancer risk among 313 sister-sets enrolled in the New York site of the Breast Cancer Family Registry (BCFR) (n=744) using conditional logistic regression analysis. An increase in breast cancer risk was observed for women with the MUTYH_rs3219489 variant allele (odds ratio (OR)=2.23, 95% confidence interval (CI)=1.10-4.52) and for women with the MSH2_rs2303428 variant allele (OR=1.73, 95% CI=1.00-2.99). Deficiencies in DNA repair pathways, such as MMR, have implications for the onset of familial breast cancer.

Abstract 2555: Promoter DNA methylation patterns in breast tumor and matched adjacent non-tumor tissues in the breast cancer family registry

Abstract Alterations in DNA methylation occur frequently in breast carcinogenesis, but little is known about the DNA methylation changes in familial breast tumors. To examine whether the DNA methylation profiles in breast cancer tissues from high risk women from breast cancer families are similar to breast tumor tissues from The Cancer Genome Atlas project (TCGA), we measured DNA methylation by next generation sequencing in 48 genes identified in TCGA in 40 formalin-fixed, paraffin-embedded tumor tissues, and the corresponding adjacent non-tumor tissues from women with invasive breast cancer at the New York site of the Breast Cancer Family Registry (BCFR). We observed differences in DNA methylation patterns between tumor and normal adjacent tissue for five of the selected genes (RYR2, C1orf14, SLC7A14, SEPW1, and RPTOR). The methylation levels in tumor and adjacent tissues, respectively were 24% and 14% for RYR2, (p = 0.01), 55% and 29% for C1orf14 (p = 0.01), 32% and 21% for SLC7A14 (p = 0.002), 53% and 28% for RPTOR (p = 0.01) and 74% and 38% SEPW1 (p<0.0001). We only confirmed 5 of the 48 loci identified in TCGA in our sample of high risk women, suggesting genes identified from TCGA may be different than those in high-risk women. As tissue-specific methylation may prove to have strong prognostic significance, this suggests a critical need to engage in large-scale studies examining genome-wide DNA methylation profiles in high risk women in order to understand the etiology of familial breast cancer. Citation Format: Hui-Chen Wu, Hanina Hibshoosh, Regina Santella, Mary Beth Terry. Promoter DNA methylation patterns in breast tumor and matched adjacent non-tumor tissues in the breast cancer family registry. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2555.

ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry.

Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer.

Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab.

PurposeThis study examined the utility of sets of Single Nucleotide Polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC).MethodsWe derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the BCFR and kConFab familial BC cohorts. We compared scores in women based on cancer status at baseline. 2,599 women unaffected at enrollment were followed for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone.ResultsThe mean (SD) PRS baseline was 2.25 (0.35) for the affected and 2.17 (0.35) for unaffected women from combined cohorts (p<10−6). During follow-up, 205 BCs occurred. The hazard ratios for continuous PRS (per SD), and upper vs. lower quintiles were 1.38 (95% CI: 1.22–1.56) and 3.18 (95% CI: 1.84–5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered.ConclusionIncluding BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women.

Dietary Intake of Isoflavone and All‐Cause Mortality in Women with Breast Cancer: the Breast Cancer Family Registry

Dietary Intake of Isoflavone and All‐Cause Mortality in Women with Breast Cancer: the Breast Cancer Family Registry

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

BackgroundBRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group...

Breast Cancer Risk Prediction Using Clinical Models and 77 Independent Risk-Associated SNPs for Women Aged Under 50 Years: Australian Breast Cancer Family Registry.

