Effects of KMT2D mutation and its exon 39 mutation on the immune microenvironment and drug sensitivity in colorectal adenocarcinoma

Background: KMT2D mutation (KMT2D(MT)) was found to play an important role in cancer immunity and response to immune checkpoint inhibitors (ICIs). The present study aims to investigate the association between KMT2D exon 39 mutation (K-ex39(MT)) and molecular and clinical characteristics in colorectal adenocarcinoma (CRAD). Methods: We performed profiling of KMT2D(MT) and K-ex39(MT) via Kaplan-Meier analysis, cBioportal, Immune-related functional analysis and correlation analysis with TCGA and MSK cohorts to explore their effects on the prognosis, immune landscape, molecular characteristics and drug sensitivity in CRAD. Panel gene sequencing of 30 in-house CRAD tissues and multiple immunofluorescences (mIF) were also used. Results: In multi-cancer, patients with KMT2D(MT) have a worse overall survival (OS), and CRAD with K-ex39(MT) exhibited a greater degree of immune cellular infiltration. For CRAD, compared with KMT2D exon39 wild type (K-ex39(WT)), K-ex39(MT) patients had higher tumor mutational burden (TMB) and lower copy number alteration (CNA), and were accompanied by more immune cell infiltration including activated T cells, NK cells, Treg cells and exhausted T cells and enrichment of immune-related genes and pathways. In drug sensitivity prediction, K-ex39(MT) patients have a lower CTX-S score and IC50 of 5-Fluorouracil and irinotecan, and higher Tumor Immune Dysfunction and Rejection (TIDE) dysfunction score. Conclusions: CRAD patients with K-ex39(MT) have more abundant immune cell infiltration and enrichment of immune-related pathways and signatures. And they may be more sensitive to some chemotherapies but less to cetuximab.