Somatic mutations in FAT cadherin family members constitute an underrecognized subtype of colorectal adenocarcinoma with unique clinicopathologic features

BACKGROUND: The FAT cadherin family members (FAT1, FAT2, FAT3 and FAT4) are conserved tumor suppressors that are recurrently mutated in several types of human cancers, including colorectal carcinoma (CRC). AIM: To characterize the clinicopathologic features of CRC patients with somatic mutations in FAT cadherin family members. METHODS: We analyzed 526 CRC cases from The Cancer Genome Atlas PanCancer Atlas dataset. CRC samples were subclassified into 2 groups based on the presence or absence of somatic mutations in FAT1, FAT2, FAT3 and FAT4. Individual clinicopathological data were collected after digital slide review. Statistical analysis was performed using t tests and chi-square tests. RESULTS: This CRC study cohort had frequent mutations in the FAT1 (10.5%), FAT2 (11.2%), FAT3 (15.4%) and FAT4 (23.4%) genes. Two hundred CRC patients (38.0%) harbored somatic mutations in one or more of the FAT family genes and were grouped into the FAT mutated CRC subtype. The FAT-mutated CRC subtype was more commonly located on the right side of the colon (51.0%) than in the rest of the cohort (30.1%, P < 0.001). It showed favorable clinicopathologic features, including a lower rate of positive lymph nodes (pN1-2: 33.5% vs 46.4%, P = 0.005), a lower rate of metastasis to another site or organ (pM1: 7.5% vs 16.3%, P = 0.006), and a trend toward an early tumor stage (pT1-2: 25.0% vs 18.7%, P = 0.093). FAT somatic mutations were significantly enriched in microsatellite instability CRC (28.0% vs 2.1%, P < 0.001). However, FAT somatic mutations in microsatellite stable CRC demonstrated similar clinicopathologic behaviors, as well as a trend of a better disease-free survival rate (hazard ratio = 0.539; 95% confidence interval: 0.301-0.967; log-rank P = 0.073). CONCLUSION: FAT cadherin family genes are frequently mutated in CRC, and their mutation profile defines a subtype of CRC with favorable clinicopathologic characteristics.