Abstract 5197: Alterations of the circadian clock genes and their association with tumor mutation burden and response to immunotherapy in NSCLC
Authors: Jia Dong-Dong , Niu Yanling , Zhang Xin , Ma Tonghui 
Published: June 2022

Background: Circadian rhythms are 24-hour cycles that are part of our body’s internal clock. These processes rely on a transcription-translation feedback loop controlled by a family of circadian-relevant genes, including the transcription factors (CLOCK/BMAL1) and key circadian genes (Cryptochromes (CRY1 and CRY2) and Period (PER1, PER2, and PER3)). Previous studies showed that the circadian clock could affect the DNA damage response pathway. Therefore, we hypothesized that alterations of the circadian clock genes might associate with tumor mutation burden (TMB). Here, we explored the associations of mutations in the circadian clock genes with TMB and response to immune-checkpoint inhibitors (ICIs) in NSCLC.

Methods: The ICIs treatment NSCLC cohort from the Memorial Sloan Kettering Cancer Center (MSKCC) was used for exploring the associations of mutations in the clock genes (CLOCK, BMAL1, CRY1, CRY2, PER1, PER2, and PER3) with TMB, tumor neoantigen burden (TNB), and ICIs efficacy. The relationships between the clock genes mutations and TMB, PD-L1 expression, levels of tumor infiltrating lymphocytes (TILs), and prognostic value were investigated in the TCGA-NSCLC cohort.

Results: In the TCGA-NSCLC cohort, the most frequently mutated gene was PER3 (1.4%), followed by PER1 (1.3%), CRY1 (1.1%), and CRY2 (0.7%). The median TMB was significantly higher in the clock genes mutations (MT) group compared to the wild type (WT) group (10.1 vs 5.9 muts/Mb, P &lt; 0.0001). However, the data revealed that PD-L1 expression and the levels of TILs did not have any associations with mutations of the clock genes. Furthermore, there was no difference in overall survival (OS) for patients with MT or WT tumors. In the MSKCC ICIs cohort, mutations in the clock genes were also associated with higher TMB (16.7 vs 4.3 muts/Mb, P &lt; 0.0001) and higher median predicted neoantigen burden (1338 vs 293, P &lt; 0.0001). Compared to the WT group, patients in the MT group had a significantly longer median progression-free survival (PFS) (23.0 vs 5.2 months, HR: 0.45 [95%CI: 0.25-0.81], P = 0.0216) with PD-1 plus CTLA-4 blockade. About (70.6%) showed a durable clinical benefit (DCB) in the MT group, while 43.1% of patients showed DCB in the WT group (P = 0.046).

Conclusions: Our data indicated that mutations in the clock genes were associated with higher TMB and improved clinical outcomes in NSCLC patients treated with ICIs, suggesting that these mutations might be a potential predictive biomarker for ICIs treatment in NSCLC. However, they did not have significant prognostic value.

Citation Format: Dong-Dong Jia, Yanling Niu, Xin Zhang, Tonghui Ma. Alterations of the circadian clock genes and their association with tumor mutation burden and response to immunotherapy in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5197.