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. 2023 Nov 13;41(11):1963-1971.e3.
doi: 10.1016/j.ccell.2023.10.003. Epub 2023 Oct 26.

Tumor sequencing of African ancestry reveals differences in clinically relevant alterations across common cancers

Evelyn Jiagge  1 , Dexter X Jin  2 , Justin Y Newberg  3 , Tomin Perea-Chamblee  4 , Kelly R Pekala  5 , Christopher Fong  4 , Michele Waters  4 , David Ma  4 , Yvonne Dei-Adomakoh  6 , Gilles Erb  7 , Kanika S Arora  8 , Sophia L Maund  9 , Njoki Njiraini  10 , Atara Ntekim  11 , Susie Kim  4 , Xuechun Bai  4 , Marlene Thomas  7 , Ronwyn van Eeden  12 , Priti Hegde  3 , Justin Jee  13 , Debyani Chakravarty  14 , Nikolaus Schultz  4 , Michael F Berger  14 , Garrett M Frampton  3 , Ethan S Sokol  3 , Jian Carrot-Zhang  15
Affiliations

Tumor sequencing of African ancestry reveals differences in clinically relevant alterations across common cancers

Evelyn Jiagge et al. Cancer Cell. .

Abstract

Cancer genomes from patients with African (AFR) ancestry have been poorly studied in clinical research. We leverage two large genomic cohorts to investigate the relationship between genomic alterations and AFR ancestry in six common cancers. Cross-cancer type associations, such as an enrichment of MYC amplification with AFR ancestry in lung, breast, and prostate cancers, and depletion of BRAF alterations are observed in colorectal and pancreatic cancers. There are differences in actionable alterations, such as depletion of KRAS G12C and EGFR L858R, and enrichment of ROS1 fusion with AFR ancestry in lung cancers. Interestingly, in lung cancer, KRAS mutations are less common in both smokers and non-smokers with AFR ancestry, whereas the association of TP53 mutations with AFR ancestry is only seen in smokers, suggesting an ancestry-environment interaction that modifies driver rates. Our study highlights the need to increase representation of patients with AFR ancestry in drug development and biomarker discovery.

Keywords: African ancestry; driver alteration; next-generation sequencing; precision oncology; real-world data.

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Conflict of interest statement

Declaration of interests E.J. reports consulting fees for a Ghanaian breast cancer patient care pathway from Genentech, Inc. D.X.J., J.Y.N., G.M.F., and E.S.S. are employees of Foundation Medicine, Inc., a member of the Roche group, and hold stock in F. Hoffmann-La Roche Ltd. Y.D.-A. has received a grant from the National Heart, Lung, and Blood Institute in the USA, outside of the submitted work. G.E. and M.T. are employees of and hold stock in F. Hoffmann-La Roche Ltd. S.L.M. is an employee of Genentech, Inc., a member of the Roche group, and holds stock in F. Hoffmann-La Roche Ltd. N.N. has received honoraria for Breast Preceptorship training and the KESHO meeting, and is a member of a Global Advisory Board. A.N. has received honoraria for lectures and investigational products for clinical trials from F. Hoffmann-La Roche Ltd. R.v.E. has received honoraria for lectures and presentations from F. Hoffmann-La Roche Ltd, Takeda, MSD, Boehringer Ingelheim, and AstraZeneca, has received support for attending meetings and/or travel from F. Hoffmann-La Roche Ltd, Janssen, and MSD, and has participated in a data safety monitoring board or advisory board for Takeda and F. Hoffmann-La Roche Ltd. All authors received research funding in the form of third-party editorial support from F. Hoffmann-La Roche Ltd.

