The pan-cancer mutational landscape of MLL3 and its impact on prognosis and immunochemotherapy

Although recurrent mutations of MLL3 are reported in various 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. Here, we report that the genetic alterations in MLL3 in 33 cancer types are primarily driven by point mutations or small insertions and deletions (indels) and exhibit lineage-specific variations. These variations 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 predict better overall survival and favorable response to immunochemotherapy. Concurrent mutations of MLL3 and POLE in UCEC signify a better immune response, which is validated in mouse models with Mll3-ablated colon cancer. 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.