Abstract P4-14-01: Whole exome sequencing reveals greater intratumor genetic heterogeneity in primary breast cancer arising in African American compared to Caucasian women

Abstract

Abstract Introduction: Multiple studies have reported that African American women have higher mortality from breast cancer than Caucasian women. While the higher mortality could be due to several factors including access to care, relatively little is known about tumor genetic differences that may contribute to this disparity. A particularly uncharted area of investigation is intratumor genetic heterogeneity arising from various subclones within a tumor. The primary objective of this study was to characterize the differences in mutation patterns and evaluate intratumor heterogeneity in primary breast cancer between African American and Caucasian women. Methods: Somatic mutations based on whole exome sequencing of primary breast cancers were analyzed using data from The Cancer Genome Atlas (TCGA). Individuals with races that were Native American, Asian, or not reported were omitted. Logistic regression analyses were conducted to compare the odds ratio (OR) with 95% confidence interval (CI) of non-silent gene mutations by race. Total non-silent gene mutations and genetic heterogeneity, measured by the mutant-allele tumor heterogeneity (MATH) algorithm (Mroz et al. Cancer 2013), were compared by race with Mann-Whitney two-sample tests and linear regression analyses, respectively. All regression analyses were adjusted for age and stage. A p value of 0.05 was considered statistically significant. Results: The analytical dataset comprised non-silent somatic mutations in unique genes of primary breast cancers from 799 women (689 Caucasian; 110 African American). TP53 mutations were significantly more prevalent in African Americans than Caucasians (OR 1.7; CI 1.1-2.7, p = 0.01). However, there was no difference in TP53 mutation prevalence after further adjustment for triple negative status (OR 1.2; CI 0.7-2.0, p = 0.53). Total non-silent gene mutations per patient were significantly greater in African Americans compared to Caucasians (Table, p = 0.01). Similarly, MATH was significantly greater in African Americans than Caucasians (Table), specifically 5.3 units (CI 2.6-7.9, p <0.001) greater after adjustment for age and stage. Further adjustment for triple negative status showed that MATH was still 4.2 units (CI 1.6-6.9, p = 0.002) greater in African Americans than Caucasians. Somatic mutations and genetic heterogeneity by race CaucasiansAfrican AmericansTotal non-silent mutations per patient (median, interquartile range)33 (21-60)39.5 (26-74)Intratumor genetic heterogeneity (mean, 95% CI)39.0 (38.0-40.0)43.9 (41.3-46.5)CI, confidence interval. Conclusions: Primary breast cancers in African Americans exhibit significantly greater total non-silent somatic mutations and intratumor genetic heterogeneity but not higher frequency of TP53 mutations, suggesting African Americans have genetically more complex tumors as compared to Caucasian women. Additional research is needed to determine if the observed tumor genetic differences could contribute to the known racial disparity in breast cancer mortality. Citation Format: Tanya E Keenan, Edmund A Mroz, James W Rocco, Leif W Ellisen, Beverly Moy, Aditya Bardia. Whole exome sequencing reveals greater intratumor genetic heterogeneity in primary breast cancer arising in African American compared to Caucasian women [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-14-01.