Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors with 2 or More Somatic Mutations in Mismatch Repair Genes.

Publication Type:

Journal Article


Gastroenterology (2016)


BACKGROUND & AIMS: Some colorectal and endometrial tumors with microsatellite instability not attributable to MLH1 hypermethylation or germline mutations contain 2 or more somatic mutations in genes encoding mismatch repair (MMR) proteins. We sought to define the molecular phenotype of this newly recognized tumor subtype.

METHODS: From 2 prospective studies of the efficacy of screening for Lynch syndrome, we identified patients with colorectal and endometrial tumors who had 2 or more somatic (but not germline) mutations in genes encoding MMR proteins (double somatic). We determined the frequencies of tumor mutations in PIK3CA, BRAF, KRAS, NRAS, and PTEN by targeted next-generation sequencing and used logistic-regression models to compare them with those from patients with Lynch syndrome, MLH1-hypermethylated, or microsatellite-stable tumors. We validated our findings using independent datasets from The Cancer Genome Atlas.

RESULTS: Among colorectal cancer cases, we found that 14/21 (67%) of patients with double somatic tumors also had PIK3CA mutations, compared to 4/18 (22%) of tumors from patients with Lynch syndrome, 2/10 (20%) tumors with MLH1 hypermethylation, and 12/78 (15%) tumors with microsatellite stability (P<.0001 for patients with double somatic tumors vs other subgroups). Mutations in PIK3CA were detected in all 13 patients with double somatic endometrial cancers (P=.04 compared to other subgroups). We did not detect BRAF mutations in patients with double somatic colorectal tumors or Lynch syndrome. We found highly similar results in a validation cohort from The Cancer Genome Atlas (113 patients with colorectal tumors, 178 endometrial tumors); 100% of double somatic cases carried a somatic mutation in PIK3CA (P<.0001 compared with other subgroups).

CONCLUSIONS: Most patients with colorectal or endometrial tumors with 2 or more somatic (but not germline) mutations in MMR proteins also have mutations in PIK3CA; mutations in PIK3CA are detected at substantially higher frequencies in these double somatic tumors than in than other microsatellite instability subgroups. PIK3CA mutation status might be used to identify a specific group of colorectal tumors, and to select treatment or determine prognosis.