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SETD2-dependent H3 Lysine-36 trimethylation (H3K36me3) has been recently linked to the deposition of de-novo DNA methylation. SETD2 is frequently mutated in cancer, however, the functional impact of SETD2 loss and depletion on DNA methylation across cancer types and tumorigenesis is currently unknown. Here, we perform a pan-cancer analysis and show that both SETD2 mutation and reduced expression are associated with DNA methylation dysregulation across 21 out of the 24 cancer types tested. In renal cancer, these DNA methylation changes are associated with altered gene expression of oncogenes, tumour suppressors, and genes involved in neoplasm invasiveness, including TP53, FOXO1, and CDK4. This suggests a new role for SETD2 loss in tumorigenesis and cancer aggressiveness through DNA methylation dysregulation. Moreover, using a robust machine learning methodology, we develop and validate a 3-CpG methylation signature which is sufficient to predict SETD2 mutation status with high accuracy and correlates with patient prognosis.

Original publication

DOI

10.1186/s12885-023-11162-0

Type

Journal article

Journal

BMC cancer

Publication Date

08/2023

Volume

23

Addresses

Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.

Keywords

Humans, Carcinoma, Renal Cell, Kidney Neoplasms, Cell Transformation, Neoplastic, Histones, DNA Methylation, Carcinogenesis