Abstract 5766: Pan-cancer analysis revealed characteristics of reversion mutations in homologous recombination repair genes
Authors: Li Jing , Wu Xiaoying , Shi Yan , Wang Di , Chen Yedan , Shao Yang 
Published: June 2022

Background: Reversion mutations of BRCA1/2 are associated with decreased response to platinum-based chemotherapies and PARP inhibitors. While patient with homologous recombination repair (HRR) genes have proven efficacy to PARP inhibitors, reversion mutations in these genes have not been widely studied. Here, we performed pan-cancer analysis to reveal the characteristics of HRR reversion mutations.

Methods: We assessed 1,992 patients with at least one loss of function mutation in BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, ERCC3, RAD51, WRN, FANCI, MRE11A, ATR, FANCD2, FANCA, FANCC, BLM and NBN. Somatic reversion mutations were indel or missense mutations that restore the open reading frame and potentially protein function fully or partially. Definitive reversion mutations are confirmed secondary mutations in patients with known pathogenic germline HRR gene mutations, or in a subsequent sample of previously detected somatic pathogenic mutants. Other reversion mutations are putative due to lack of matched samples.

Results: Overall, we found 31/1,992 (1.6%) tumors with definitive or putative HRR reversion mutations, including 17 with germline and 14 with somatic predisposed pathogenic HRR mutations. Of these, we identified 9 BRCA1 (29%, 2 sBRCA1 and 7 gBRCA1) and 12 BRCA2 (39%, 4 sBRCA2 and 8 gBRCA2). We also found pathogenic germline PALB2 (1, 3%) and RAD41D (1, 3%), and somatic mutations in CDK12 (3, 9%), ATM (2, 6%), WRN (1, 3%), FANCD2 (1, 3%), and ATR (1, 3%). Overall, 43 reversion mutations were detected (37 definitive and 6 putative), with eight patients carrying multiple reversion mutations. Importantly, 40/43 reversion mutations were found within 2bp upstream to the start site of original deleterious variants, and all were unique to currently known database. Missense-induced reversions were found in 74% primary stop-gain mutations, while indel-induced reversions were associated with 59% primary frameshift mutations. These HRR reversion mutations were primarily found in breast cancer (9%, 10/107) and ovarian cancer (6%, 3/54), and also in cases of prostate (1/25, 4%), pancreatic (1/29, 3%), colorectal (2%, 9/418), and non-small cell lung cancer (1%, 6/703). Of note, the incidence of multiple HRR reversion mutations was higher in breast cancer (75%, 6/8). Lastly, reversion mutations were detectable in plasma, pleural and ascites fluid samples, suggesting great clinical utility of ctDNA to monitor reversion mutations.

Conclusions: This study analyzed clinical and mutational characteristics of reversion mutations in HRR genes, which could occur as single or multiple variants to restore the function of predisposed pathogenic HRR mutations, resulting in resistance to platinum-based chemotherapies or PARP inhibitors. Monitoring these mutations with tissue or liquid biopsy samples are crucial for treatment guidance.

Citation Format: Jing Li, Xiaoying Wu, Yan Shi, Di Wang, Yedan Chen, Yang Shao. Pan-cancer analysis revealed characteristics of reversion mutations in homologous recombination repair genes [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 5766.