Abstract B067: Whole-exome sequencing of matched longitudinal primary and metastatic prostate cancers from African American men Free

The incidence and associated mortality and morbidity from prostate cancer (PCa) are disproportionately higher among African Americans (AA). Most deaths from PCa are attributable to the metastatic phase of the disease; the molecular underpinnings of which remain poorly understood. To identify somatic genomic variations associated with PCa metastases, we performed whole-exome sequencing (WES) on matched normal, primary, and metastatic prostate cancer tissue trios from AA patients. Microdissected formalin fixed paraffin embedded archival tissue was the source of the samples. The analysis to identify significant driver mutations and somatic copy number events was deduced using publicly available tools and custom bioinformatics processes. The cohort was comprised of matched tissue trios from 18 AA prostate cancer cases. Mean WES coverage for normal, primary and metastatic tumor were 79X, 76X and 72.5X, respectively. Percent African ancestry ranged from 0.755 to 0.997 based upon admixture informative markers from WES data. Somatic mutation counts varied among individual primary (26 to1,457) and metastatic (22 to 323) tumors. The extent of mutation overlaps between primary and metastatic PCa genomes varied substantially from 0 (0%) to 53 (14%). Recurrent mutations in the TECPR2 and PARP4 genes were found unique to metastatic cancers. Three missense mutations in the TECPR2 gene were found in the metastatic lesions of three individual patients: G344R (novel), S514N (novel) and R1066C (rs776056002). In silico functional annotation of these mutations showed to have a potentially deleterious (SIFT) and possibly/probably damaging (PolyPhen) effect. Two potentially deleterious missense mutations in the PARP4 gene namely E216V (novel) and L1080F (rs201405094) were found in the metastatic lesions in two patients. We observed differentially altered copy number events between primary and metastatic tumors. Significantly higher recurrent amplifications of chromosomal regions harboring JAK3 and ANK2 genes were observed in 26% of metastatic cases (p<0.05). Copy number losses (p<0.05) specific to metastatic tumors included regions harboring TPO, AFF3, and CYP7B1 genes. Here we report identification of recurrent potentially deleterious missense mutations in the TECPR2 and PARP4 genes in a subset of metastatic PCa that were not present in matched primary tumors. Several copy number alterations including amplifications of the JAK3 and ANK2 genes were also found unique to metastases. Further examination of the biological role of the identified novel mutations in the etiopathogenesis of PCa metastases is warranted, and is currently underway.

Citation Format: Zarko Manojlovic, Babak Shokrani, John D Carpten, Mezbah U Faruque. Whole-exome sequencing of matched longitudinal primary and metastatic prostate cancers from African American men [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B067.