Association of MUC16 Mutation With Tumor Mutation Load and Outcomes in Patients With Gastric Cancer.

Importance: MUC16, which encodes cancer antigen 125 (CA-125), is frequently mutated in gastric cancer (GC); however, its association with tumor mutation load (TML) and outcome in patients with GC has not been established, to date.

Objective: To investigate whether MUC16 mutations are associated with TML and prognosis in patients with GC.

Design, Setting, and Participants: Statistical analysis of genomic data from 437 GC samples obtained from The Cancer Genome Atlas (TCGA) and 256 samples from an Asian cohort. Both cohorts contained data of patients with GC involved in previous genomic studies. Data were obtained from TCGA on September 3, 2017, and from the Asian cohort on March 5, 2013, and analyzed from September 3 to December 1, 2017. The TCGA cohort was used as a discovery set and the Asian cohort as a validation set. Kaplan-Meier survival analysis and multivariate Cox and logistic regression models were applied. Regression models addressed confounding factors; Bayesian variant nonnegative matrix factorization was used to extract mutational signatures. The MutSigCV algorithm was used to identify significantly mutated genes.

Main Outcomes and Measures: Primary outcomes were mutation frequency, overall survival, and TML, calculated using Kaplan-Meier survival analysis, odds ratios (ORs), and significance of signaling pathways.

Results: MUC16 was mutated in 168 of 437 (38.4%) of the GC samples from the TCGA cohort and in 57 of 256 (22.3%) from the Asian cohort. In both cohorts, GC samples with MUC16 mutations exhibited significantly greater TML than those without MUC16 mutations (median mutation counts: TCGA cohort, 264 with MUC16 mutation vs 115 without; Asian cohort, 134 with MUC16 mutation vs 74 without; Wilcoxon rank sum test, both P < .001). This association was independent of mutations in POLE and BRCA1/2 and mutational signatures in the TCGA cohort (OR, 1.87; 95% CI, 1.49-2.36; P < .001) and the Asian cohort (OR, 1.69; 95% CI, 1.25-2.29; P < .001). MUC16 mutations were significantly associated with better prognosis in both cohorts (median overall survival, 46.9 [95% CI, 26.4-NA (not available)] vs 26.7 [95% CI, 20.2-43.1] months; log-rank test, P = .007 [TCGA cohort] and not calculable [the median overall survival of patients with GC and MUC16 mutations could not be calculated because more than half the patients in the group were alive] vs 36.8 months; P = .04 [Asian cohort]). The association remained statistically significant after controlling for age, sex, TNM stage, mutations in POLE and BRCA1/2, and mutational signatures (hazard ratio, 0.61 [95% CI, 0.42-0.89]; log rank test, P = .01). Immune response and cell cycle regulation circuits were among the top altered signaling pathways in samples with MUC16 mutations (normalized enrichment score, 1.70 [95% CI, 1.57-1.79] and 2.04 [95% CI, 1.90-2.18]; adjusted P < .001). The prognostic significance of MUC16 mutation identified in the TCGA cohort was validated in the Asian cohort.

Conclusions and Relevance: These findings indicate that MUC16 mutations may be associated with higher TML, better survival outcomes, and immune response and cell cycle pathways. These findings may be immediately applicable for guiding immunotherapy treatment for patients with GC.