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Grant Details

Grant Number: 5R01CA142996-03 Interpret this number
Primary Investigator: Olopade, Olufunmilayo
Organization: University Of Chicago
Project Title: Genome-Wide Association Study of Breast Cancer in the African Diaspora
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): The paucity of data on the genetic epidemiology of breast cancer for racial/ethnic groups other than those of European ancestry hinders the development of innovative interventions to reduce health disparities. Women in the African Diaspora experience a disproportionate burden of pre-menopausal breast cancer in comparison to all other races for reasons that remain unknown and understudied. This higher proportion of early-onset breast cancer might suggest a stronger genetic component in these populations. Genome-wide association studies (GWAS) have revealed several genetic loci that confer risk of breast cancer. Because all GWAS started the discovery stage in women of European ancestry and replicated mainly in women of European ancestry, we propose a novel approach for a GWAS in indigenous African women to identify alleles associated with breast cancer risk which will then be replicated in other populations. This innovative design builds on our current understanding of the etiologic heterogeneity in breast cancer and the distribution of breast cancer molecular subtypes which differ between women of African ancestry and women of European ancestry. The major objective of the proposed studies is to get to the "root" causes of breast cancer by identifying breast cancer risk alleles in a pooled sample of women of African ancestry and to replicate our findings in other populations. To achieve this objective, we propose the following specific aims: 1) Genotype 1,796 breast cancer cases and 1,988 controls of African ancestry using the Illumina Human1M BeadChip platform. These include 944 cases and 665 controls form Ibadan, Nigeria, 171 cases and 378 controls from Barbados, and 681 cases and 945 controls from Chicago, Detroit, Philadelphia and Baltimore; 2) Conduct both standard and novel genetic analyses of the data to map genes associated with breast cancer susceptibility, 3) Verify genotyping and carry out fine-mapping studies in genes or regions showing association with breast cancer risk and related clinical phenotypes and 4) Replicate in other African American and non-African American populations. By pooling unique resources from studies throughout the African Diaspora, this study has the potential to identify risk alleles in several genes that contribute to increased breast cancer risk and may have implications for early detection, prognosis and treatment of breast cancer in ALL women. This should ultimately lead to improved outcomes for those who suffer a disproportionate burden of early-onset breast cancer. PUBLIC HEALTH RELEVANCE: Of all the racial/ethnic groups in the United States, African Americans have the highest mortality rate of breast cancer diagnosed in women under 35 years of age, and in Africa, breast cancer is a uniformly fatal affliction of young women, in part, due to poor access to care and ignorance of the disease. This project focuses on the understudied global problem of breast cancer in the African Diaspora and attempts to translate recent advances in genomics research to benefit women who are at risk of developing hormone receptor negative breast cancer, an aggressive form of breast cancer that often affects younger women. Better understanding of the genetic risks of breast cancer for women in the African Diaspora should lead to better clinical risk assessment and the development of more effective strategies for prevention, early detection and treatment of breast cancer for ALL women.

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Publications

Genetic variants demonstrating flip-flop phenomenon and breast cancer risk prediction among women of African ancestry.
Authors: Wang S. , Qian F. , Zheng Y. , Ogundiran T. , Ojengbede O. , Zheng W. , Blot W. , Nathanson K.L. , Hennis A. , Nemesure B. , et al. .
Source: Breast Cancer Research And Treatment, 2018-01-04 00:00:00.0; , .
EPub date: 2018-01-04 00:00:00.0.
PMID: 29302764
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Genetic variation in the vitamin D related pathway and breast cancer risk in women of African ancestry in the root consortium.
Authors: Wang S. , Huo D. , Kupfer S. , Alleyne D. , Ogundiran T.O. , Ojengbede O. , Zheng W. , Nathanson K.L. , Nemesure B. , Ambs S. , et al. .
Source: International Journal Of Cancer, 2018-01-01 00:00:00.0; 142(1), p. 36-43.
EPub date: 2017-09-23 00:00:00.0.
PMID: 28891071
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Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.
Authors: Milne R.L. , Kuchenbaecker K.B. , Michailidou K. , Beesley J. , Kar S. , Lindström S. , Hui S. , Lemaçon A. , Soucy P. , Dennis J. , et al. .
Source: Nature Genetics, 2017 Dec; 49(12), p. 1767-1778.
EPub date: 2017-10-23 00:00:00.0.
PMID: 29058716
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Trans-ethnic predicted expression genome-wide association analysis identifies a gene for estrogen receptor-negative breast cancer.
Authors: Gao G. , Pierce B.L. , Olopade O.I. , Im H.K. , Huo D. .
