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Published on: October 30, 2013
Association of MUC16 Mutation With Response to Immune Checkpoint Inhibitors in Solid Tumors
Lei Zhang1, Xiaohong Han1,2, Yuankai Shi1
1Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Department of Medical Oncology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Importance:
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.
Objective:
To examine whether MUC16 mutation is associated with genomic factors in ICI response in solid tumors and with outcomes in ICI-treated patients.
Design, Setting, And Participants:
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.
Main Outcomes And Measures:
Genomic factors associated with ICI response, overall survival, and clinical response.
Results:
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).
Conclusions And Relevance:
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.
Insights
MUC16 mutations are linked to better responses and outcomes in solid tumors treated with immune checkpoint inhibitors (ICIs). This finding suggests MUC16 mutations may predict ICI treatment success.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- MUC16 is the third most frequently mutated gene in cancers.
- The association between MUC16 mutations and response to immune checkpoint inhibitors (ICIs) in solid tumors is not well understood.
Purpose of the Study:
- To investigate the link between MUC16 mutations and genomic factors influencing ICI response.
- To determine if MUC16 mutations correlate with patient outcomes in ICI-treated solid tumors.
Main Methods:
- Analysis of genomic data from 10,195 TCGA patients across 30 solid tumor types.
- Examination of MUC16 mutation association with tumor mutational burden, neoantigens, immune gene signatures, and tumor immune microenvironment.
- Evaluation of outcomes in 56 NSCLC and 145 melanoma patients treated with ICIs using survival analysis and Cox models.
Main Results:
- MUC16 mutations (19.68%) were associated with higher tumor mutational burden and neoantigen load.
- MUC16-mutated tumors showed an enriched CD8A and PD-L1 positive immune microenvironment.
- MUC16 mutation correlated with improved overall survival and higher response rates to ICIs in NSCLC and melanoma cohorts.
Conclusions:
- MUC16 mutations are associated with genomic profiles that predict favorable responses to ICIs.
- MUC16 mutation may serve as a predictive biomarker for guiding immunotherapy decisions in solid tumors.
