Abstract P6-03-17: Genomic landscape of breast cancers from women of African ancestry across the diaspora

Abstract

Objectives: Of all ethnic/racial groups, age-standardized mortality rate from breast cancer is highest for African American women in the US for reasons that remain understudied. The paucity of genomic studies of breast tumors across the African Diaspora further restricts our understanding of the biology of breast cancer in underserved populations. To gain a better understanding of the genomic landscape of breast cancer in women of African Ancestry, we have developed a cross continent translational research infrastructure to examine the spectrum of genetic alterations in breast tumors from West Africa compared to the spectrum of alterations observed in tumors from African-American and other women who are predominantly white in The Cancer Genome Atlas (TCGA) dataset. Methods: Peripheral blood and breast cancer biopsy tissues were collected from 214 patients enrolled in the West Africa Breast Cancer Study (WABCS) at the University of Ibadan/University College Hospital (UI/UCH) and at Lagos State University Teaching Hospital (LASUTH). Blood DNA as well as breast cancer tissue DNA and RNA were extracted at the Novartis Institutes for Biomedical Research (NIBR), UI/UCH, and LASUTH using a modified protocol of PAXgene Tissue DNA and RNA extraction method. Whole-exome (WES) and transcriptome (RNA-seq) sequencing were performed on the Illumina HiSeq2000 platform at NIBR. Single Nucleotide Variants (SNVs) and insertions/deletions (indels) were called using MuTect and Pindel, while Copy Number Alterations (CNAs) were called using an in-house implementation of the ABSOLUTE method. Observed mutations were compared against those reported in the TCGA dataset. ER, PR and HER2 status were determined by immunohistochemistry (IHC) at UI/UCH, LASUTH and UChicago. Results: WES data for 95 tumors have been analyzed thus far. Genes commonly mutated in breast cancer in TCGA are also mutated in WABCS but the mutational spectrum is vastly different. TP53 (64%), MYC (31%), and GATA3 (26%), showed significantly higher alteration frequencies in WABCS and African Americans. In contrast, PIK3CA (20%), CDH1 (2%), and MAP3K1 (2%) were less frequently mutated in women of African ancestry. In addition to the high proportion with TP53 mutations, the proportion with HER2 positive subtype of 42.1% and triple-negative subtype of 37.9% suggest that tumors with the most aggressive features are overrepresented in breast cancer patients in West Africa. Conclusions: In the first study of its kind, high throughput genomic analysis of the largest cohort of women of African ancestry has uncovered alterations in cancer genes, some of which may be amenable to treatment with targeted therapies. Furthermore, we provide evidence that population differences in frequency and spectrum of mutations should drive the design and deployment of precision medicine initiatives. Only then can we develop innovative interventions to reduce the unacceptably high rates of mortality from breast cancer in underserved and under resourced populations. Citation Format: Olopade OI, Odetunde A, Riester M, Yoshimatsu T, Labrot E, Ademola A, Sanni A, Okedere B, Mahan S, Nwosu I, Leary R, Ajani M, Johnson RS, Sveen E, Zheng Y, Clayton W, Khramtsova G, Oludara M, Omodele F, Benson O, Adeoye A, Morhason-Bello O, Ogundiran T, Babalola C, Popoola A, Morrissey M, Huo D, Falusi A, Winckler W, Obafunwa J, Papoutsakis D, Ojengbede O, Ibrahim N, Oluwasola O, Barretina J. Genomic landscape of breast cancers from women of African ancestry across the diaspora. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-17.