Prevalence of Homologous Recombination–Related Gene Mutations Across Multiple Cancer Types

TLDR

The prevalence of homologous recombination DNA damage repair (HR‑DDR) deficiencies across tumor types is poorly defined, though HR‑D directed therapies are approved for ovarian and breast cancers and may benefit other malignancies. The authors performed next‑generation sequencing on 52,426 solid‑tumor samples, using a 592‑gene NGS panel (NGS600) and a 47‑gene hotspot MiSeq panel, to identify pathogenic mutations in 21 HR‑DDR genes. HR‑DDR mutations were detected in 17.4 % of tumors, most frequently in endometrial (34.4 %), biliary tract (28.9 %), bladder (23.9 %), hepatocellular (20.9 %), gastroesophageal (20.8 %) and ovarian (20.0 %) cancers, with ARID1A (7.2 %) as the most common mutated gene, underscoring the potential for HR‑D‑targeted therapies across diverse cancers.

Abstract

The prevalence of homologous recombination DNA damage repair (HR-DDR) deficiencies among all tumor lineages is not well characterized. Therapy directed toward homologous recombination DDR deficiency (HRD) is now approved in ovarian and breast cancer, and there may be additional opportunities for benefit for patients with other cancers. Comprehensive evaluations for HRD are limited in part by the lack of a uniform, cost-effective method for testing and defining HRD.Molecular profiles of 52,426 tumors were reviewed to identify pathogenic mutations in the HR-DDR genes ARID1A, ATM, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, or WRN. From solid tumors submitted to Caris Life Sciences, molecular profiles were generated using next-generation sequencing (NGS; average read depth, 500×). A total of 17,566 tumors were sequenced with NGS600 (n = 592 genes), and 34,860 tumors underwent hotspot Illumina MiSeq platform testing (n = 47 genes).Of the tumors that underwent NGS600 testing, the overall frequency of HRDDR mutations detected was 17.4%, and the most commonly mutated lineages were endometrial (34.4%; n = 1,475), biliary tract (28.9%; n = 343), bladder (23.9%; n = 201), hepatocellular (20.9%; n = 115), gastroesophageal (20.8%; n = 619), and ovarian (20.0%; n = 2,489). Least commonly mutated lineages included GI stromal (3.7%; n = 108), head and neck (6.8%; n = 206), and sarcoma (9.3%; n = 592). ARID1A was the most commonly mutated gene (7.2%), followed by BRCA2 (3.0%), BRCA1 (2.8%), ATM (1.3%), ATRX (1.3%), and CHEK2 (1.3%).HR-DDR mutations were seen in 17.4% of tumors across 21 cancer lineages, providing a path to explore the role of HRD-directed therapies, including poly-ADP ribose polymerase inhibitors, DNA-damaging chemotherapies, and newer agents such as ATR inhibitors.