Mucinous Histology, BRCA1/2 Mutations, and Elevated Tumor Mutational Burden in Colorectal Cancer

Abstract

Mucinous colorectal carcinomas (MC) constitute 10% of colorectal malignancies. Recently, an increased risk of colorectal cancer has been demonstrated in germline BRCA1/2 mutation carriers. Furthermore, BRCA1/2 germline mutation carriers have exhibited a higher-than-expected frequency of MC tumors. Here, we investigate the relationship between BRCA mutations and mucinous histology in colorectal carcinoma patients, using both an existing cohort of sequenced colorectal tumors and a prospective case-control study comparing MC and conventional adenocarcinoma (AC) patients tested for BRCA mutations. We discovered that MC tumors exhibit a statistically significantly higher incidence of BRCA mutations in addition to a higher average mutation count when compared to AC tumors in the existing cohort. The strongest predictor of the mutation count was mucinous histology, independently of other variables including microsatellite instability. Contrary to our hypothesis, the first association did not recur in the prospective case-control study, likely due to our pathological definition of MC tumors and small sample size. Finally, we observed a higher tumor mutational burden (TMB) in MC tumors compared with AC tumors. We suggest that the association between MC histology, BRCA mutations, and increased TMB may open the door to the utilization of simple tests (such as histopathologic characterization) to detect patients who may benefit from immunotherapy in colorectal cancer.