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

Yalei Chen,Craig G Rogers,Indrani Datta,Jia Li,Dhananjay Chitale,Ruicong She,Nilesh Gupta,Lisa A Newman,Benjamin A Rybicki,Pamela L Paris,Kanika Taneja,Albert M Levin,Sudha M Sadasivan,Melissa B Davis

doi:10.1186/s12920-020-00765-2

Abstract

BackgroundPan-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, pan-cancer 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.MethodsUtilizing 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).ResultsWe 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.ConclusionsThis study identified race-differentiated SCNAs shared by two related cancers. The association of SCNA-defined patient groups with survival demonstrates the clinical significance of combinations of these race-differentiated genomic aberrations, and the higher frequency of these alterations in AA relative to EA patients may explain racial disparities in risk of aggressive breast and prostate cancer.

Highlights

Pan-cancer studies of somatic copy number alterations (SCNAs) have demonstrated common Somatic copy number alterations (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
SCNAs in The Cancer Genome Atlas (TCGA) breast tumors and differences by race Given the higher frequency of tumor data for European American (EA) in comparison to AAs in TCGA breast and prostate tumor sets, we elected to identify SCNAs separately by race group in order not to obscure SCNAs that might be specific to AAs
In summary, using TCGA data, we demonstrated that a majority of race-differentiated SCNAs in breast and prostate tumors have greater magnitude alterations in AAs relative to EAs and that this was the case for all of six race-differentiated SCNAs that were shared consistently across these tumor types

Summary

Introduction

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. As breast and prostate cancer share some of the same biologic pathways, such as the steroid-hormone metabolism and insulin-like growth factor signaling, which when altered can lead to either cancer, a biologic rationale exists to investigate shared somatic genetic mechanisms between these two hormonally-driven cancers [3]. This concept of a shared somatic genetic etiology between breast and prostate cancer is supported by a recent study which used a gene expression panel, the PAM50, developed to molecularly subtype breast cancer, to classify prostate tumors into luminal- and basal-like subtypes [4]. Recent pan-cancer analyses have shown breast and prostate cancer to have similar levels of insertion/deletion mutations [5] and intra-tumor heterogeneity [6], suggesting a similar mutational landscape may exist between the two cancers

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