Figures

Figure 1.
Figure 1.. Ancestry representation across cancer types in the discovery cohort.
(A) Overall patient population distribution across the ancestry cohorts–European (EUR), South Asian (SAS), East Asian (EAS), American (AMR), African (AFR) (left). Prevalence of ancestry cohorts within the diseases and sample size of each disease (right). Tumor types that are abbreviated are listed here: Adenoid Cystic Carcinoma (ACC), Central nervous system (CNS), Diffuse Large B-Cell Lymphoma (DLBCL), Gastrointestinal (GI), Gastrointestinal Stromal Tumor (GIST), Myelodysplastic syndrome (MDS), Myelodysplastic-Myeloproliferative Neoplasm (MDS-MPN), Myeloproliferative Neoplasm (MPN), Natural Killer (NK), Not Otherwise Specified (NOS), Non-Small Cell Lung Carcinoma (NSCLC), Peripheral Nervous System (PNS). (B) Fraction of East African (EAFR) ancestry signature, West African (WAFR) ancestry signature, and European (EUR) ancestry signature in each sample classified as Admixed AFR (AAFR). AMR American, EAFR East African, EAS East Asian, EUR European, MDS Myelodysplastic-Myeloproliferative Neoplasm, MPN NK Natural Killer, NOS, NSCLC Non-Small Cell Lung Carcinoma, PNS Peripheral Nervous System.
Figure 2.
Figure 2.. Cancer genes associated with African ancestrys.
(A) Distribution of gene alterations in each ancestry group across diseases. The size of each dot represents the prevalence of a given gene alteration in the African (AFR) cohort in the disease. Colors reflect the logistic regression coefficient (LR coefficient), where values > 0 indicate a positive association with the African (AFR) ancestry percentage (red) and values < 0 indicate a negative association with the AFR ancestry percentage (blue). The fully outlined circles passed the FDR correction of P<0.05 and the partially outlined circles passed an FDR correction of P<0.1. (B) Volcano plot of the association between AFR ancestry percentage and gene alterations that were altered in at least 100 samples within the non-small cell lung cancer (NSCLC) – lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) subtypes. (C) Volcano plot of the association between AFR percentage and gene alterations that were altered in at least 100 samples within the triple negative breast cancer (TNBC) and ER+HER2- breast cancer subtypes. Replication with AFR ancestry in the MSK-IMPACT cohort is indicated by two asterisks ** (same LR coefficient direction and P<0.05) and trended is indicated by one asterisk * (same LR coefficient direction).
Figure 3.
Figure 3.. Ancestry-smoking interaction associated with driver mutations in lung cancer.
(A) Logistic regression showing the associations between the African (AFR) ancestry percentage and KRAS, ROS1 fusion, and TP53 in the discovery cohort in a smoking signature positive (right) and smoking signature negative (left; tumor mutational burden (TMB) < 5) cohort. Points represent the prevalence of alterations within AFR ancestry percentage tertile. One asterisk * indicates FDR P<0.05 in the stratified analysis. Red lines indicate that the ancestry-smoking interaction term was statistically significant, FDR P<0.05. (B) Logistic regression showing the associations between AFR ancestry percentage and KRAS, ROS1 fusion, and TP53 in the validation cohort in a former/current smoker (right) and never smoker (left) cohort. Points represent the prevalence of alterations within AFR ancestry signature quartiles. One asterisk * indicates P<0.05 in the stratified analysis. Red lines indicate that the ancestry-smoking interaction term was statistically significant, P<0.05.
Figure 4.
Figure 4.. Biomarkers associated with African ancestry.
Forest plots of the logistic regression coefficients and their confidence intervals showing the associations between African (AFR) ancestry percentage and four biomarkers (homologous recombination repair [HRR] gene set alterations [BRCA1/2], tumor mutational burden-high [TMB-H], mismatch repair [MMR] gene set [MLH1/MSH2/MSH6/PMS2], and microsatellite instability-high (MSI-H) across breast cancers, colorectal cancers, non-small cell lung cancers (NSCLC), ovarian cancers, pancreatic cancers, and prostate cancers. Points colored in pink indicate significant values, FDR P<0.05. Bars indicate the confidence intervals. Replication with AFR ancestry in the MSK-IMPACT cohort is indicated by two asterisks ** (same logistic regression [LR] coefficient direction and P<0.05) and trended is indicated by one asterisk * (same LR coefficient direction).
Figure 5.
Figure 5.. Clinically actionable alterations associated with African ancestry.
Volcano plots of the association between African (AFR) ancestry percentage and alterations annotated with OncoKB actionability in smoking signature-negative and TMB <5 lung adenocarcinomas (LUAD), smoking signature-positive LUAD, all non-small cell lung cancers (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, breast cancer and colorectal cancer.
Figure 6.
Figure 6.. Ancestry specificity of CCNE1 amplification as a biomarker.
Visualization of the interaction of African (AFR) ancestry percentage and CCNE1 amplification on survival in patients with triple negative breast cancer (TNBC). Hazard ratio (HR) for overall survival with AFR ancestry >50% (left) and AFR ancestry <50% (right) is shown. Bars indicate the 95% confidence intervals. Asterisks represent significant associations (P<0.05) with survival in the stratified analysis using the multivariate Cox regression model.
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