A role for SETD2 loss in tumorigenesis through DNA methylation dysregulation.

SETD2-dependent H3 Lysine-36 trimethylation (H3K36me3) has been recently linked to the deposition of DNA methylation. is frequently mutated in cancer, however, the functional impact of 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 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 , and . This suggests a new role for 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 mutation status with high accuracy and correlates with patient prognosis.