Background: Multiple types of tumors exhibit DNA repair dysfunction via homologous recombination deficiency (HRD) due to genetic and epigenetic alterations of HR pathway genes, including BRCA1/2, PALB2, ATM, ATR, CHK1/2, BARD1, BIRP1, MRE11A, RAD51 family and FANC family. Some studies showed that tumors with homologous recombination deficiency might result in more mutations than tumors with non-deficient HR. Accumulating evidence suggests that tumor mutational burden (TMB) evaluated by comprehensive genomic profiling was associated with the responses of immune checkpoint inhibitors in solid tumors.

Methods: FFPE tumor samples of 777 Chinese patients were collected for next-generation sequencing (NGS)-based targeted panel assay across multiple types of tumors, including lung, breast, soft tissue, gastrointestinal and gynecology cancers. There were 471 males (60.6%) and 306 females (39.4%) with a median age of 58 years old. Genomic alterations of HR-related genes and TMB values were assessed by next-generation sequencing assay, including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangements.

Results: In total, 25% of the 777 solid tumor patients had at least one genomic alteration of the HR genes (N=197, HRD group). The top mutant HR genes included BRCA1/2 (28.8%), FANC family (27.6%), ATM (27.4%), ATR (11.2%), RAD51 family (8%), BARD1 (7.6%), PALB2 (7.1%), BIRP1 (5.6%), CHK1/2 (5.0%) and MRE11A (4.6%). TMB was 10.4 muts/Mb in the HRD group compared to 6.4 muts/Mb in the rest of the patients (p<0.01). In addition, 43.2% of the patients in the HRD group had TMB-high values, which was higher than in the non-HRD group at 22.8% (P<0.01). High TMB values were more commonly detected in the colorectal cancer patients.

Conclusions: Our study revealed that the solid tumors harboring HR gene mutation were more likely to have higher TMB values. BRCA1/2, FANC family and ATM were the most common mutant genes. CRC was the dominant cancer type showing high TMB values associated with HRD. Further analysis is warranted to investigate the association.

Citation Format: Hua Li, Liqun Wu, Tao Shou, Bo Jiang, Li Zhuang, Kunsong Li, Xiang Tan, Chao Guo, Weidong Guo, Yan Guan, Zheng Chen, Xiao Ding, Jun Guo, Zhenfang Du, Qiang Cui, Yue Che, Ming Yao. Analysis of association between homologous recombination deficiency and tumor mutational burden in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1369.