Abstract 5690: The landscape of homologous recombination repair gene mutations and prognosis in Chinese patients with clear cell renal cell carcinoma
Authors: Chen Peng , Zhang Yuan , Bi Xing , Niu Yue , Shayiti Fuerhaiti , Yuan Shuai , Pan Ting , Wang Yan 
Published: June 2022

Abstract
Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer with poor prognosis. Mutations in homologous recombination repair (HRR) genes are associated with human tumorigenesis and response to DNA-damage-inducing therapeutics, such as platinum agents and PARP inhibitors. A better understanding of the genomic features of HRR pathway genes and its correlations with prognosis will facilitate precise personalized treatment selection.
Methods: Tumor tissues and matched blood were collected from 269 ccRCC patients at the 3rd Affilated Teaching Hospital of Xinjiang Medical University(Affiliated Tumor Hospital) from 2011 to 2017. A panel targeting 450 cancer-related gene test was performed at OrigiMed (Shanghai, China). Using targeted capture genomic sequencing, we assessed patients for germline and somatic mutations in 23 HRR related genes. Survival analysis was performed using a Cox proportional hazards model and the p-value was determined with a log-rank test.
Results: In total, 269 ccRCC patients, including 95 females and 174 males with a median age of 55 (range 21-87 years old), were recruited. Fifty patients developed distant metastases. The most frequently mutated genes were VHL (83%) and PBRM1 (38%). The median tumor mutational burden (TMB) of this cohort was 4 muts/Mb (0-43.9 muts/Mb), and 4.1% (11/269) of patients displayed high TMB (defined as ≥ 10 muts/Mb). HRR pathway gene mutations were detected in 90/269 patients (33.46%). The most frequently altered genes were BAP1(13.4%), ARID1A (5.2%), BRCA1 (3.72%), ATM (3.35%), and BRCA2 (1.86%). Truncation (23.05%) was the most common mutation type. 4.46% (12/269) of patients carried HRR-related germline mutations, and the most frequently mutated germline genes were RAD51C/D (33.33%,4/9) and BRCA (16.67%, 2/9). Patients with HRR pathway gene mutations were found to have a significantly higher TMB (median, 4.45 vs. 4 muts/Mb, p &lt; 0. 05). We additionally identified that mutations in HRR pathways were significantly associated with decreased relapse-free survival (RFS)( p &lt; 0.05). The 3-year RFS rate of the HRR-mutated group was significantly lower than the negative group (78.8% vs.90.6%, p&lt;0.01).
Conclusion: HRR gene alterations, associated with increased recurrence, occurred at a high frequency of 33.46% in Chinese ccRCC patients. Further studies regarding to therapeutic agents targeting the HRR pathway in this population should be considered in the future.
Citation Format: Peng Chen, Yuan Zhang, Xing Bi, Yue Niu, Fuerhaiti Shayiti, Shuai Yuan, Ting Pan, Yan Wang. The landscape of homologous recombination repair gene mutations and prognosis in Chinese patients with clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5690.