Abstract A122: Comparison of mutational profiles in primary prostate cancers between men with African and European ancestry

Abstract

Abstract Background: African American men have more than twice the age-adjusted mortality rate from prostate cancer than European American men. Lower rate of PSA screening, less aggressive treatment, and other socioeconomic factors have been raised as possible reasons for this disparity, but genetic differences between prostate cancers from African and European ancestry have not been fully investigated as most sequencing studies so far have studied the latter group. The goal of this study is to perform a meta-analysis across various publicly available sequencing datasets and identify mutational profiles associated with African American ancestry in prostate cancer. Methods: Whole exome sequencing data from 499 treatment-naive prostate cancers were analyzed from The Cancer Genome Atlas (TCGA). The ethnicity of each patient was inferred using previously published method (1). Our analysis included whole-exome sequencing data from 404 European and 159 African prostate cancers. African American samples were aggregate of TCGA and recently published African American prostate cancer data (2). We looked at previously shown 97 significantly mutated genes in prostate cancer (3). Using coding mutations, a Fisher's exact test was performed for each gene to compare the frequencies between populations. In a separate analysis, these two exome datasets were combined with two other targeted sequencing datasets from Huang et al. (2) (n = 86) and Abida et al. (4) (n = 424) using only genes common to all platforms. Results: Among 97 genes, only KDM6A was significantly enriched in African American samples (p = 0.039). NCOR1, ERF, and AR tended to be more mutated in African American samples. TP53, SPEN, and PIK3CA were more mutated in prostate cancer of European ancestry (p < 0.05). PTEN and CTNNB1 tended to be more mutated in European tumors even though they did not meet statistical significance. For the meta-analysis across both exome and targeted sequencing datasets, we observed that ZFHX3 was significantly more frequent in tumors from African American versus other populations (8% versus 2%, FDR = 0.0001). ZFHX3 was also strongly enriched for loss-of-function mutations (p = 1.2e-9), further supporting its role as a tumor suppressor. Discussion: The contribution of tumor genetics to outcome disparities in African American prostate cancer is under active investigation. Our analysis shows that African American prostate cancers tend to harbor fewer mutations in previously identified prostate cancer genes such as PIK3CA, TP53, PTEN, and CTNNB1 and potentially more mutations in KDM6A and ZFHX3. As prostate cancers have a lower mutation rate, the number of tumors needed to detect low frequency mutations is high. More sequencing of African American prostate cancers may elucidate additional genetic contributions to higher mortality. Citation Format: Eejung Kim, Yusuke Koga, Jian Carrot-Zhang, Joshua D. Campbell, Franklin Huang. Comparison of mutational profiles in primary prostate cancers between men with African and European ancestry [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A122.