African Ancestry–Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent

Martini, Rachel; Delpe, Princesca; Chu, Timothy R.; Arora, Kanika; Lord, Brittany; Verma, Akanksha; Bedi, Deepa; Karanam, Balasubramanyam; Elhussin, Isra; Chen, Yalei; Gebregzabher, Endale; Oppong, Joseph K.; Adjei, Ernest K.; Suleiman, Aisha Jibril; Awuah, Baffour; Muleta, Mahteme Bekele.; Abebe, Engida; Kyei, Ishmael; Aitpillah, Frances S.; Adinku, Michael O.; Ankomah, Kwasi; Osei-Bonsu, Ernest Baawuah.; Chitale, Dhananjay A.; Bensenhaver, Jessica M.; Nathanson, David S.; Jackson, Latoya; Petersen, Lindsay F.; Proctor, Erica; Stonaker, Brian; Gyan, Kofi K.; Gibbs, Lee D.; Manojlovic, Zarko; Kittles, Rick A.; White, Jason; Yates, Clayton C.; Manne, Upender; Gardner, Kevin; Mongan, Nigel; Cheng, Esther; Ginter, Paula; Hoda, Syed; Elemento, Olivier; Robine, Nicolas; Sboner, Andrea; Carpten, John D.; Newman, Lisa; Davis, Melissa B.

Abstract

Women of sub-Saharan African descent have disproportionately higher incidence of triple-negative breast cancer (TNBC) and TNBC-specific mortality across all populations. Population studies show racial differences in TNBC biology, including higher prevalence of basal-like and quadruple-negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily U.S. populations. Due to heterogeneous genetic admixture and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNA sequencing on an international cohort of AAs, as well as West and East Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2,000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed that tumor-associated immunologic profiles are distinct in patients of African descent. SIGNIFICANCE: Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race–group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an Africanenriched international multiethnic cohort.

Citation

Martini, R., Delpe, P., Chu, T. R., Arora, K., Lord, B., Verma, A., …Davis, M. B. (2022). African Ancestry–Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent. Cancer Discovery, 12(11), 2530-2551. https://doi.org/10.1158/2159-8290.CD-22-0138

• Journal Article Type: Article
• Acceptance Date: Aug 23, 2022
• Online Publication Date: Sep 19, 2022
• Publication Date: Sep 19, 2022
• Deposit Date: Sep 24, 2022
• Publicly Available Date: Sep 20, 2023
• Journal: Cancer Discovery
• Print ISSN: 2159-8274
• Electronic ISSN: 2159-8290
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 11
• Pages: 2530-2551
• DOI: https://doi.org/10.1158/2159-8290.CD-22-0138
• Keywords: Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/11472714
• Publisher URL: https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-22-0138/709181/African-Ancestry-Associated-Gene-Expression