The extent to which clinical breast cancer risk prediction models can be improved by including information on known susceptibility SNPs is not known. Using 750 cases and 405 controls from the population-based Australian Breast Cancer Family Registry who were younger than 50 years at diagnosis and recruitment, respectively, Caucasian and not BRCA1 or BRCA2 mutation carriers, we derived absolute 5-year risks of breast cancer using the BOADICEA, BRCAPRO, BCRAT, and IBIS risk prediction models and combined these with a risk score based on 77 independent risk-associated SNPs. We used logistic regression to estimate the OR per adjusted SD for log-transformed age-adjusted 5-year risks. Discrimination was assessed by the area under the receiver operating characteristic curve (AUC). Calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. We also constructed reclassification tables and calculated the net reclassification improvement. The ORs for BOADICEA, BRCAPRO, BCRAT, and IBIS were 1.80, 1.75, 1.67, and 1.30, respectively. When combined with the SNP-based score, the corresponding ORs were 1.96, 1.89, 1.80, and 1.52. The corresponding AUCs were 0.66, 0.65, 0.64, and 0.57 for the risk prediction models, and 0.70, 0.69, 0.66, and 0.63 when combined with the SNP-based score. By combining a 77 SNP-based score with clinical models, the AUC for predicting breast cancer before age 50 years improved by >20%. Our estimates of the increased performance of clinical risk prediction models from including genetic information could be used to inform targeted screening and prevention.

Abstract 3835: DNA methylation levels in mononuclear DNA in breast cancer from the New York site of the BCFR

Abstract Alterations in DNA methylation both at specific loci and overall, have been associated with breast cancer. These alterations have primarily been observed at the tissue level, although emerging studies are evaluating white blood cell (WBC) DNA methylation. To examine whether DNA methylation change measured prospectively in a family-based cohort are associated with breast cancer risk, we measured methylation levels of two repetitive elements (LINE-1, and Sat2) and three genes in mononuclear cell DNA (BLNK, CUEDC1, and IBSP) previously identified as differentially methylated in breast cancer in a genome-wide association study. After an average of 8 years of followup, we observed 81 invasive incident breast cancers and compared their methylation levels measured with baseline bloods with the remaining 1,508 women not affected with breast cancer in the New York site of the Breast Cancer Family Registry (BCFR). We found that the overall percent methylation in CUEDC1 was statistically significantly higher in breast cancer cases than in controls (78.0% versus 76.8%, respectively, p = 0.02). In a multivariable Cox Proportional Hazards model adjusting for age at blood draw, with each 1 unit increase in CUEDC1 methylation level, the OR for breast cancer increased by 1.07 (95% Confidence Interval (CI) = 1.00-1.14). We did not find the other methylation markers to be related to risk. The area under the curve was 67.6% (95% CI = 61.4% to 73.8%) for the 5 methylation markers and Gail risk score, compared with 63.3% for the Gail score only. Our finding for CUEDC1 replicates the finding from the Sisters Study supporting that selected markers selected markers of epigenetic changes measured in WBC may be potential biomarkers of breast cancer risk. Citation Format: Hui-Chen Wu, Qiao Wang, Regina M. Santella, Mary B. Terry. DNA methylation levels in mononuclear DNA in breast cancer from the New York site of the BCFR. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3835. doi:10.1158/1538-7445.AM2015-3835

Abstract 2782: Risk loci for a breast-colon cancer phenotype: results from a genome-wide association study

