Breast and prostate cancers harbor common somatic copy number alterations that consistently differ by race and are associated with survival

Abstract

Background: Pan-cancer studies of somatic copy number alterations (SCNAs) have demonstrated common SCNA patterns across cancer types, but despite demonstrable differences in aggressiveness of some cancers by race, pancancer SCNA variation by race has not been explored. This study investigated a) racial differences in SCNAs in both breast and prostate cancer, b) the degree to which they are shared across cancers, and c) the impact of these shared, race-differentiated SCNAs on cancer survival. Methods: Utilizing data from The Cancer Genome Atlas (TCGA), SCNAs were identified using GISTIC 2.0, and in each tumor type, differences in SCNA magnitude between African Americans (AA) and European Americans (EA) were tested using linear regression. Unsupervised hierarchical clustering of the copy number of genes residing in race-differentiated SCNAs shared between tumor types was used to identify SCNA-defined patient groups, and Cox proportional hazards regression was used to test for association between those groups and overall/progression-free survival (PFS). Results: We identified SCNAs that differed by race in breast (n = 58 SCNAs; permutation p < 10 − 4) and prostate tumors (n = 78 SCNAs; permutation p = 0.006). Six race-differentiated SCNAs common to breast and prostate found at chromosomes 5q11.2-q14.1, 5q15-q21.1, 8q21.11-q21.13, 8q21.3-q24.3, 11q22.3, and 13q12.3-q21.3 had consistent differences by race across both tumor types, and all six were of higher magnitude in AAs, with the chromosome 8q regions being the only amplifications. Higher magnitude copy number differences in AAs were also identified at two of these race-differentiated SCNAs in two additional hormonally-driven tumor types: endometrial (8q21.3-q24.3 and 13q12.3-q21.3) and ovarian (13q12.3-q21.3) cancers. Race differentiated SCNA-defined patient groups were significantly associated with survival differences in both cancer types, and these groups also differentiated within triple negative breast cancers based on PFS. While the frequency of the SCNA-defined patient groups differed by race, their effects on survival did not.

Gene-level germline contributions to clinical risk of recurrence scores in Black and White breast cancer patients

“…Among BW, the singular TWAS-gene explained ∼1% of the variation in Proliferation score and ROR-P. Differences in the number and effect of identified TWAS-genes by race may point to factors that warrant further investigation: (1) potentially greater contribution of trans -regulation in tumor gene expression in BW, as shown previously, and (2) potential racial differences in tumor methylation and somatic alternations, which could not be accounted for in CBCS[16, 42-47].…”

“…First, the range of MMP1 GReX was manifold among WW than BW, suggesting sparser cis -eQTL architecture of MMP1 in BW and more influence from trans -acting signals. Potential differences in influence of germline genetics on tumor expression and ROR by race could be an artifact of divergent somatic or epigenetic factors that CBCS has not assayed [44-47]. Second, while studies generally report that MMP1 tumor expression is higher in triple-negative and Basal-like breast cancer, one study reported that MMP1 expression in tumor cells does not significantly differ by subtype [61-63].…”

“…Differences in the number and effect of identified TWAS-genes by race point to factors that warrant further investigation: (1) potential greater contribution of trans -regulation in tumor gene expression in BW (methods for capturing trans -regulation in gene expression predictive models are not as well-developed as those for cis -regulation) (18) and (2) potential racial differences in tumor methylation and somatic alternations, which were not assayed in CBCS (18,72-77). These factors should be investigated further as transcriptomic and epigenomic datasets for racially-diverse cohorts of breast cancer patients become available.…”

“…While heritability and proportion of variance in MMP1 expression were similar across WW and BW predictive models, we found that the range of MMP1 GReX was manifold among WW than BW. Potential differences in influence of germline genetics on tumor expression and CRS by race could be an artifact of divergent somatic or epigenetic factors that CBCS has not assayed (73)(74)(75)(76).…”

“…Analyses by race instead of genetic ancestry yielded associations similar in magnitude and direction. Racial differences in non-germline components of tumor expression, including tumor methylation and somatic alternations, may partly explain race-specific differences in GReX-prioritized genes (18,(73)(74)(75)(76)82,83). Other factors that warrant further investigation include potential greater contribution of trans-regulation in tumor gene expression in BW (methods for capturing transregulation in gene expression predictive models are not as well-developed as those for cis-regulation) (18).…”