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Abstract PD805: Comparative analysis of the genomic landscape of breast cancers from women of African and European ancestry

Authors: Olopade , Pitt , Reister , Odetunde , Yoshimatsu , Labrot , Ademola , Sanni , Okedere , Mahan , Nwosu , Leary , AJANI Mustapha , Johnson , Sveen , Zheng , Wang , Fitzgerald , Grundstad , Tuleja , Clayton , Khramstova , Oludara , Omodele , Benson , Adeoye , Morhason-bello , Ogundiran , Babalola , Popoola , Morrissey , Chen , Huo , Falusi , Winckler , Obafunwa , Papoutsakis , Ojengbede , White , Ibrahim , Oluwasola , Barretina J

Publication Type: Conference proceedings

Journal: Cancer Research

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Abstract

Objectives: Paucity of data on populations of African Ancestry in clinical trials continues to limit our ability to design and implement innovative solutions to narrow the breast cancer survival gap amongst Africans, African Americans, and European Americans. We have developed a cross continent research infrastructure to examine the spectrum of genomic alterations in breast tumors from West Africa and subsequently, to compare them to tumors from African American women and women of European Ancestry in The Cancer Genome Atlas (TCGA) database.

Methods: Consecutive women with breast cancer presenting for treatment at the University College Hospital, Ibadan and at Lagos State University Teaching Hospital, Lagos, Nigeria gave informed consent and were recruited to the West African Breast Cancer Study (WABCS) between 2013- 2016.Tumor- normal pairs were subjected to exome and/or highdepth (90x) genome sequencing. High confidence somatic mutations (substitutions, insertions/deletions and structural variants) were obtained by using multiple variant callers. Furthermore, 1,089 exomic and 80 genomic breast tumor-normal pairs from TCGA were harmonized with WABCS samples, resulting in a cohort of 147 West Africans (147 exome? 40 genome), 154 African Americans (154 exome? 31 genome), and 776 Caucasians (776 exome? 43 genome).

Results: Across the exomes, genes commonly altered in breast cancer in TCGA are also altered in women of African ancestry, but the mutational spectrum is quite different, demonstrating overrepresentation of tumors with aggressive phenotypes. Overall, TP53 (65%), ERBB2 (27%), and GATA3 (17%) showed statistically significant higher alteration frequencies in West Africans and African Americans. In contrast, PIK3CA (24%) was less frequently mutated. Of note, GATA3 mutation was statistically significantly more frequent in Nigerians (39%) and African Americans (16.7%) compared to Caucasians (10.5%), in ER positive cancers. Analysis on Structural Variants (SV), on the other hand, has shown that the genomewide SV counts among three populations are comparable in ERnegative cancers, while Nigerians have significantly more SV counts compared to African Americans (P=0.0013) or European Americans (P=2.9x10 ) in ERpositive cancers. Similarly, genomewide substitution patterns in ER+ and ERcancers varied widely by race/ethnicity. In ERcases, West Africans carried the highest proportion of canonical APOBEC-associated substitutions, particularly C>T transitions. Conversely, European Americans with ER+ disease showed a higher proportion of C>T than both West Africans (Welch ttest P = 0.044) and African Americans (Welch ttest P = 0.011). Mutation signature analyses highlighted multiple APOBEC signatures, with notable contribution differences across ancestry and ER status. A signature likely corresponding to DNA damage repair correlated with the proportion of genetic ancestry, being most prevalent in European Americans and least common in Nigerians, particularly in ER-negative cancers, with African Americans showing a degree of this signature's contribution in between the two populations (linear model adjusted for age, P=1.0x10 ).

Conclusions: Overall, our data suggests mutation spectra differences in across race/ethnicity and geography. Identification of molecular characteristics such as higher rates of HER2 enriched tumors and higher rates of GATA3 mutations in ER positive tumors are beginning to reveal the genomic basis of race associated phenotypes and outcomes in breast cancer. Population differences in frequency and spectrum of mutations should now inform the design of innovative clinical trials that improve health equity and accelerate Precision Oncology care in diverse populations.

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Olopade,O. Pitt,J. Reister,M. Odetunde,A. Yoshimatsu,T. Labrot,E. Ademola,A. Sanni,A. Okedere,B. Mahan,S. Nwosu,I. Leary,R. AJANI,M. Johnson,R. Sveen,E. Zheng,Y. Wang,S. Fitzgerald,D. Grundstad,J. Tuleja,J. Clayton,W. Khramstova,G. Oludara,M. Omodele,F. Benson,O. Adeoye,A. Morhason-bello,O. Ogundiran,T. Babalola,C. Popoola,A. Morrissey,M. Chen,L. Huo,D. Falusi,A. Winckler,W. Obafunwa,J. Papoutsakis,D. Ojengbede,O. White,K. Ibrahim,N. Oluwasola,O. Barretina,J. . (0000). Abstract PD805: Comparative analysis of the genomic landscape of breast cancers from women of African and European ancestry, 77 (), 1-1.

