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
Association of ESR1 germline variants with TP53 somatic variants in breast tumors in a genome-wide study.
Authors: Tjader N.P.
, Beer A.J.
, Ramroop J.
, Tai M.C.
, Ping J.
, Gandhi T.
, Dauch C.
, Neuhausen S.L.
, Ziv E.
, Sotelo N.
, et al.
.
Source: Cancer Research Communications, 2024-05-28 00:00:00.0; , .
EPub date: 2024-05-28 00:00:00.0.
PMID: 38836758
Related Citations
Association of ESR1 germline variants with TP53 somatic variants in breast tumors in a genome-wide study.
Authors: Tjader N.P.
, Beer A.J.
, Ramroop J.
, Tai M.C.
, Ping J.
, Gandhi T.
, Dauch C.
, Neuhausen S.L.
, Ziv E.
, Sotelo N.
, et al.
.
Source: Medrxiv : The Preprint Server For Health Sciences, 2023-12-06 00:00:00.0; , .
EPub date: 2023-12-06 00:00:00.0.
PMID: 38106140
Related Citations
Profiling the Somatic Mutational Landscape of Breast Tumors from Hispanic/Latina Women Reveals Conserved and Unique Characteristics.
Authors: Ding Y.C.
, Song H.
, Adamson A.W.
, Schmolze D.
, Hu D.
, Huntsman S.
, Steele L.
, Patrick C.S.
, Tao S.
, Hernandez N.
, et al.
.
Source: Cancer Research, 2023-08-01 00:00:00.0; 83(15), p. 2600-2613.
PMID: 37145128
Related Citations
Whole exome sequencing and replication for breast cancer among Hispanic/Latino women identifies FANCM as a susceptibility gene for estrogen-receptor-negative breast cancer.
Authors: Nierenberg J.L.
, Adamson A.W.
, Hu D.
, Huntsman S.
, Patrick C.
, Li M.
, Steele L.
, Tong B.
, Shieh Y.
, Fejerman L.
, et al.
.
Source: Medrxiv : The Preprint Server For Health Sciences, 2023-01-28 00:00:00.0; , .
EPub date: 2023-01-28 00:00:00.0.
PMID: 36747679
Related Citations
Differences in somatic TP53 mutation type in breast tumors by race and receptor status.
Authors: Pollock N.C.
, Ramroop J.R.
, Hampel H.
, Troester M.A.
, Conway K.
, Hu J.J.
, Freudenheim J.L.
, Olopade O.I.
, Huo D.
, Ziv E.
, et al.
.
Source: Breast Cancer Research And Treatment, 2022-03-14 00:00:00.0; , .
EPub date: 2022-03-14 00:00:00.0.
PMID: 35286522
Related Citations
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, 2020-09-09 00:00:00.0; , .
EPub date: 2020-09-09 00:00:00.0.
PMID: 32901135
Related Citations
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 00:00:00.0; 7(10), p. 270-285.
EPub date: 2020-07-20 00:00:00.0.
PMID: 33015141
Related Citations
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 00:00:00.0; 112(6), p. 590-598.
PMID: 31553449
Related Citations
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 00:00:00.0; 37(5), p. 639-654.e6.
PMID: 32396860
Related Citations
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 00:00:00.0; 80(9), p. 1893-1901.
EPub date: 2020-04-03 00:00:00.0.
PMID: 32245796
Related Citations
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, 2020-03-16 00:00:00.0; , .
EPub date: 2020-03-16 00:00:00.0.
PMID: 32175645
Related Citations
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, 2019-06-26 00:00:00.0; , .
EPub date: 2019-06-26 00:00:00.0.
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, 2019-06-17 00:00:00.0; , .
EPub date: 2019-06-17 00:00:00.0.
PMID: 31206626
Related Citations
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 00:00:00.0; 21(1), p. 3.
EPub date: 2019-01-14 00:00:00.0.
PMID: 30642363
Related Citations
The Immune Landscape of Cancer.
Authors: Thorsson V.
, Gibbs D.L.
, Brown S.D.
, Wolf D.
, Bortone D.S.
, Ou Yang T.H.
, Porta-Pardo E.
, Gao G.F.
, Plaisier C.L.
, Eddy J.A.
, et al.
.
Source: Immunity, 2018-04-17 00:00:00.0; 48(4), p. 812-830.e14.
EPub date: 2018-04-05 00:00:00.0.
PMID: 29628290
Related Citations
Association analysis identifies 65 new breast cancer risk loci.
Authors: Michailidou K.
, Lindström S.
, Dennis J.
, Beesley J.
, Hui S.
, Kar S.
, Lemaçon A.
, Soucy P.
, Glubb D.
, Rostamianfar A.
, et al.
.
Source: Nature, 2017-11-02 00:00:00.0; 551(7678), p. 92-94.
EPub date: 2017-10-23 00:00:00.0.
PMID: 29059683
Related Citations
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, 2017-09-02 00:00:00.0; , .
EPub date: 2017-09-02 00:00:00.0.
PMID: 28864920
Related Citations
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, 2017-03-20 00:00:00.0; , .
PMID: 28319063
Related Citations
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 00:00:00.0.
PMID: 28362817
Related Citations
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 Nov; 160(1), p. 121-129.
EPub date: 2016-09-13 00:00:00.0.
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.
PMID: 27565998
Related Citations
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.
PMID: 26364163
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