Source: Plos Genetics, 2017 Sep; 13(9), p. e1006727.
EPub date: 2017-09-28 00:00:00.0.
PMID: 28957356
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Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.
Authors: Lecarpentier J. , Silvestri V. , Kuchenbaecker K.B. , Barrowdale D. , Dennis J. , McGuffog L. , Soucy P. , Leslie G. , Rizzolo P. , Navazio A.S. , et al. .
Source: Journal Of Clinical Oncology : Official Journal Of The American Society Of Clinical Oncology, 2017-07-10 00:00:00.0; 35(20), p. 2240-2250.
EPub date: 2017-04-27 00:00:00.0.
PMID: 28448241
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Characterizing Genetic Susceptibility To Breast Cancer In Women Of African Ancestry
Authors: Feng Y. , Rhie S.K. , Huo D. , Ruiz-Narvaez E.A. , Haddad S.A. , Ambrosone C.B. , John E.M. , Bernstein L. , Zheng W. , Hu J.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, 2017-04-04 00:00:00.0; , .
PMID: 28377418
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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 00:00:00.0.
PMID: 28362817
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Association Of Breast Cancer Risk In Brca1 And Brca2 Mutation Carriers With Genetic Variants Showing Differential Allelic Expression: Identification Of A Modifier Of Breast Cancer Risk At Locus 11q22.3
Authors: Hamdi Y. , Soucy P. , Kuchenbaeker K.B. , Pastinen T. , Droit A. , Lemaçon A. , Adlard J. , Aittomäki K. , Andrulis I.L. , Arason A. , et al. .
Source: Breast Cancer Research And Treatment, 2016-10-28 00:00:00.0; , .
PMID: 27796716
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Functional Mechanisms Underlying Pleiotropic Risk Alleles At The 19p13.1 Breast-ovarian Cancer Susceptibility Locus
Authors: Lawrenson K. , Kar S. , McCue K. , Kuchenbaeker K. , Michailidou K. , Tyrer J. , Beesley J. , Ramus S.J. , Li Q. , Delgado M.K. , et al. .
Source: Nature Communications, 2016-09-07 00:00:00.0; 7, p. 12675.
PMID: 27601076
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Genetic Variants In Microrna And Microrna Biogenesis Pathway Genes And Breast Cancer Risk Among Women Of African Ancestry
Authors: Qian F. , Feng Y. , Zheng Y. , Ogundiran T.O. , Ojengbede O. , Zheng W. , Blot W. , Ambrosone C.B. , John E.M. , Bernstein L. , et al. .
Source: Human Genetics, 2016-07-05 00:00:00.0; , .
PMID: 27380242
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.
Authors: Zeng C. , Guo X. , Long J. , Kuchenbaecker K.B. , Droit A. , Michailidou K. , Ghoussaini M. , Kar S. , Freeman A. , Hopper J.L. , et al. .
Source: Breast Cancer Research : Bcr, 2016-06-21 00:00:00.0; 18(1), p. 64.
EPub date: 2016-06-21 00:00:00.0.
PMID: 27459855
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No Clinical Utility Of Kras Variant Rs61764370 For Ovarian Or Breast Cancer
Authors: Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2 , Hollestelle A. , van der Baan F.H. , Berchuck A. , Johnatty S.E. , Aben K.K. , Agnarsson B.A. , Aittomäki K. , Alducci E. , Andrulis I.L. , et al. .
Source: Gynecologic Oncology, 2016 May; 141(2), p. 386-401.
PMID: 25940428
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Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2.
Authors: Silvestri V. , Barrowdale D. , Mulligan A.M. , Neuhausen S.L. , Fox S. , Karlan B.Y. , Mitchell G. , James P. , Thull D.L. , Zorn K.K. , et al. .
Source: Breast Cancer Research : Bcr, 2016-02-09 00:00:00.0; 18(1), p. 15.
EPub date: 2016-02-09 00:00:00.0.
PMID: 26857456
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Genetic And Epigenetic Regulation Of Tox3 Expression In Breast Cancer
Authors: Han Y.J. , Zhang J. , Zheng Y. , Huo D. , Olopade O.I. .
Source: Plos One, 2016; 11(11), p. e0165559.
PMID: 27806084
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An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.
Authors: Blein S. , Bardel C. , Danjean V. , McGuffog L. , Healey S. , Barrowdale D. , Lee A. , Dennis J. , Kuchenbaecker K.B. , Soucy P. , et al. .
Source: Breast Cancer Research : Bcr, 2015-04-25 00:00:00.0; 17, p. 61.
EPub date: 2015-04-25 00:00:00.0.