Abstract Purpose: Clustering of breast and colorectal cancer has been observed within families in population-based studies giving rise to speculation that there are “breast-colon” cancer susceptibility genes. We performed a genome-wide association study (GWAS) to identify genetic markers associated with a potential breast-colon cancer phenotype. Methods: Cases and controls were ascertained from the Breast and Colon Cancer Family Registries’ (CFR) GWAS subjects. “Breast-colon phenotype” definition was based on 2 or more breast and colon cancer cases diagnosed in first- or second-degree relatives within a family. Cases (n = 985) were women with a history of breast cancer and a family history of colorectal cancer, or persons with colorectal cancer with a family history of breast cancer. Unrelated controls (n = 1769) were frequency matched to cases for age and gender. Following standard quality control measures, 6,220,060 directly measured and imputed single nucleotide polymorphisms (SNPs) were included in the discovery set. SNPs associated at p&amp;lt;1×10−5 were analyzed in a replication dataset of cases (n = 293) and controls (n = 2103) from the Genetics and Epidemiology of Colorectal Cancer Consortium. Results: In a regression model that included gender, age, CFR center and 6 principal components, the top association in the discovery set was in the chromosome 8q22.3 region overlying the BAALC gene (top SNP rs12548629, P = 3.63×10−7). In the replication dataset, of 341 SNPs tested, the top signal was found in multiple correlated SNPs overlying the ROBO1 gene on chromosome 3p12 (rs7429100, P = 2.8×10−3), however, the signal on chromosome 8, the BAALC gene did not replicate. In the discovery set, P values for the SNPs overlaying ROBO1 gene ranged from 2.2×10−5 to 9.7×10−5 (rs7429100, P = 3.9×10−5). The combined meta-analysis showed strongest association at the ROBO1 gene (rs7429100, Pfixed effects 1.84×10−6, Pheterogeneity &amp;gt;0.05 for testing for heterogeneity between the overall discovery set and the replication set). ROBO1 (roundabout, axon guidance receptor, homolog 1) is a transmembrane receptor of the immunoglobulin family and is differentially expressed in human cancers, with a possible role as a tumor suppressor gene. Low ROBO1 expression has been shown to be an adverse prognostic factor for invasive ductal breast cancer and may also play a role in pathogenesis of colorectal cancer. BAALC (brain and acute leukemia, cytoplasmic) is predominantly expressed by neural and blood cells and is largely implicated in acute leukemia. Conclusion: In this exploratory analysis, to elucidate genes/regions associated with pleiotropic effect for breast and colorectal cancer risk we identified germline variation in the region of ROBO1 and BAALC. Validation in a larger dataset and functional characterization of the loci is warranted to elucidate mechanisms by which these genes/SNPs may contribute to the development of breast and colorectal cancer. Citation Format: Mala Pande, Aron Joon, Sanjay Shete, Abenaa M. Brewster, Cathy Eng, Wei V. Chen, Habibul Ahsan, Irene L. Andrulis, Esther M. John, Yi Lin, Polly A. Newcomb, Noralane M. Lindor, Christopher I. Amos, John Hopper, Patrick M. Lynch. Risk loci for a breast-colon cancer phenotype: results from a genome-wide association study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2782. doi:10.1158/1538-7445.AM2015-2782

Abstract 2759: Possible later age of breast cancer onset for Hispanic BRCA1 carriers with the protective rs140068132-G allele

Abstract Hispanic women in the U.S. have lower incidence of breast cancer compared to Non-Hispanic Whites (NHW). A genome-wide association study (GWAS) of breast cancer in Hispanics reported a relatively strong protective variant near the ESR1 gene, only observed among women with Indigenous American ancestry (rs140068132-A/G). The study also reported lower mammographic density among women who were homozygous for the Indigenous American variant (G) and a stronger protective effect for estrogen receptor negative (ER-) breast cancer. In the present study, we assessed if this variant had an effect on age at breast cancer diagnosis among Hispanic BRCA1 carriers, who commonly present with ER- disease. We combined data from four studies of Hispanic BRCA1 mutation carriers with breast cancer: the Clinical Cancer Genetics Community Research Network (CCGCRN; N = 152), Northern California Breast Cancer Family Registry (NC-BCFR, N = 27), and two studies in Latin America, one from Colombia (N = 33) and one from Chile (N = 27). We genotyped the rs140068132 variant using a Taqman assay following the recommended protocol. We used a non-parametric Kruskal-Wallis equality-of-populations rank test to evaluate if the age of breast cancer diagnosis was associated with the rs140068132 polymorphism among BRCA1 carriers. We conducted separate analyses of Hispanic women from California and women from Colombia and Chile. For the California studies, we also had information on ovarian cancer status and were able to conduct stratified analyses. Among 239 BRCA1 carriers, we observed 201 homozygous AA, 36 heterozygous AG, and 2 missing genotypes, with an overall allele frequency of the G allele of 7.6%. We did not find a statistically significant effect of rs140068132 on age at diagnosis among Hispanic BRCA1 carriers overall. However, we found a suggestion of later age at diagnosis, with median age at diagnosis of 39.8 years (33-46 years) in AA homozygous compared to 44 years (34-50 years) in heterozygous (p value = 0.1) women from California. Among women without ovarian cancer either before or after the breast cancer diagnosis, the difference in age at breast cancer diagnosis by genotype was slightly stronger (p value 0.06). We did not observe an association among the patients from Colombia and Chile. Studies of BRCA mutation carriers are often limited by selection for breast cancer cases, thus there may be a bias against enrollment of BRCA carriers with the protective allele in the present analysis. The observed suggestion of a difference in age at diagnosis in the samples from California, similar to genome-wide identified variants that have been shown to have an effect among BRCA1 and BRCA2 carriers, warrants further investigation. Citation Format: Laura Fejerman, Jeffrey N. Weitzel, Esther M. John, Cynthia Villarreal, Gary Unzeitig, Darling Horcasitas, Charite Ricker, Adrian Daneri, Kayla Castaneda, Alexander Miron, Ana Marie Tuazon, Magdalena Echeverry, Pilar Carvallo, Carolina Alvarez, Teresa Tapia, Columbus Consortium, Luis Carvajal-Carmona, Susan Neuhausen, Elad Ziv. Possible later age of breast cancer onset for Hispanic BRCA1 carriers with the protective rs140068132-G allele. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2759. doi:10.1158/1538-7445.AM2015-2759

