3012 Background: Loss of BRCA1/2 function leads to homologous recombination deficiency (HRD) and can enhance platinum and PARP inhibitor sensitivity in breast, pancreas, prostate, and ovarian cancers. In BRCA-associated cancers, resistance can result from the development of BRCA1/2 reversion mutations, which restore BRCA1/2 function. By contrast, a BRCA mutation may be an incidental finding in other tumor histologies. Methods: To determine the distribution of reversion mutations in a pan-cancer cohort, the MSK-IMPACT clinical sequencing cohort was mined to identify patients who had both a germline BRCA1/2 mutation and a frameshift somatic reversion mutation that restored BRCA1/2 function. Whole exome resequencing was used to detect HRD signatures. Chart review enabled collection of data on treatment history in patients consented to germline testing. Results: Of the 33,277 patients with matched tumor and normal sequencing profiled in this study, 861 patients were found to have germline pathogenic BRCA1/2 alterations, including 347 (40%) in BRCA1 and 514 (60%) in BRCA2. Somatic BRCA1/2 driver alterations were also found in tumor tissue from an additional 447 patients, with 156 (35%) having BRCA1 mutations, and the remainder having alterations in BRCA2 (65%) . Among the 1,308 germline or somatic BRCA1/2 mutant tumors, we identified reversion mutations in 12 patients, all of whom were germline carriers of BRCA1/2, comprising 3 BRCA1 and 9 BRCA2 tumors. 7 patients consented to germline testing enabling review of clinical characteristics and treatment history, 5 of whom received PARP inhibitor or platinum-therapy prior to reversion detection. Ten of 12 tumors with reversion mutations were in canonical BRCA-associated cancers. Interestingly, reversion mutations were also found in patients with lung adenocarcinoma (n=1) and gastroesophageal junction adenocarcinoma (n=1). In both these non-canonical histologies, the reversion was detected following progression on platinum-based therapy. Whole exome resequencing of the lung tumor revealed the classic somatic molecular phenotypes of HRD that are characteristic of BRCA-dependent tumors, including in terms of large-scale transitions, HRD-loss of heterozygosity, signature 3, and the number of telomeric allelic imbalance score. Conclusions: Matched tumor and normal sequencing from a large cohort of patients with diverse cancer histologies reveals that reversion mutations are found across BRCA-associated cancer types. In rare cases, reversion mutations in BRCA1/2 following platinum-based therapy may be indicative of prior BRCA-dependence in select non-canonical tumor histologies.
Large-scale pan-cancer analysis reveals broad prognostic association between TGF-β ligands, not Hedgehog, and GLI1/2 expression in tumors
