Immunotherapy · 2025
Ataxia Telangiectasia Mutated (ATM) gene alterations as biomarkers of response to immune checkpoint inhibitors.
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Baral Maun R, Abushukair Hassan, Abdelrahim Maen, Abdullah Esmail, Al Diffalha Sameer, Manne Upender, Singh Ajay P, Patel Girijesh Kumar, Bhandari Sambhawana, Khushman Moh'd
Аннотация
AIMS: Molecular alterations of the ataxia telangiectasia mutated (ATM) gene, a DNA damage repair (DDR) gene, predispose to cancer, but its association with response to immune checkpoint inhibitors (ICIs) remains unclear. We explored the association between ATM mutations and response to ICIs in two ICI-treated cohorts and a possible underlying molecular explanation.
MATERIALS & METHODS: Genomic data were obtained from the cBioPortal (https://www.cbioportal.org/). ICI-treated patients were identified from two cohorts: Tumor mutational burden (TMB) and Immunotherapy (n = 1661) and MSK-CORD (n = 3341). Kaplan-Meier survival was generated using log-rank tests. The TCGA cohort was used to assess neoantigen load and predicted immunogenic mutations.
RESULTS: In the TMB and Immunotherapy cohort, median OS (mOS) was longer in DDR-mutant vs. DDR-Wild type (WT) (34 vs. 17 months (m), p = 0.00014) and ATM-mutant vs. ATM-WT (40 vs. 18 m, p = 0.0394). In MSK-CORD, mOS was longer in ATM-mutant vs. ATM-WT (34 vs. 24 m, p < 0.001). In the TCGA cohort, ATM-mutant had higher predicted immunogenic mutations than DDR-mutant or DDR-WT.
CONCLUSION: We demonstrated that ATM-mutant status is associated with longer mOS compared to ATM-WT and has higher predicted immunogenetic mutations. Our results are rather hypothesis-generating and would benefit from further validation in prospective trials.
MATERIALS & METHODS: Genomic data were obtained from the cBioPortal (https://www.cbioportal.org/). ICI-treated patients were identified from two cohorts: Tumor mutational burden (TMB) and Immunotherapy (n = 1661) and MSK-CORD (n = 3341). Kaplan-Meier survival was generated using log-rank tests. The TCGA cohort was used to assess neoantigen load and predicted immunogenic mutations.
RESULTS: In the TMB and Immunotherapy cohort, median OS (mOS) was longer in DDR-mutant vs. DDR-Wild type (WT) (34 vs. 17 months (m), p = 0.00014) and ATM-mutant vs. ATM-WT (40 vs. 18 m, p = 0.0394). In MSK-CORD, mOS was longer in ATM-mutant vs. ATM-WT (34 vs. 24 m, p < 0.001). In the TCGA cohort, ATM-mutant had higher predicted immunogenic mutations than DDR-mutant or DDR-WT.
CONCLUSION: We demonstrated that ATM-mutant status is associated with longer mOS compared to ATM-WT and has higher predicted immunogenetic mutations. Our results are rather hypothesis-generating and would benefit from further validation in prospective trials.