Prevalence of mutations associated with NCCN criteria for hereditary prostate cancer testing in an Indian population.
Authors: Bernardino Rui Miguel , Batra Atul , Cockburn Jessica Grace , Sildva Tiiu , Wettstein Marian , Gund Sneha , Chowdhary Sunakshi , Ghany Mikaeel , Ahmed Sayeed , Wagner Heidi , Akbari Mohammad R. , Fleshner Neil E. 
Published: June 2024

e17087 Background: Germline mutations in various genes increase the risk of lethal metastatic prostate cancer (PCa). It is well established that mutations including BRCA1, BRCA2, ATM, and CHEK2 are known to increase the risk of developing metastatic PCa, as 1 in 8 men with this disease are likely to harbour such mutations. The majority of research has focused on the role of DNA-repair genes in PCa risk, but more work is needed to clarify the distribution and frequency of mutations in different populations and genes. The primary aim of this study is to determine the germline genetic mutations in a northern Indian cohort of patients with high-risk PCa. Methods: We recruited 287 men that meet NCCN criteria for hereditary PCa testing. Five millilitres of blood was collected in EDTA tubes. Subsequently, DNA was extracted from the samples utilizing isolation kits and stored at -80°C until sequencing. The DNA extracted was sent for Whole Exome Sequencing genetic testing. The presence of germline mutations in genes known to be associated with prostate and other cancers was determined using established bioinformatic pipelines. Results: In our study involving 287 patients, pathogenic mutations were detected in 79 individuals. The total count of gene mutations observed was 43, with 13 patients exhibiting more than one mutation.These mutations spanned across 44 genes, with varying frequencies. Notably, BRCA2 mutations were found in 12 men (4.2%), ATM mutations in 5 individuals (1.7%), and CUBN mutations in 4 patients (1.4%). Additionally, ATR, LZTR1, PALB2, and RASA2 mutations were each observed in 3 patients (1.1%), while ADA2, BUB1B, CLCN7, ERCC2, FANCA, HNF1A, MSH2, PIEZO1, and VPS13B mutations were identified in 2 patients (0.69% of the cohort). Among the mutations detected, several were related to DNA repair genes. Specifically, BRCA2 mutations were observed in 12 cases (4.2%), ATM mutations in 5 cases (1.7%), PALB2 mutations in 3 cases (1.04%), ERCC2 mutations in 2 cases (0.7%), and BRCA1, ERCC5, and RAD51D mutations each in 1 case (0.35%). Overall, 25 (8.7%) of the total patients displayed alterations in DNA repair genes. Regarding variants of uncertain significance (VUS), the distribution among patients was as follows: 64 patients (22.3%) showed 3 VUS, 54 patients (18.8%) had 2 VUS, 46 patients (16.0%) had 4 VUS, 37 patients (12.9%) had 5 VUS, 28 patients (9.75%) had 1 VUS, and 19 patients (6.6%) had either 0 or 6 VUS. Conclusions: In our study, the incidence of germline mutations in genes mediating DNA-repair processes among men that meet NCCN criteria for hereditary PCa was 8.7% in this population in Northern India. This is 3.1% lower when comparing to the incidence reporting by Pritchard for metastatic PCa. Additional insights into the genetic risk of PCs are provided by this study which can be used to guide genetic testing.