Li X, et al. - Researchers gauged whether or not MUC16 mutations are related to tumor mutation load (TML) and prognosis in patients with gastric cancer (GC). A probable association of MUC16 mutations with higher TML, better survival outcomes, and immune response and cell cycle pathways was suggested in the findings. For guiding immunotherapy treatment for patients with GC, these findings may be immediately applicable for guiding immunotherapy treatment for patients with GC.

Methods

• Experts conducted a statistical analysis of genomic data from 437 GC samples obtained from The Cancer Genome Atlas (TCGA) and 256 samples from an Asian cohort.
• Data of patients with GC involved in previous genomic studies were contained in both cohorts.
• They obtained the data from TCGA on September 3, 2017, and from the Asian cohort on March 5, 2013 and analyzed the data from September 3 to December 1, 2017.
• They used the TCGA cohort as a discovery set and the Asian cohort as a validation set.
• They applied Kaplan-Meier survival analysis and multivariate Cox and logistic regression models.
• They used the regression models addressed confounding factors; Bayesian variant nonnegative matrix factorization to extract mutational signatures.
• Authors used the MutSigCV algorithm to identify significantly mutated genes.
• Main outcomes and measures included the primary outcomes were mutation frequency, overall survival, and TML, calculated using Kaplan-Meier survival analysis, odds ratios (ORs), and significance of signaling pathways

Results

• Findings suggested that 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.
• GC samples with MUC16 mutations, in both cohorts, 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)
• Results demonstrated that 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 < 0.001) and the Asian cohort (OR, 1.69; 95% CI, 1.25-2.29; P < .001).
• Results demonstrated a significant association of MUC16 mutations with better prognosis in both cohorts (median overall survival, 46.9 [95% CI, 26.4-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]).
• 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), the association remained statistically significant.
• In samples with MUC16 mutations immune response and cell cycle regulation circuits were among the top altered signaling pathways (normalized enrichment score, 1.70 [95% CI, 1.57-1.79] and 2.04 [95% CI, 1.90-2.18]; adjusted P < .001).
• In the Asian cohort, the prognostic significance of MUC16 mutation identified in the TCGA cohort was validated.