Association of MUC16 Mutation With Response to Immune Checkpoint Inhibitors in Solid Tumors

TL;DR

MUC16 mutations in solid tumors are linked to better responses to immune checkpoint inhibitors and improved survival, possibly due to higher tumor mutational burden and immune activity.

Contribution

This study identifies MUC16 mutation as a potential biomarker for improved immunotherapy response in solid tumors.

Findings

MUC16-mutated tumors had higher tumor mutational burden and neoantigen load compared to wild-type tumors.

MUC16 mutation was associated with improved overall survival in NSCLC and melanoma patients treated with ICIs.

MUC16 mutation correlated with greater response rates to ICIs in NSCLC and melanoma cohorts.

Abstract

What is the association between MUC16 mutation and response to immune checkpoint inhibitors (ICIs) in solid tumors?

In this cohort study of 3 groups of patients, including The Cancer Genome Atlas cohort with 10 195 patients across 30 solid tumor types, 56 patients with non–small cell lung cancer, and 145 patients with melanoma, MUC16 mutation was associated with greater response rates, prolonged overall survival, and genomic factors associated with ICI response, including tumor mutational burden and programmed cell death ligand–1 expression.

These findings suggest that MUC16 mutation may be associated with superior response to ICIs in patients with solid tumors.

This cohort study examines whether MUC16 mutation is associated with response to treatment with immune checkpoint inhibitors and outcomes among patients with solid tumors, non–small cell lung cancer, and melanoma.

As the third most frequently mutated gene in cancers, the association between MUC16 mutation and response to immune checkpoint inhibitors (ICIs) in solid tumors remains unclear.

To examine whether MUC16 mutation is associated with genomic factors in ICI response in solid tumors and with outcomes in ICI-treated patients.

This cohort study used multidimensional genomic data of 10 195 patients from The Cancer Genome Atlas (TCGA) across 30 solid tumor types, 56 patients from a non–small cell lung cancer (NSCLC) cohort, and 145 patients from a melanoma cohort. Genomic factors associated with ICI response covered tumor mutational burden, neoantigens, immune-related gene signatures, and tumor immune microenvironment. Both NSCLC and melanoma cohorts included ICI-treated patients. The TCGA cohort was used to examine the association of MUC16 mutation with genomic factors. Two ICI-treated cohorts were used to explore the significance of outcomes associated with MUC16 mutation, using Kaplan-Meier curves and Cox models with adjusting for potential confounders. Gene set enrichment analysis was used to identify MUC16 mutation–associated biological processes. Data were obtained from October 1 through October 10, 2019, and were analyzed from October 11 through December 31, 2019.

Genomic factors associated with ICI response, overall survival, and clinical response.

Of the 10 195 patients, 4821 (47.6%) were men (median [interquartile range {IQR}] age, 60 [50-70] years). MUC16 was mutated in 2006 of 10 195 patients (19.68%). In this pan-cancer data set, patients with MUC16 mutation had higher tumor mutational burden (median [IQR], 230 [93-595] mutations vs 48 [25-92] mutations; difference, 182 mutations; 95% CI, 164-199 mutations; P < .001) and neoantigen load (median [IQR], 179 [74-394.5] neoantigens vs 48 [24-89] neoantigens; difference, 131 antigens; 95% CI, 116.5-145 neoantigens; P < .001) than those without mutations. The tumor immune microenvironment with dual-positive CD8A and PD-L1 was overrepresented in MUC16-mutated tumors compared with wild-type ones (43.8% vs 32.4%; odds ratio, 1.63; 95% CI, 1.46-1.80; P < .001). Of the 40 immune-related genes, 37 (92.5%) exhibited differential expression between 2 states. MUC16 mutation was associated with improved overall survival in both the NSCLC (hazard ratio, 0.34; 95% CI, 0.12-0.99; P = .04) and melanoma (hazard ratio, 0.57; 95% CI, 0.36-0.90; P = .02) cohorts. The improvement persisted after adjusting for age, sex, and dominant mutational signatures in the melanoma cohort (hazard ratio, 0.57; 95% CI, 0.33-0.96; P = .04). MUC16 mutation was associated with greater response rates in the NSCLC cohort (odds ratio, 4.03; 95% CI, 1.06-16.43; P = .03) and the melanoma cohort (odds ratio, 3.38; 95% CI, 1.07-14.25; P = .03). Gene set enrichment analysis revealed that gene sets regarding cell proliferation and immune response were enriched in MUC16-mutated tumors (false discovery rate, <.001).

MUC16 mutation appears to be associated with reported genomic factors associated with response to and improved outcomes for ICI treatment in solid tumors. It may hold promise as a marker for guiding immunotherapeutic responsiveness.

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