Abstract PR12: Using whole exome sequencing of archived FFPE tissue to characterize the mutational landscape of prostate cancer in Nigerian men
Authors:   Prostate Cancer Transatlantic Consortium Members, White Jason , Tang Wei , Ambs Stefan , Rotimi Solomon , Faruuk Mohammed , Odedina Folakemi , Yates Clayton 
Published: September 2020

Compared to other ancestral groups, men of African ancestry (MAA) have the highest incidence and mortality of prostate cancer (PCa), with African men having the highest. Multiple studies have demonstrated that genetic/biologic differences in African American (AA) tumor biology contribute to PCa development and aggressiveness; furthermore, building evidence suggests that the observed differences are population specific and form unique paths to cancer aggressiveness. Despite this, MAA continue to be underrepresented in PCa studies. This lack of adequate representation greatly diminishes the ability to identify clinical interventions to address this disparate disease. In this study, we used whole-exome sequencing of 148 Nigerian PCa FFPE samples (75 Tumor, 62 BPH, and 11 non-matched Normal) to determine the mutational landscape of PCa. Samples were collected from 6 sites in central and southwest Nigeria and quality screened. Samples passing QC were sequenced (Illumina HiSeq 4000 PE150) and read files were processed using the Tumor Only Somatic Mutation pipeline developed by the CCR Collaborative Bioinformatics Resource (CCBR). In addition to the CCBR pipeline, Exomiser was used to prioritize non-silent variants according to variant frequency, pathogenicity, quality, and model organism phenotype data. 246 genes showed significant (p ≥ 0.05) tumor mutation and high prioritization (Exomiser score ≥ 0.75). These genes included BCR, KMD1A, MSH6, TLR4, and BMPR1B with mutation rates of 17%, 13%, 12%, 11%, and 8%, respectively. These rates were higher than process matched controls and TCGA tumor samples. Mutation signature analysis showed enrichments in 4 Cosmic signatures. 38.6% of Tumor samples contained signatures similar (cosine similarity [cs] = 0.912) to Signature 1, 29.3% were similar (cs = 0.849) to Signature 4, 14.6% were similar (cs = 0.743) to Signature 5, and 17.3% were similar (cs = 0.635) to Signature 25. Groupwise comparisons of gene mutations and mutation signatures showed that 8 of the 29 tumors (p ≤ 0.06), having a Signature 1 similar signature, contained a BCR frameshift insertion (c.3275_3278dup), which duplicates a four-nucleotide CCGG sequence in exon 19. The relationship between BCR and prostate cancer is still poorly understood; however, within the TCGA PRAD cohort, low BCR expression does significantly (p ≤ 0.024) correlate with poor survival. These results suggest that mutations within BCR result in a disruption of methylation and expression patterns that could contribute to worse outcomes in Nigerian PCa patients. Without tumor/normal matched pairs, more analysis is needed to ensure the accuracy of this characterization; however, completion of this study would comprise the largest mutational analysis of Nigerian PCa to date. Understanding the genetic underpinnings of PCa in Nigerian patients will add much-needed context to the study of the disease in MAA, further illuminating clinical interventions that may prove beneficial in diminishing outcome disparities.

This abstract is also being presented as Poster B079.

Citation Format: Prostate Cancer Transatlantic Consortium Members, Jason White, Wei Tang, Stefan Ambs, Solomon Rotimi, Mohammed Faruuk, Folakemi Odedina, Clayton Yates. Using whole exome sequencing of archived FFPE tissue to characterize the mutational landscape of prostate cancer in Nigerian 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 PR12.