Introduction
- BRCA1 and BRCA2 are important tumor suppressor proteins involved in double-stranded DNA break repair using homologous recombination.1
- In 1994, the Breast Cancer Linkage Consortium presented an increased risk of colorectal cancer (CRC) among BRCA1 mutation carriers, which ushered more research into BRCA1 genetic alterations in CRC.1
- To date, studies have shown that BRCA1/2 mutations increase the risk of CRC and are associated with earlyonset disease, younger age, MSI and left-sided tumors. 2,3 However, further characterization of these mutations in CRC is needed to better understand their prognostic role.
Methods
- A total of 6396 CRC tumor samples were tested with NextGeneration Sequencing (NGS) on a 592-gene panel
- Pathogenic or presumed pathogenic variants were counted as mutations (mt).
- Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS.
- Statistical correlations were investigated using ANOVA, Chisquare and t-test.
Conclusions
- This is the first study to show that BRCA1/2 mutations are more frequent in MSI-H, independently associated with higher TMB, pathogenic POLE
mutations, and right-sided tumors in CRCs. - Given their relationship with TMB in MSS tumors, the presence of BRCA1/2 mutations are indicator for impaired DNA damage repair and could be potential
predictive biomarkers for checkpoint or PARP inhibitors in CRC, a finding that should be prospectively evaluated.