The importance of analysis of long-range rearrangement of BRCA1 and BRCA2 in genetic diagnosis of familial breast cancer

Germline BRCA gene mutations are reportedly associated with hereditary breast and ovarian cancers. Identification of BRCA mutations greatly improves the preventive strategies and management of breast cancer. Sanger sequencing has been the gold standard in identifying these mutations. However, 4-28% of inherited BRCA mutations may be due to large genomic rearrangements (LGRs), which could be missed by using Sanger sequencing alone. Our aim is to evaluate the pick-up rate of LGRs in our cohort. A total of 1,236 clinically high-risk patients with breast and/or ovarian cancers were recruited through The Hong Kong Hereditary Breast Cancer Family Registry from 2007 to 2014. Full gene sequencing (either Sanger or next generation sequencing) and multiplex ligation-dependent probe amplification (MLPA) were performed. We identified 120 deleterious BRCA mutations: 57 (4.61%) were in BRCA1 and 63 (5.10%) were in BRCA2. LGRs accounted for 6.67% (8 of 120) of all BRCA mutations, whereas 8.77 % (5 of 57) were BRCA1 mutations and 4.76% (3 of 63) were BRCA2 mutations. Through this integrated approach, both small nucleotide variations and LGRs could be detected. We suggest that MLPA should be incorporated into the standard practice for genetic testing to avoid false-negative results, which would greatly affect the management of these high-risk families.

Prevalence of PALB2 mutations in the Creighton University breast cancer family registry.

e12519 Background: PALB2 (i.e., the partner and localizer of BRCA2) plays an important role in double-strand DNA damage repair through interaction with BRCA1, BRCA2, and RAD51. Xia et al. (Nat Gene...

Second primary breast cancer in BRCA1 and BRCA2 mutation carriers: 10-year cumulative incidence in the Breast Cancer Family Registry.

BReast CAncer genes 1 and 2 (BRCA1 and BRCA2) mutation carriers diagnosed with breast cancer are at increased risk of developing a second primary breast cancer. Data from high-risk clinics may be subject to different biases which can cause both over and underestimation of this risk. Using data from a large multi-institutional family registry we estimated the 10-year cumulative risk of second primary breast cancer including more complete testing information on family members. We prospectively followed 800 women diagnosed with breast cancer from the Breast Cancer Family Registry (BCFR) who were carriers of a BRCA1 or BRCA2 pathogenic mutation or a variant of unknown clinical significance. In order to limit survival and ascertainment bias, cases were limited to those diagnosed with a first primary breast cancer from 1994 to 2001 and enrolled in the BCFR within 3years after their cancer diagnosis. We excluded women enrolled after being diagnosed with a second breast cancer. We calculated 10-year incidence of second primary breast cancers. The 10-year incidence of a second primary breast cancer was highest in BRCA1 mutation carriers (17%; 95% CI 11-25%), with even higher estimates in those first diagnosed under the age of 40 (21%; 95% CI 13-34%). Lower rates were found in BRCA2 mutation carriers (7%; 95% CI 3-15%) and women with a variant of unknown clinical significance (6%; 95% CI 4-9%). Whereas the cumulative 10-year incidence of second primary breast cancer is high in BRCA1 mutation carriers, the estimates in BRCA2 mutation carriers and women with variants of unknown clinical significance are similar to those reported in women with sporadic breast cancer.

