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Grant Details

Grant Number: 5R01CA184585-05 Interpret this number
Primary Investigator: Neuhausen, Susan
Organization: Beckman Research Institute/City Of Hope
Project Title: Germline and Tumor Genomic Analyses of Breast Cancer in Latinas
Fiscal Year: 2018


Abstract

DESCRIPTION (provided by applicant): With advances in technology, genomics is becoming increasingly important for precision medicine, both for determining risk to develop disease and for treatment decisions. The high-risk breast cancer genes, BRCA1 and BRCA2, were discovered in the mid-1990s. Since then, many other risk loci have been identified by genome-wide association and, more recently, by sequencing studies. However, despite these efforts, the combined effects of known breast cancer loci only explain approximately one-third of the genetic risk. Most of the genes predisposing to breast cancer still have not been identified, thus limiting the potential for identification of many individuals at high risk of developing the disease. Whole-exome sequencing is a potentially powerful approach to discover rare mutations in genes that may be associated with breast cancer susceptibility. However, the number of variants discovered in these studies is large and prioritizing them for replication is difficult. Somatic mutations and copy number and other changes in genes in tumors may provide biological insights that can guide gene selection for replication. In particular, many cancer susceptibility genes act by a pathogenic mutation of the germline copy and then somatic inactivation of the second copy. Use of datasets such as The Cancer Genome Atlas (TCGA) may help to identify additional cancer genes by determining which genes display germline and somatic events in the same individual. However, Latinos, African Americans and Asians are under-represented in TCGA, and because rare variants are usually population specific, it is important that populations of all ancestral backgrounds be included in gene discovery. Latinos represent the largest and fastest-growing minority population in the U.S., yet they have been largely under-studied in terms of genetic susceptibility to breast cancer. Although Latinas have an overall lower incidence of breast cancer than non-Latina Caucasians, Latinas are more likely to be diagnosed at a younger age and to have more aggressive disease at diagnosis. Our proposal will use a combined germline and somatic genetics approach to discover breast cancer susceptibility genes in Latinas. In Specific Aim 1, we will identify mutations in genes from whole-exome sequencing of 1,400 Latina breast cancer cases diagnosed under age 50 and/or with a family history and 1,400 healthy Latina controls. We will perform gene-based association tests to prioritize genes based on p-value for more testing in Aim 2 and for replication in Aim 3. In Specific Aim 2, we will perform targeted sequencing and expression analysis of 800 genes from Aim 1 in DNA and RNA from 384 breast tumors of cases from Aim 1. In Specific Aim 3, we will use custom capture to target and sequence the top 1,000 candidate genes in 2,300 Latina breast cancer cases and 2,300 controls. At the end of this project, we will have identified a set of genes that are significantly associated with breast cancer in Latinas. A long-term goal is to develop a clinical genetic test that can help to determine risk in individual Latinas who have not been diagnosed to aid in their decision-making with regard to preventive options.



Publications

Cancer health disparities in racial/ethnic minorities in the United States.
Authors: Zavala V.A. , Bracci P.M. , Carethers J.M. , Carvajal-Carmona L. , Coggins N.B. , Cruz-Correa M.R. , Davis M. , de Smith A.J. , Dutil J. , Figueiredo J.C. , et al. .
Source: British journal of cancer, 2021 01; 124(2), p. 315-332.
EPub date: 2020-09-09.
PMID: 32901135
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Variants of the human RAD52 gene confer defects in ionizing radiation resistance and homologous recombination repair in budding yeast.
Authors: Clear A.D. , Manthey G.M. , Lewis O. , Lopez I.Y. , Rico R. , Owens S. , Negritto M.C. , Wolf E.W. , Xu J. , Kenjić N. , et al. .
Source: Microbial cell (Graz, Austria), 2020-07-20; 7(10), p. 270-285.
EPub date: 2020-07-20.
PMID: 33015141
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The RAD52 S346X variant reduces risk of developing breast cancer in carriers of pathogenic germline BRCA2 mutations.
Authors: Adamson A.W. , Ding Y.C. , Mendez-Dorantes C. , Bailis A.M. , Stark J.M. , Neuhausen S.L. .
Source: Molecular oncology, 2020 06; 14(6), p. 1124-1133.
EPub date: 2020-04-25.
PMID: 32175645
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A Polygenic Risk Score for Breast Cancer in US Latinas and Latin American Women.
Authors: Shieh Y. , Fejerman L. , Lott P.C. , Marker K. , Sawyer S.D. , Hu D. , Huntsman S. , Torres J. , Echeverry M. , Bohórquez M.E. , et al. .
Source: Journal of the National Cancer Institute, 2020-06-01; 112(6), p. 590-598.
PMID: 31553449
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Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer.
Authors: Carrot-Zhang J. , Chambwe N. , Damrauer J.S. , Knijnenburg T.A. , Robertson A.G. , Yau C. , Zhou W. , Berger A.C. , Huang K.L. , Newberg J.Y. , et al. .
Source: Cancer cell, 2020-05-11; 37(5), p. 639-654.e6.
PMID: 32396860
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Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Is Associated with Indigenous American Ancestry in Latin American Women.
Authors: Marker K.M. , Zavala V.A. , Vidaurre T. , Lott P.C. , Vásquez J.N. , Casavilca-Zambrano S. , Calderón M. , Abugattas J.E. , Gómez H.L. , Fuentes H.A. , et al. .
Source: Cancer research, 2020-05-01; 80(9), p. 1893-1901.
EPub date: 2020-04-03.
PMID: 32245796
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Assessing the performance of in silico methods for predicting the pathogenicity of variants in the gene CHEK2, among Hispanic females with breast cancer.
Authors: Voskanian A. , Katsonis P. , Lichtarge O. , Pejaver V. , Radivojac P. , Mooney S.D. , Capriotti E. , Bromberg Y. , Wang Y. , Miller M. , et al. .
Source: Human mutation, 2019 09; 40(9), p. 1612-1622.
EPub date: 2019-08-17.
PMID: 31241222
Related Citations

Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer.
Authors: Weitzel J.N. , Neuhausen S.L. , Adamson A. , Tao S. , Ricker C. , Maoz A. , Rosenblatt M. , Nehoray B. , Sand S. , Steele L. , et al. .
Source: Cancer, 2019-08-15; 125(16), p. 2829-2836.
EPub date: 2019-06-17.
PMID: 31206626
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Identification of novel common breast cancer risk variants at the 6q25 locus among Latinas.
Authors: Hoffman J. , Fejerman L. , Hu D. , Huntsman S. , Li M. , John E.M. , Torres-Mejia G. , Kushi L. , Ding Y.C. , Weitzel J. , et al. .
Source: Breast cancer research : BCR, 2019-01-14; 21(1), p. 3.
EPub date: 2019-01-14.
PMID: 30642363
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Discovery of mutations in homologous recombination genes in African-American women with breast cancer.
Authors: Ding Y.C. , Adamson A.W. , Steele L. , Bailis A.M. , John E.M. , Tomlinson G. , Neuhausen S.L. .
Source: Familial cancer, 2018 04; 17(2), p. 187-195.
PMID: 28864920
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Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.
Authors: Foo T.K. , Tischkowitz M. , Simhadri S. , Boshari T. , Zayed N. , Burke K.A. , Berman S.H. , Blecua P. , Riaz N. , Huo Y. , et al. .
Source: Oncogene, 2017-07-20; 36(29), p. 4161-4170.
EPub date: 2017-03-20.
PMID: 28319063
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Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk.
Authors: Hoffman J.D. , Graff R.E. , Emami N.C. , Tai C.G. , Passarelli M.N. , Hu D. , Huntsman S. , Hadley D. , Leong L. , Majumdar A. , et al. .
Source: PLoS genetics, 2017 Mar; 13(3), p. e1006690.
EPub date: 2017-03-31.
PMID: 28362817
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Haplotype analyses of the c.1027C>T and c.2167_2168delAT recurrent truncating mutations in the breast cancer-predisposing gene PALB2.
Authors: Catucci I. , Casadei S. , Ding Y.C. , Volorio S. , Ficarazzi F. , Falanga A. , Marchetti M. , Tondini C. , Franchi M. , Adamson A. , et al. .
Source: Breast cancer research and treatment, 2016 11; 160(1), p. 121-129.
EPub date: 2016-09-13.
PMID: 27624329
Related Citations

Breast cancer risk prediction using a clinical risk model and polygenic risk score.
Authors: Shieh Y. , Hu D. , Ma L. , Huntsman S. , Gard C.C. , Leung J.W. , Tice J.A. , Vachon C.M. , Cummings S.R. , Kerlikowske K. , et al. .
Source: Breast cancer research and treatment, 2016 Oct; 159(3), p. 513-25.
EPub date: 2016-08-26.
PMID: 27565998
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Interaction between common breast cancer susceptibility variants, genetic ancestry, and nongenetic risk factors in Hispanic women.
Authors: Fejerman L. , Stern M.C. , John E.M. , Torres-Mejía G. , Hines L.M. , Wolff R.K. , Baumgartner K.B. , Giuliano A.R. , Ziv E. , Pérez-Stable E.J. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2015 Nov; 24(11), p. 1731-8.
EPub date: 2015-09-12.
PMID: 26364163
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