Abstract 995P
Background
Lysine methyltransferase 2D (KMT2D), which encodes a histone H3 lysine 4 methyltransferase, is one of the most frequently mutated genes in cancer patients. Previous studies showed that KMT2D-mutant tumor cell lines exhibited increasing immune infiltration and KMT2D mutation was correlated with higher tumor mutation burden (TMB) in multiple types of human cancers in TCGA datasets, suggesting that KMT2D-deficient tumors might be more sensitive to immune checkpoint inhibitors (ICIs), but the correlation of KMT2D mutation status with immune response in clinical remains unknown.
Methods
Next generation sequencing (NGS) data of 10336 pan-cancer patients were obtained from the MSK-IMPACT Clinical Sequencing cohort (MSKCC, NAT Med 2017). NGS data and clinical data of 1661 pan-cancer patients (MSKCC, NAT Genet 2019) treated with ICIs were analyzed to explore the association between KMT2D gene alteration and TMB. Moreover, the association between KMT2D alteration and therapeutic efficacy of ICIs was explored in the MSKCC-2019 cohort.
Results
A total of 9% (1087/11997) of the pan-cancer patients in all cohorts carried KMT2D alteration, and the highest alteration frequency cancer types were mature B-cell neoplasms (51/134, 38.06%), skin cancer (non-Melanoma, 42/149, 28.19%) and bladder cancer (178/638, 27.9%), respectively. The commonly variant types of KMT2D were non-structural variants. In MSKCC-2019 cohort treatment with ICIs, the TMB level of KMT2D-altered group was significantly higher than wild group (P<0.01) and the overall survival (OS) of KMT2D-altered group were significantly longer than wild group (OS, median, 27.00 vs 15.00 months; HR=0.7675 [95%CI: 0.6249-0.9426], P=0.0189). However, in the MSKCC-2017 cohort without immunotherapy, the OS of the KMT2D-altered group was significantly shorter than wild group (OS, median, 22.22 vs 26.36 months; HR=1.202 [95%CI: 1.039-1.391], P=0.0075), suggesting KMT2D might be an immunotherapy efficacy predictive factor but not a prognostic factor.
Conclusions
The results indicated that KMT2D gene alteration was associated with a higher TMB level in pan-cancer patients, and patients carrying KMT2D alteration might easily benefit from ICIs.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
X. Zhong: Financial Interests, Personal and Institutional, Member: 3DMed. Inc. T. Chen: Financial Interests, Personal and Institutional, Member: 3DMed. Inc. M. Huang: Financial Interests, Personal and Institutional, Member: 3DMed. Inc. All other authors have declared no conflicts of interest.