Germline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes

• Published in: Nature communications Vol. 13; no. 1; p. 1361
• Main Authors: Kohaar, Indu, Zhang, Xijun, Tan, Shyh-Han, Nousome, Darryl, Babcock, Kevin, Ravindranath, Lakshmi, Sukumar, Gauthaman, Mcgrath-Martinez, Elisa, Rosenberger, John, Alba, Camille, Ali, Amina, Young, Denise, Chen, Yongmei, Cullen, Jennifer, Rosner, Inger L., Sesterhenn, Isabell A., Dobi, Albert, Chesnut, Gregory, Turner, Clesson, Dalgard, Clifton, Wilkerson, Matthew D., Pollard, Harvey B., Srivastava, Shiv, Petrovics, Gyorgy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.03.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 631/67/589/466; 631/67/68; 631/67/69; African Americans; African Americans - genetics; BRCA1 protein; Damage; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; DNA repair; Gene sequencing; Genes; Genomes; Germ-Line Mutation; Humanities and Social Sciences; Humans; Male; Minority & ethnic groups; multidisciplinary; Mutation; Mutation rates; Nucleotide sequence; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Repair; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28945-x

In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs ( N  = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes ( RAD51, RAD54L, RAD54B ), which are potentially targetable, as well as PMS2 and BRCA1 , are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients. DNA damage repair genes have been linked with increased aggressiveness of prostate cancer, however, the extent of mutation of these genes has not been analyzed within a cohort of African American patients. Here, the authors identify increased mutation rates in specific DNA repair genes, compared with prostate cancer patients with European Ancestry.