Olopade,O. Pitt,J. Reister,M. Odetunde,A. Yoshimatsu,T. Labrot,E. Ademola,A. Sanni,A. Okedere,B. Mahan,S. Nwosu,I. Leary,R. AJANI,M. Johnson,R. Sveen,E. Zheng,Y. Wang,S. Fitzgerald,D. Grundstad,J. Tuleja,J. Clayton,W. Khramstova,G. Oludara,M. Omodele,F. Benson,O. Adeoye,A. Morhason-bello,O. Ogundiran,T. Babalola,C. Popoola,A. Morrissey,M. Chen,L. Huo,D. Falusi,A. Winckler,W. Obafunwa,J. Papoutsakis,D. Ojengbede,O. White,K. Ibrahim,N. Oluwasola,O. Barretina,J. . "Abstract PD805: Comparative analysis of the genomic landscape of breast cancers from women of African and European ancestry" 77, no (), (0000): 1-1.

Olopade,O. and Pitt,J. and Reister,M. and Odetunde,A. and Yoshimatsu,T. and Labrot,E. and Ademola,A. and Sanni,A. and Okedere,B. and Mahan,S. and Nwosu,I. and Leary,R. and AJANI,M. and Johnson,R. and Sveen,E. and Zheng,Y. and Wang,S. and Fitzgerald,D. and Grundstad,J. and Tuleja,J. and Clayton,W. and Khramstova,G. and Oludara,M. and Omodele,F. and Benson,O. and Adeoye,A. and Morhason-bello,O. and Ogundiran,T. and Babalola,C. and Popoola,A. and Morrissey,M. and Chen,L. and Huo,D. and Falusi,A. and Winckler,W. and Obafunwa,J. and Papoutsakis,D. and Ojengbede,O. and White,K. and Ibrahim,N. and Oluwasola,O. and Barretina,J. and . (0000). Abstract PD805: Comparative analysis of the genomic landscape of breast cancers from women of African and European ancestry, 77 (), pp1-1.

OlopadeO, PittJ, ReisterM, OdetundeA, YoshimatsuT, LabrotE, AdemolaA, SanniA, OkedereB, MahanS, NwosuI, LearyR, AJANIM, JohnsonR, SveenE, ZhengY, WangS, FitzgeraldD, GrundstadJ, TulejaJ, ClaytonW, KhramstovaG, OludaraM, OmodeleF, BensonO, AdeoyeA, Morhason-belloO, OgundiranT, BabalolaC, PopoolaA, MorrisseyM, ChenL, HuoD, FalusiA, WincklerW, ObafunwaJ, PapoutsakisD, OjengbedeO, WhiteK, IbrahimN, OluwasolaO, BarretinaJ, . Abstract PD805: Comparative analysis of the genomic landscape of breast cancers from women of African and European ancestry. 0000, 77 ():1-1.

Olopade,Oi , Pitt,Jj , Reister,M , Odetunde,A , Yoshimatsu,T , Labrot,E , Ademola,A , Sanni,A , Okedere,B , Mahan,S , Nwosu,I , Leary,R , AJANI,Mustapha , Johnson,Rs , Sveen,E , Zheng,Y , Wang,S , Fitzgerald,Dj , Grundstad,J , Tuleja,J , Clayton,W , Khramstova,G , Oludara,M , Omodele,F , Benson,O , Adeoye,A , Morhason-bello,O , Ogundiran,T , Babalola,C , Popoola,A , Morrissey,M , Chen,L , Huo,D , Falusi,A , Winckler,W , Obafunwa,J , Papoutsakis,D , Ojengbede,O , White,Kp , Ibrahim,N , Oluwasola,O , and Barretina,J . "Abstract PD805: Comparative analysis of the genomic landscape of breast cancers from women of African and European ancestry", 77 . (0000) : 1-1.

O.Oi P.Jj R.M O.A Y.T L.E A.A S.A O.B M.S N.I L.R A.Mustapha J.Rs S.E Z.Y W.S F.Dj G.J T.J C.W K.G O.M O.F B.O A.A M.O O.T B.C P.A M.M C.L H.D F.A W.W O.J P.D O.O W.Kp I.N O.O & B.J , "Abstract PD805: Comparative analysis of the genomic landscape of breast cancers from women of African and European ancestry" vol.77, no., pp. 1-1, 0000.

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