The predictive values of loss-of-function variants in histone methyltransferases for response to immune checkpoint inhibitors in solid tumors.

Abstract

2586 Background: Dysregulation of histone methyltransferases (HMTs) has been reported to play critical roles in cancer development. Previous studies showed that many HMTs were recruited to DNA damage sites where they posttranslationally modified chromatin to regulate chromatin-based DNA damage repair (DDR) activities. We hypothesized that loss-of-function (LOF) variants of HMTs may associate with genome instability and tumor mutational burden (TMB). Thus, we explored the associations of LOF variants in some HMTs with TMB and benefit from immune checkpoint inhibitors (ICIs) in solid tumors. Methods: An ICIs treatment cohort from the Memorial Sloan Kettering Cancer Center (MSKCC) was analyzed. The following solid tumor types were enrolled: NSCLC (n = 350), colorectal cancer (n = 110), bladder cancer (n = 215), breast cancer (n = 44), esophagogastric cancer (n = 126), head and neck cancer (n = 139), glioma (n = 117), melanoma (n = 320), and renal cell carcinoma (n = 151). We evaluated 15 HMTs (KMT2A, KMT2B, KMT2C, KMT2D, SETD2, SETD8, EZH1, EZH2, PRDM1, PRDM14, SMYD3, NSD1, WHSC1, WHSC1L1, and DOT1L). Results: The data revealed that LOF variants of KMT2D, SETD2, and KMT2C were more frequent in pan-cancer dataset. Furthermore, we found that LOF variants of 7 HMTs, including KMT2A, KMT2B, KMT2C, KMT2D, NSD1, SETD2, and EZH2, were associated with higher TMB (P < 0.0001). Then we analyzed the associations between LOF variants and overall survival (OS) after ICIs therapy. The results indicated that LOF variants of KMT2A (P = 0.0295), KMT2B (P = 0.0329), KMT2C (P = 0.0122), and SETD2 (P = 0.0004) were significantly associated with prolonged median OS for all the enrolled patients. In this cohort, LOF variants of KMT2A, KMT2B, KMT2C, and SETD2 were most common in bladder cancer, colorectal cancer, colorectal cancer, and renal cell carcinoma, respectively. Then we assessed the predictive values of these four genes for each type of cancer. It was noteworthy that KMT2C LOF variants were significantly correlated with longer median OS in colorectal cancer (P = 0.0171), but not in other cancer types. Surprisingly, we did not observe the predictive roles of LOF variants in KMT2A, KMT2B, and SETD2 genes for response to ICIs therapy in any types of cancer. Conclusions: In pan-cancer dataset, we found that LOF variants of 4 HMTs, such as KMT2A, KMT2B, KMT2C, and SETD2, were correlated with better outcomes of ICIs treatment. However, for different types of cancer, only KMT2C LOF variants were associated with longer median OS in colorectal cancer, suggesting that it may be used as a predictive biomarker for ICIs efficacy in colorectal cancer. Because the sample sizes of patients with KMT2A, KMT2B, or SETD2 LOF variants were small, we did not find the predictive values of LOF variants in these three genes for different types of cancer. Next, we will enroll more patients to address this question.