Tumor Mutation Burden Forecasts Outcome in Ovarian Cancer with BRCA1 or BRCA2 Mutations

open access (technical)


Background
Increased number of single nucleotide substitutions is seen in breast and ovarian cancer genomes carrying disease-associated mutations in BRCA1 or BRCA2. The significance of these genome-wide mutations is unknown. We hypothesize genome-wide mutation burden mirrors deficiencies in DNA repair and is associated with treatment outcome in ovarian cancer.

......."Our results are based on a relatively small set of patients carrying BRCA1 ...and BRCA2 mutations, and should be considered hypothesis generating until confirmed in a larger cohort. In addition, tumors may possess de novo mechanisms leading to resistance to chemotherapy and targeted treatments. Our preliminary results suggest low tumor Nmut may identify BRCA-associated primary tumors in which the original deficiency of BRCA1 and BRCA2 pathways, including impaired DNA repair, is compensated for by alternative pathways."

Conclusions
Tumor Nmut (non-synonymous exome mutations) was associated with treatment response and with both PFS and OS in patients with high-grade serous ovarian cancer carrying BRCA1 or BRCA2 mutations. In the TCGA cohort, low Nmut predicted resistance to chemotherapy, and for shorter PFS and OS, while high Nmut forecasts a remarkably favorable outcome in mBRCA-associated ovarian cancer. Our observations suggest that the total mutation burden coupled with BRCA1 or BRCA2 mutations in ovarian cancer is a genomic marker of prognosis and predictor of treatment response. This marker may reflect the degree of deficiency in BRCA-mediated pathways, or the extent of compensation for the deficiency by alternative mechanisms.