Homologous recombination-related (HRR) gene mutation profiling and the association with TMB in Chinese patients with urological cancer.

Abstract

e16561 Background: Homologous recombination deficiency (HRD) is associated with tumorigenesis and could predict the response of PARP inhibitor (PARPi) therapy and immunotherapy. Loss of function or deleterious mutations in homologous recombination-related (HRR) genes contribute to HRD phenotype. Methods: Tumor tissue samples from 484 Chinese patients with urological cancer were sequenced with 551 cancer-related genes. 957 patients with WES data from the TCGA datasets were included for analysis. Results: In the Chinese cohort, 35.88% (47/131) bladder cancer (BCa) patients, 15.47% (28/181) renal cell carcinoma (RCC) and 37.21% (64/172) prostate cancer (PCa) patients exhibited somatic HRR (sHRR) gene mutations. The most frequently mutated genes were BRCA2 (12% in BCa, 5% in RCC) and CDK12 (17% in PCa), respectively. The germline HRR (gHRR) gene mutations were identified in 62.6% (82/131) BCa, 55.33% (96/180) RCC and 60.62% (97/160) PCa patients. The most frequently mutated gene was BRCA2 (24% in BC, 18% in RCC, 26% in PCa). 7.6% (10/131) BCa patients, 1.7% (3/181) RCC patients and 2.9% (5/173) Pca patients carried both germline and somatic HRR gene mutations. In the TCGA cohort, 38.69% (159/411) BCa patients, 11.62% (43/370) RCC and 6.25% (11/176) PCa patients exhibited somatic HRR (sHRR) gene mutations. The most frequently mutated gene was ATM (14% in BCa, 4% in RCC, 5% in PCa). Interestingly, for the patients with PCa, the somatic mutant frequency of HRR genes in Chinese cohort was higher than that in TCGA cohort (37.21% vs 6.25%, p < 0.001). The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (Chinese cohort: BCa 13.97 vs 4.96, p < 0.001; RCC, 4.96 vs 2.84, p < 0.001; PCa, 5.64 vs 2.84, p < 0.001, TCGA cohort: BCa, 7.21 vs 3.63, p < 0.001; RCC, 1.68 vs 1.42, p = 0.003; PCa, 1.03 vs 0.71, p < 0.001). However, the median TMB was similar between the gHRR-Mut and the gHRR-WT patients (Chinese cohort, BCa 6.38 vs 7.09 p = 0.646; RCC, 3.55 vs 2.84, p = 0.229; PCa, 3.55 vs 2.84, p = 0.111). Conclusions: Our data reported the genetic landscape of HRR gene in Chinese urological cancer patients and suggested that patients with altered HRR genes may be rational candidates for precision oncology treatment and provide new opportunities to predict the tumor response to multiple treatments.