Abstract P3-08-04: Aspirin and breast cancer risk for BRCA1 and BRCA2 mutation carriers

Abstract Background : Although epidemiologic studies have found evidence that aspirin use may be inversely associated with breast cancer (BC) risk, little is known about whether this applies to BRCA1 and BRCA2 mutation carriers. Methods : We compared aspirin use in 613 women with BRCA1 or BRCA2 mutations from the six centers of the Breast Cancer Family Registry (BCFR) who were recruited at baseline and completed a questionnaire at 10 year follow-up. We defined cases as carriers with BC (n = 215 with BRCA1 mutations and 137 with BRCA2 mutations) and controls as carriers unaffected with BC (n = 141 with BRCA1 mutations and 120 with BRCA2 mutations). We used logistic regression to estimate odds ratios and 95% confidence intervals separately by gene mutation type. Results : Three cases (1.4%) and 27 controls (19.1%) among the BRCA1 carriers and 3 cases (2.2%) and 25 controls (20.8%) among the BRCA2 carriers reported ever use of aspirin-based medications before diagnosis. Aspirin use before diagnosis was inversely associated with BC risk for both BRCA1 (OR, 0.13; 95% CI, 0.04-0.46 for ever vs. never use) and BRCA2 (OR, 0.12; 95% CI, 0.03-0.41 for ever vs. never use) carriers, after adjusting for age and center for BRCA1 carriers and age for BRCA2 carriers. Conclusion : If replicated by larger, prospective studies, aspirin use could become an inexpensive and acceptable risk-reducing measure for BRCA1 and BRCA2 mutation carriers. Citation Format: Naomi Kornhauser, Mary Beth Terry, Linda T Vahdat, Irene Andrulis, Saundra Buys, Mary Daly, Esther John, John L Hopper, Tessa Cigler. Aspirin and breast cancer risk for BRCA1 and BRCA2 mutation carriers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-08-04.

Abstract P6-09-05: Value of adding single-nucleotide polymorphism panel markers to phenotypic algorithms of breast cancer risk

Abstract Currently, breast cancer risk prediction algorithms incorporate phenotypic risk factors, including age, family history, reproductive history and benign breast disease. Since 2007, genome-wide association studies have identified a growing number of single-nucleotide polymorphisms (SNPs) that are associated with an increased risk of breast cancer. While no single SNP is very informative on its own, a polygenic approach to genetic screening could improve estimates of individual risk, creating the possibility of screening strategies individually tailored to each woman. We studied cases and controls recruited to the Australian Breast Cancer Family Registry, to investigate whether a SNP risk score derived from a panel of 77 SNPs can improve risk estimates obtained from the commonly used breast cancer risk prediction models (BCRAT, IBIS, BRCAPRO and BOADICEA). SNP risk scores were calculated using previously published Odds Ratios (ORs) and risk-allele frequencies based on the assumption of independence of additive risks on the log OR scale. SNP risk scores were calculated by multiplying adjusted risk scores for each of the SNPs. Combined risk scores were calculated by multiplying the SNP risk score and the algorithm derived risk scores, under the assumption of independence. Overall, the inclusion of data on 77 SNPs improved the area under the receiver operating characteristic curve (AUC) for all of the breast cancer risk prediction models: Preliminary data analysis provided AUC values as follows: BCRAT+SNP = 0.656, IBIS+SNP= 0.628, BRCAPRO+SNP= 0.689, BOADICEA+SNP= 0.698. The breast cancer risk prediction models examined place different weighting on the phenotypic components. For example, the IBIS model is weighted towards uncommon high-risk phenotypes, while the BCRAT is weighted towards lower risks in the general population. A combination of the 77 SNP score and the most appropriate model might substantially improve the ability to identify high-risk women in different screening populations. Citation Format: Gillian Dite, Richard Allman, John L Hopper. Value of adding single-nucleotide polymorphism panel markers to phenotypic algorithms of breast cancer risk [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-09-05.

