Genomic landscape and homologous recombination repair (HRR) genes analysis in Chinese prostate cancer (PCa) patients.

Abstract

e17020 Background: HRR gene mutations have been proven to be effective biomarkers for PARP inhibitor (PARPi) therapy in metastatic castration resistant PCa. The epidemiological data of genomic variation and the characteristic of HRR gene alterations in Chinese population is still insufficient. Methods: Tumor tissue samples (including surgical and biopsy samples) and blood samples from 250 pathologically confirmed PCa patients were collected and analyzed using next generation sequencing (733-gene panel). Tumor mutation burden (TMB) was defined as total number of somatic non-synonymous mutations in coding region. Homologous recombination deficiency (HRD) was evaluated by the sum of the loss of heterozygosity, telomeric allelic imbalance and large-scale state transition. Somatic or germline alterations (including copy number reduction, CNV-loss) of HRR pathway genes were classified as HRR-altered positive. Results: In total, the top three alteration frequency somatic genes were FOXA1 (24.9%), TP53 (15.2%) and MYC (13.6%) while the top three alteration frequency germline genes were DPYD (17.1%), UGT1A1 (13.2%) and SLX4 (4.3%). In HRR pathway genes, the top three alteration frequency somatic genes were CDK12 (9.7%), ATM (4.7%) and BRCA2 (3.9%) while the top three alteration frequency germline genes were BRCA2 (3.1%), PALB2 (1.9%) and BRCA1 (1.6%). 25.6% (64/250) cases carried HRR gene alterations. Among HRR-altered positive cases with HRD score, only 8.9% (4/45) carried more than one HRR gene alteration and most carried a single HRR gene alteration (40.0% [18/45] in CDK12, 17.8% [8/45] in ATM or BRCA2, 11.1% [5/45] in BRCA1 and 2.2% [1/45] in PALB2 or FANCA). 61 HRR gene alterations were detected in these 45 cases and the commonly alteration types of HRR genes were single base substitution (47.5%, 29/61). The alteration type of CNV-loss (14.8%, 9/61) was only detected in somatic samples. The HRD score of HRR-altered group was significantly higher than wild group (median HRD socre, altered-type vs. wild-type = 23.5 vs. 19.0, P= 0.0097). And there was no significant difference in HRD score between CNV-loss and other alteration types. Moveover, the TMB level of HRR-altered group tended to be higher than wild group (median TMB, altered-type vs. wild-type = 4.5 vs. 2.8 Muts/Mb, P= 0.5). Conclusions: The results illustrated the molecular characteristics of HRR gene in Chinese PCa and indicated that HRR gene alterations (including CNV-loss) were associated with higher HRD score. These data provide further evidence for the clinical management of PARPi personalized therapy.