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The association of MUC16 mutation with tumor mutation burden and its prognostic implications in cutaneous melanoma


Wang, Xuefeng; Yu, Xiaoqing; Krauthammer, Michael; Hugo, Willy; Duan, Chunzhe; Kanetsky, Peter A; Teer, Jamie K; Thompson, Zachary J; Kalos, Denise; Tsai, Kenneth Y; Smalley, Keiran SM; Sondak, Vernon K; Chen, Y Ann; Conejo-Garcia, Jose R (2020). The association of MUC16 mutation with tumor mutation burden and its prognostic implications in cutaneous melanoma. Cancer Epidemiology Biomarkers & Prevention, 29(9):1792-1799.

Abstract

Background: MUC16 is a mucin marker that is frequently mutated in melanoma, but whether MUC16 mutations could be useful as a surrogate biomarker for tumor mutation burden (TMB) remains unclear.
Methods: This study rigorously evaluates the MUC16 mutation as a clinical biomarker in cutaneous melanoma by utilizing genomic and clinical data from patient samples from The Cancer Genome Atlas (TCGA) and two independent validation cohorts. We further extended the analysis to studies with patients treated with immunotherapies.
Results: Analysis results showed that samples with MUC16 mutations had a higher TMB than the samples of wild-type, with strong statistical significance (P < 0.001) in all melanoma cohorts tested. Associations between MUC16 mutations and TMB remained statistically significant after adjusting for potential confounding factors in the TCGA cohort [OR, 9.28 (95% confidence interval (CI), 5.18-17.39); P < 0.001], Moffitt cohort [OR, 31.95 (95% CI, 8.71-163.90); P < 0.001], and Yale cohort [OR, 8.09 (95% CI, 3.12-23.79); P < 0.01]. MUC16 mutations were also found to be associated with overall survival in the TCGA [HR, 0.62; (95% CI, 0.45-0.85); P < 0.01] and Moffitt cohorts [HR, 0.49 (95% CI, 0.28-0.87); P = 0.014]. Strikingly, MUC16 is the only top frequently mutated gene for which prognostic significance was observed. MUC16 mutations were also found valuable in predicting anti-CTLA-4 and anti-PD-1 therapy responses.
Conclusions: MUC16 mutation appears to be a useful predictive marker of global TMB and patient survival in melanoma.
Impact: This is, to the best of our knowledge, the first systematic evaluation of MUC16 mutation as a clinical biomarker and a predictive biomarker for immunotherapy in melanoma.

Abstract

Background: MUC16 is a mucin marker that is frequently mutated in melanoma, but whether MUC16 mutations could be useful as a surrogate biomarker for tumor mutation burden (TMB) remains unclear.
Methods: This study rigorously evaluates the MUC16 mutation as a clinical biomarker in cutaneous melanoma by utilizing genomic and clinical data from patient samples from The Cancer Genome Atlas (TCGA) and two independent validation cohorts. We further extended the analysis to studies with patients treated with immunotherapies.
Results: Analysis results showed that samples with MUC16 mutations had a higher TMB than the samples of wild-type, with strong statistical significance (P < 0.001) in all melanoma cohorts tested. Associations between MUC16 mutations and TMB remained statistically significant after adjusting for potential confounding factors in the TCGA cohort [OR, 9.28 (95% confidence interval (CI), 5.18-17.39); P < 0.001], Moffitt cohort [OR, 31.95 (95% CI, 8.71-163.90); P < 0.001], and Yale cohort [OR, 8.09 (95% CI, 3.12-23.79); P < 0.01]. MUC16 mutations were also found to be associated with overall survival in the TCGA [HR, 0.62; (95% CI, 0.45-0.85); P < 0.01] and Moffitt cohorts [HR, 0.49 (95% CI, 0.28-0.87); P = 0.014]. Strikingly, MUC16 is the only top frequently mutated gene for which prognostic significance was observed. MUC16 mutations were also found valuable in predicting anti-CTLA-4 and anti-PD-1 therapy responses.
Conclusions: MUC16 mutation appears to be a useful predictive marker of global TMB and patient survival in melanoma.
Impact: This is, to the best of our knowledge, the first systematic evaluation of MUC16 mutation as a clinical biomarker and a predictive biomarker for immunotherapy in melanoma.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Quantitative Biomedicine
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Epidemiology, Oncology
Language:English
Date:1 September 2020
Deposited On:26 Jan 2021 16:29
Last Modified:26 Jan 2021 16:30
Publisher:American Association for Cancer Research
ISSN:1055-9965
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/1055-9965.epi-20-0307

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