PMID: 25925750
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Assessing Associations Between The Aurka-hmmr-tpx2-tubg1 Functional Module And Breast Cancer Risk In Brca1/2 Mutation Carriers
Authors: Blanco I. , Kuchenbaecker K. , Cuadras D. , Wang X. , Barrowdale D. , de Garibay G.R. , Librado P. , Sánchez-Gracia A. , Rozas J. , Bonifaci N. , et al. .
Source: Plos One, 2015; 10(4), p. e0120020.
PMID: 25830658
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A comprehensive examination of breast cancer risk loci in African American women.
Authors: Feng Y. , Stram D.O. , Rhie S.K. , Millikan R.C. , Ambrosone C.B. , John E.M. , Bernstein L. , Zheng W. , Olshan A.F. , Hu J.J. , et al. .
Source: Human Molecular Genetics, 2014-10-15 00:00:00.0; 23(20), p. 5518-26.
EPub date: 2014-10-15 00:00:00.0.
PMID: 24852375
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Dna Glycosylases Involved In Base Excision Repair May Be Associated With Cancer Risk In Brca1 And Brca2 Mutation Carriers
Authors: Osorio A. , Milne R.L. , Kuchenbaecker K. , Vaclová T. , Pita G. , Alonso R. , Peterlongo P. , Blanco I. , de la Hoya M. , Duran M. , et al. .
Source: Plos Genetics, 2014 Apr; 10(4), p. e1004256.
PMID: 24698998
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Associations Of Common Breast Cancer Susceptibility Alleles With Risk Of Breast Cancer Subtypes In Brca1 And Brca2 Mutation Carriers
Authors: Kuchenbaecker K.B. , Neuhausen S.L. , Robson M. , Barrowdale D. , McGuffog L. , Mulligan A.M. , Andrulis I.L. , Spurdle A.B. , Schmidt M.K. , Schmutzler R.K. , et al. .
Source: Breast Cancer Research : Bcr, 2014; 16(6), p. 3416.
PMID: 25919761
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Expression Of Polycomb Targets Predicts Breast Cancer Prognosis
Authors: Jene-Sanz A. , Váraljai R. , Vilkova A.V. , Khramtsova G.F. , Khramtsov A.I. , Olopade O.I. , Lopez-Bigas N. , Benevolenskaya E.V. .
Source: Molecular And Cellular Biology, 2013 Oct; 33(19), p. 3951-61.
PMID: 23918806
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Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers.
Authors: Zheng Y. , Ogundiran T.O. , Falusi A.G. , Nathanson K.L. , John E.M. , Hennis A.J. , Ambs S. , Domchek S.M. , Rebbeck T.R. , Simon M.S. , et al. .
Source: Carcinogenesis, 2013 Jul; 34(7), p. 1520-8.
PMID: 23475944
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A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.
Authors: Monda K.L. , Chen G.K. , Taylor K.C. , Palmer C. , Edwards T.L. , Lange L.A. , Ng M.C. , Adeyemo A.A. , Allison M.A. , Bielak L.F. , et al. .
Source: Nature Genetics, 2013 Jun; 45(6), p. 690-6.
PMID: 23583978
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Novel germline PALB2 truncating mutations in African American breast cancer patients.
Authors: Zheng Y. , Zhang J. , Niu Q. , Huo D. , Olopade O.I. .
Source: Cancer, 2012-03-01 00:00:00.0; 118(5), p. 1362-70.
EPub date: 2012-03-01 00:00:00.0.
PMID: 21932393
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Lack of association between common single nucleotide polymorphisms in the TERT-CLPTM1L locus and breast cancer in women of African ancestry.
Authors: Zheng Y. , Ogundiran T.O. , Adebamowo C. , Nathanson K.L. , Domchek S.M. , Rebbeck T.R. , Simon M.S. , John E.M. , Hennis A. , Nemesure B. , et al. .
Source: Breast Cancer Research And Treatment, 2012 Feb; 132(1), p. 341-5.
PMID: 22134622
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Microsatellites In The Estrogen Receptor (esr1, Esr2) And Androgen Receptor (ar) Genes And Breast Cancer Risk In African American And Nigerian Women
Authors: Zheng Y. , Huo D. , Zhang J. , Yoshimatsu T.F. , Niu Q. , Olopade O.I. .
Source: Plos One, 2012; 7(7), p. e40494.
PMID: 22792352
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Germline mutational analysis of the C19orf62 gene in African-American women with breast cancer.
Authors: Zheng Y. , Zhang J. , Niu Q. , Olopade O.I. , Huo D. .
Source: Breast Cancer Research And Treatment, 2011 Jun; 127(3), p. 871-7.
PMID: 21431873
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