Prevalence of PALB2 mutations in the Creighton University Breast Cancer Family Registry.

The purpose of this study is to determine the prevalence of PALB2 mutations among breast cancer families from the United States. The PALB2 gene was screened for mutations in 90 familial breast cancer patients from the Creighton University Breast Cancer Family Registry. These patients had previously tested negative for mutations in BRCA1 and BRCA2. Two of 90 breast cancer patients (2.2 %) were found to carry a truncating mutation in PALB2 (c.2411_2412delCT and c.2053delC). Both probands were diagnosed with breast cancer before age 35 and each had three relatives with breast cancer. Mutations in PALB2 are less common than BRCA1 and BRCA2 in familial breast cancer patients. However, testing for PALB2 mutations is a useful adjunct for patients undergoing testing for BRCA1 and BRCA2.

Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry.

Loss-of-function mutations in PALB2 are associated with an increased risk of breast cancer, with recent data showing that female breast cancer risks for PALB2 mutation carriers are comparable in magnitude to those for BRCA2 mutation carriers. This study applied targeted massively parallel sequencing to characterize the mutation spectrum of PALB2 in probands attending breast cancer genetics clinics in the USA. The coding regions and proximal intron-exon junctions of PALB2 were screened in probands not known to carry a mutation in BRCA1 or BCRA2 from 1,250 families enrolled through familial cancer clinics by the Breast Cancer Family Registry. Mutation screening was performed using Hi-Plex, an amplicon-based targeted massively parallel sequencing platform. Screening of PALB2 was successful in 1,240/1,250 probands and identified nine women with protein-truncating mutations (three nonsense mutations and five frameshift mutations). Four of the 33 missense variants were predicted to be deleterious to protein function by in silico analysis using two different programs. Analysis of tumors from carriers of truncating mutations revealed that the majority were high histological grade, invasive ductal carcinomas. Young onset was apparent in most families, with 19 breast cancers under 50 years of age, including eight under the age of 40 years. Our data demonstrate the utility of Hi-Plex in the context of high-throughput testing for rare genetic mutations and provide additional timely information about the nature and prevalence of PALB2 mutations, to enhance risk assessment and risk management of women at high risk of cancer attending clinical genetic services.

The impact of cancer prevention guideline adherence on overall mortality in a high-risk cohort of women from the New York site of the Breast Cancer Family Registry.

The American Cancer Society (ACS) recommends at least 150 min of moderate intensity physical activity per week, alcohol intake of ≤1 drink per day, and maintaining a body mass index (BMI) of <25 kg/m2 for breast cancer prevention. Adherence to these guidelines has been linked to lower overall mortality in average-risk populations, it is not known if mortality reduction extends to women at higher risk given their family history of breast cancer. We followed 2,905 women from a high-risk Breast Cancer Family Registry in New York, of which 77 % were white non-Hispanic and 23 % were Hispanic. We collected information on BMI, physical activity, and alcohol intake at baseline and prospectively followed our cohort for outcomes based on questionnaires and National Death Index linkage. We used Cox regression to examine the relation between adherence to ACS guidelines and overall mortality and examined effect modification by race, age, and BRCA status. There were 312 deaths after an average of 9.2 ± 4.1 years of follow-up. Adherence to all three ACS recommendations was associated with 44–53 % lower mortality in women unaffected with breast cancer at baseline [Hazard Ratio (HR) 0.56, 95 % CI (0.33–0.93)] and in women affected with breast cancer at baseline [HR 0.47, 95 % CI (0.30–0.74)]. These associations remained after stratification by age, race, and BRCA status {e.g., BRCA1 and/or BRCA2 carriers [HR 0.39, 95 % CI (0.16–0.97)]}. These results support that women at high risk, similar to women at average risk, may also have substantial benefits from maintaining the ACS guidelines.