Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

Abstract

PARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

Figure 1

Mutations to genes associated with the homologous recombination pathway predict for poor clinical outcomes in a large pan-cancer study. We determined the mutation status of ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, DMC1, FAAP20, FAN1, FANCD2, FANCE, FANCL, FANCM, PALB2, POLQ, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, and XRCC3 in a in a pooled pan-cancer cohort of 55,586 patients from 32 different cancer types. Of these patients, survival data was available from 27,629, which were used for subsequent analyses. Kaplan Meier plots are displayed showing overall survival from patients with or without a mutation to: (A) one or more of the genes listed above, (B) BARD1, (C) ATM, or (D) BRCA1 and/or BRCA2.

Figure 2

Mutations to genes associated with the homologous recombination pathway are frequent in several cancer histologies for which PARP inhibitors are not currently approved. (A) We determined the mutation status of ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, DMC1, FAAP20, FAN1, FANCD2, FANCE, FANCL, FANCM, PALB2, POLQ, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, and XRCC3 in a in The Cancer Genome Atlas (TCGA) pan-cancer cohort of 12,153 patents, and show the combined mutation frequency across all genes by percent for the most represented cancer types. DLBC: diffuse large B cell lymphoma, NSCLC: non-small cell lung cancer, ACC: adenoid cystic carcinoma, ccRCC: clear cell renal cell carcinoma, GBM: glioblastoma multiforme, pRCC: papillary renal cell carcinoma, chRCC: chromophobe renal cell carcinoma. (B) Of these 12,153 patients, survival data was available from 11,337, which were used for subsequent analyses. A Kaplan–Meier plot is displayed showing overall survival from patients with or without a mutation to one or more of the genes listed above.

Figure 3

Location of the most frequently represented mutations in genes associated with the homologous recombination pathway in The Cancer Genome Atlas cohort. Lolipop plots displaying the most common mutations to (A) ATM (B) BRCA2 (C) POLQ (D) BARD1 (E) BRCA1 (F) CHEK2 (G) CDK12 (H) FANCD2 (I) BRIP1 (J) FANCM.