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Pan-Cancer MLL3 Mutational Landscape and Its Association with Immunotherapy

ABSTRACT: Translocation-linked Mixed Lineage Leukemia (MLL) genes were discovered ~ 30 years ago and are homologs of Trithorax in Drosophila. MLL3 is a histone methyltransferase catalyzing the monomethylation of histone H3 lysine 4 (H3K4me1), a hallmark for gene enhancers. Although recurrent mutations of MLL3 are reported across a broad spectrum of cancers and MLL3 represents one of the most commonly mutated cancer genes, a pan-cancer-wide portrait of this high-frequency mutational event is still lacking. We report here a comprehensive analysis of MLL3 mutation and its association with molecular, cellular, and clinical features in 33 cancer types. The genetic alterations of MLL3 are primarily driven by point mutations or small INDELs rather than large-scale chromosomal perturbations and exhibit lineage-specific variations, which spontaneously yet heterogeneously impinge on the clinical behaviors of cancers and are intrinsically linked to hot tumor microenvironments, especially in uterine corpus endometrial carcinoma (UCEC) and colon adenocarcinoma (COAD), where MLL3 aberrances surprisingly predict better overall survivals and favorable responses to immunochemotherapy. Concurrent mutation of MLL3 and POLE in UCEC is associated with high immune cell infiltration and immune checkpoint gene expression, endowing the applicability of immune checkpoint inhibitors in these patients. Mouse models with Mll3-ablated colon cancer validate the immunostimulatory trait of Mll3 aberration. Our study provides a pan-cancer spectrum of the MLL3 mutational event and will contribute to the understanding of the genetic evolution and disease management of cancers, especially COAD and UCEC.

ORGANISM(S): Mus musculus

PROVIDER: GSE307073 | GEO | 2025/09/07

REPOSITORIES: GEO

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Project description:Background: An increasing body of evidence has linked fructose intake to colorectal cancer (CRC). African Americans (AAs) consume greater quantities of fructose and are more likely to develop right-side colon cancer than European Americans. Objective: We examined the hypothesis that fructose consumption leads to genomic differences associated with CRC tumor biology. Methods: DNA methylation data from this study was obtained using the Illumina Infinium MethylationEPIC kit (GSE151732). Right and left colon differentially methylated regions (DMRs) were identified using DMRcate through analysis of fructose consumption in normal AA colon biopsies (n=79) undergoing screening colonoscopy. Secondary analysis of CRC tumors was carried out using data derived from TCGA-COAD, GSE101764 and GSE193535. Right colon organoids derived from AA normal colon tissues were exposed to 4.4mM of fructose for 72 hours. Fructose-associated differentially expressed genes (DEGs) were identified using DESeq2. This package was also used to identify DEGs in CRC tumors from TCGA-COAD. Results: We identified 4,263 right colon fructose-associated DMRs (FDR<0.05). In contrast, only 24 DMRs survived multiple testing corrections (FDR<0.05) in matched, left colon. Almost 50% of right colon fructose-associated DMRs overlapped regions implicated in CRC in at least one of three datasets. A highly significant enrichment was also observed between genes corresponding to right colon fructose-associated DMRs and DEGs associated with fructose exposure in AA right colon organoids (P=3.28E-30). Further, overlapping and significant enrichments for a number of fatty acid metabolism, glycolysis and cell proliferation pathways were also found. By further examining the overlap of genes within these pathways that were also differentially expressed in TCGA-COAD, our analysis reveals potential role for PFKP and ANKRD23 in fructose-mediated CRC risk. Conclusions: Our data support that dietary fructose exerts a greater CRC risk-related effect in right than left colon among AAs, alluding to its potential role in contributing to racial disparities in CRC.

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Pan-Cancer MLL3 Mutational Landscape and Its Association with Immunotherapy

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