Credit: CORBIS

There is a continued debate regarding the clinical predictive value of lesions in BRCA1 and BRCA2 in ovarian cancer. A new study suggests that BRCA1 and BRCA2 may have more divergent clinical relevance than was previously thought.

Inherited loss-of-function mutations in BRCA1 or BRCA2 substantially increase the risk of developing breast or ovarian cancers. Despite having distinct biochemical roles, BRCA1 and BRCA2 are both required for homologous recombination-based DNA repair. The homologous recombination defect that results from the loss of expression of either gene is thought to contribute to genomic instability during tumorigenesis, and to sensitize tumours to therapies, such as platinum agents, that induce the types of DNA damage that are substrates for homologous recombination-based DNA repair.

Wei Zhang and colleagues studied the clinical outcomes of 316 patients with high-grade serous ovarian cancer, who all received surgery followed by platinum-based chemotherapy. Patients were stratified according to the presence of BRCA1 mutations (37 cases), BRCA2 mutations (29 cases) or BRCA1 promoter methylation (33 cases), according to data from The Cancer Genome Atlas (TCGA). For BRCA1-methylated samples, BRCA1 silencing was confirmed at the mRNA level.

the outcomes of BRCA1-mutated or BRCA1-methylated cases were not significantly different from BRCA-wild-type cases

The authors found unexpected differences in the clinical predictive value of BRCA1 versus BRCA2 lesions when comparing overall survival and progression-free survival (PFS) as primary outcomes and chemotherapy response as a secondary outcome. Whereas BRCA2 mutations were associated with improved overall survival and PFS, the outcomes of BRCA1-mutated or BRCA1-methylated cases were not significantly different from BRCA-wild-type cases. BRCA2 mutations were also associated with an increased rate of response to primary platinum chemotherapy.

In addition, the authors used TCGA exome sequencing data to correlate the genotypes with the extent of accumulated mutations. An increase in genomic instability was found in BRCA2-mutated, but not in BRCA1-mutated or BRCA1-methylated, samples. This could indicate that BRCA2 lesions cause more substantial homologous recombination defects than BRCA1 lesions in this disease, because both genomic instability and sensitivity to platinum-based chemotherapy are greater. Overall, such differences led the authors to highlight the need to stratify patients with serous ovarian cancer according to their BRCA1 and BRCA2 statuses in future clinical cohorts.

It will be interesting to further investigate the predictive value of BRCA1 and BRCA2 lesions in larger patient cohorts, including the biochemical confirmation of BRCA loss of function using homologous recombination assays.