Comparison of Breast Cancer Molecular Features and Survival by African and European Ancestry in The Cancer Genome Atlas

Abstract

IMPORTANCE African Americans have the highest breast cancer mortality rate. Although racial difference in the distribution of intrinsic subtypes of breast cancer is known, it is unclear if there are other inherent genomic differences that contribute to the survival disparities. OBJECTIVES To investigate racial differences in breast cancer molecular features and survival and to estimate the heritability of breast cancer subtypes. DESIGN, SETTING, AND PARTICIPANTS Among a convenience cohort of patients with invasive breast cancer, breast tumor and matched normal tissue sample data (as of September 18, 2015) were obtained from The Cancer Genome Atlas. MAIN OUTCOMES AND MEASURES Breast cancer-free interval, tumor molecular features, and genetic variants. RESULTS Participants were 930 patients with breast cancer, including 154 black patients of African ancestry (mean [SD] age at diagnosis, 55.66 [13.01] years; 98.1% [n = 151] female) and 776 white patients of European ancestry (mean [SD] age at diagnosis, 59.51 [13.11] years; 99.0% [n = 768] female). Compared with white patients, black patients had a worse breast cancer-free interval (hazard ratio, HR=1.67, 95 CI: 1.02–2.74; P = .043). They had a higher likelihood of basal-like (odds ratio, 3.80; 95% CI, 2.46–5.87; P < .001) and human epidermal growth factor receptor 2 (ERBB2 [formerly HER2])-enriched (odds ratio, 2.22; 95% CI, 1.10–4.47; P= .027) breast cancer subtypes, with the Luminal A subtype as the reference. Blacks had more TP53 mutations and fewer PIK3CA mutations than whites. While most molecular differences were eliminated after adjusting for intrinsic subtype, the study found 16 DNA methylation probes, 4 DNA copy number segments, 1 protein, and 142 genes that were differentially expressed, with the gene-based signature having an excellent capacity for distinguishing breast tumors from black vs white patients (cross-validation C index, 0.878). Using germline genotypes, the heritability of breast cancer subtypes (basal vs nonbasal) was estimated to be 0.436 (P = 1.5 × 10−14). The estrogen receptor-positive polygenic risk score built from 89 known susceptibility variants was higher in blacks than in whites (difference, 0.24; P = 2.3 × 10−5), while the estrogen receptor-negative polygenic risk score was much higher in blacks than in whites (difference, 0.48; P = 2.8 × 10−11). CONCLUSIONS AND RELEVANCE On the molecular level, after adjusting for intrinsic subtype frequency differences, this study found a modest number of genomic differences but a significant clinical survival outcome difference between blacks and whites in The Cancer Genome Atlas data set. Moreover, more than 40% of breast cancer subtype frequency differences could be explained by genetic variants. These data could form the basis for the development of molecular targeted therapies to improve clinical outcomes for the specific subtypes of breast cancers that disproportionately affect black women. Findings also indicate that personalized risk assessment and optimal treatment could redu...

Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers

“…These pan-cancer findings are consistent with previous results from studies based on a single cancer type. For example, recent studies on breast cancer from the TCGA cohort (Ademuyiwa et al, 2017; Huo et al, 2017; Keenan et al, 2015) demonstrated that AAs had more TP53 mutations and fewer PIK3CA mutations. These observations not only further our understanding of the contributions of genetic ancestry to cancer disparities, but may also inform personalized treatment of cancer patients from racial/ethnic minority groups.…”

“…This shared genetic background may confer similarities in cancer incidence and outcomes in populations. Recent large-scale genomic profile studies in individual cancer types, such as prostate (Huang et al, 2017; Petrovics et al, 2015; Powell et al, 2013; Wang et al, 2017), breast (Ademuyiwa et al, 2017; Huo et al, 2017; Keenan et al, 2015; Loo et al, 2011), colon (Guda et al, 2015), lung (Araujo et al, 2015; Campbell et al, 2017; Kytola et al, 2017), gastric (Schumacher et al, 2017), esophageal (Deng et al, 2017), and kidney (Krishnan et al, 2016) cancers have robustly demonstrated that genomic differences in cancers exist among distinct racial and ethnic populations. Consistently, it has been reported that the genetic background of patients may influence specific somatic alterations in cancer genomes during tumorigenesis (Carter et al, 2017).…”

Race and risk of subsequent aggressive breast cancer following ductal carcinoma in situ

“…In a comprehensive analysis of genomic, transcriptomic, and proteomic data from the Cancer Genome Atlas, Huo et al 31 found that a number of molecular features differed between black and white IBCs after adjustments for age and subtypes, including the DNA copy number, gene expression, and DNA methylation. In a comprehensive analysis of genomic, transcriptomic, and proteomic data from the Cancer Genome Atlas, Huo et al 31 found that a number of molecular features differed between black and white IBCs after adjustments for age and subtypes, including the DNA copy number, gene expression, and DNA methylation.…”

Reported Biologic Differences in Breast Cancer by Race Due to Disparities in Screening

“…In conclusion, most of the reported biological differences between black and white breast cancer 2 can be explained by disparities in access to care leading to black women presenting with later stage disease. This only further highlights the need to address racial disparities in poverty and access to care.…”

“…To address the latter, Huo and colleagues recently investigated genetic differences between white and black breast cancers using data from The Cancer Genome Atlas (TCGA). 2 They reported a number of biological differences between black and white breast cancers. Interestingly, most tumor genomic differences between races were explained by subtype.…”