The landscape of homologous recombination deficiency in colorectal cancer

Tumors deficient in homologous recombination DNA damage repair (HR-DDR) demonstrate sensitivity to therapeutic agents targeting the HR-DDR pathway, such as poly-ADP ribose phosphate (PARP) inhibitors and ataxia telangiectasia and Rad-3 related kinase (ATR) inhibitors. We sought to analyze the mutational landscape of homologous recombination deficiency (HRD) pathogenic gene variants (PGVs) in colorectal cancer, stratified by histology and co-occurrence of mismatch repair (MMR) PGVs.

The American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 13.0 was queried for all colorectal tumors via cBioPortal (http://genie.cbioportal.org). This is a publicly available, multi-institutional database of next-generation sequencing (NGS) genomic profiles of multiple tumors. PGV frequencies of 27 genes involved in HR-DDR were descriptively reported for colorectal tumors, with histologic stratification: ATM, ARID1A, ATRX, BRCA1, BRCA2, BARD1, BRIP1, BLM, BAP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, MRE11, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, WRN. Prevalence of MMR PGVs was compared between colorectal tumors with ≥1 HRD PGV and those without any HRD PGVs with Chi-squared or Fischer’s exact tests with p-values calculated. A two-sided alpha of 0.05 was used as the threshold for statistical significance. The Benjamini-Hochberg method was used to control for multiple hypothesis testing with resulting q-values reported.

A total of 15,489 colorectal tumors from 14,812 patients were included for analysis. At least one somatic PGV in an HRD gene was found in 15.2% of all tumors (2359/15489). At least one somatic PGV in an MMR gene was found in 4.6% of all tumors (714/15489). When stratified by histological subtypes, highest frequencies of ≥1 PGV in HRD genes were observed in medullary colon cancer (16/23, 70.0%), mucinous colorectal cancer (74/341, 21.7%), signet ring cell colorectal cancer (17/95, 17.9%), and colorectal adenocarcinoma (2251/14161, 15.9%). These frequencies were statistically different (P < 0.05) when compared between all histologies except between signet ring cell and colorectal adenocarcinoma. Across all tumors, HRD genes with the highest frequencies of PGVs were ARID1A (9.1%), ATM (4.7%), and BRCA2 (3.0%). Tumors with ≥1 HRD PGV were more likely than tumors with no HRD PGVs to also have PGVs in MMR genes: MLH1 (10.6% vs 0.8%, q < 0.001), MSH2 (12.9% vs 1.2%, q < 0.001), MSH6 (17.4% vs 1.9%, q < 0.001), PMS2 (5.6% vs 1.2%, q < 0.001), and EPCAM (2.4% vs 0.2%, q < 0.001).

NGS data demonstrate a substantial rate of somatic PGVs in HRD genes. Tumors with somatic HRD PGVs were also more likely to have somatic MMR PGVs. These data suggest the potential utility of widespread functional HRD status assessment among colorectal tumors. Moreover, genetically targeted clinical trials are warranted to evaluate the efficacy of therapeutic agents targeting the HR-DDR pathway in colorectal cancer, such as PARP and ATR inhibitors, either as adjunctive monotherapy or in conjunction with immune checkpoint inhibitors, a combination that has demonstrated synergism in preclinical studies.

The authors.

Has not received any funding.

All authors have declared no conflicts of interest.