Reversion mutations in germline BRCA1/2-mutant tumors reveal a BRCA-mediated phenotype in non-canonical histologies

Area of Science:

• Genomics
• Oncology
• Cancer Genetics

Background:

• Loss of BRCA1/2 genes leads to homologous recombination deficiency (HRD), a phenotype linked to specific cancer types like breast and ovarian cancers.
• This HRD phenotype typically confers sensitivity to PARP inhibitors and platinum-based chemotherapies.
• Somatic reversion mutations that restore BRCA1/2 function are a known mechanism of resistance, previously observed only in BRCA-associated tumors.

Purpose of the Study:

• To investigate the occurrence and characteristics of somatic reversion mutations in BRCA1/2 across a large cohort of diverse cancer types.
• To identify if reversion mutations can occur in non-BRCA-associated cancers and their potential implications.

Main Methods:

• Analysis of matched tumor and normal sequencing data from 31,927 patients.
• Identification of germline BRCA1/2 variants and somatic reversion mutations.
• Whole exome sequencing to confirm HRD phenotype in identified tumors.

Main Results:

• Identified 846 patients (2.7%) with germline BRCA1/2 variants across 43 cancer types.
• Found 11 patients with somatic reversion mutations, nine in BRCA-associated tumors.
• Discovered two reversion mutations in non-BRCA-associated lung and esophagogastric adenocarcinomas, both detected after platinum therapy.
• Confirmed HRD phenotype in these non-BRCA-associated tumors via whole exome sequencing.

Conclusions:

• Somatic reversion mutations in BRCA1/2 are not exclusive to BRCA-associated cancers.
• The occurrence of reversion mutations post-platinum therapy in non-BRCA-associated histologies, though rare, may suggest underlying BRCA1/2-mediated tumorigenesis.
• These findings expand the understanding of resistance mechanisms and potential therapeutic strategies in a broader range of cancers.