KMT2D and KMT2C: Enhancer Regulators Lost in Many Cancers

Marking Active Enhancers

Enhancers are distal regulatory elements that boost transcription of their target genes. KMT2D and KMT2C, within COMPASS-like complexes, deposit H3K4me1 at enhancers as they are activated, and support the recruitment of histone acetyltransferases that add H3K27ac.

When these enzymes are lost, enhancers that should switch on in a given cell type are under-activated, blunting the normal transcriptional programme and, in many contexts, favouring a less differentiated state.

Where Mutations Occur

KMT2D loss is a defining early event in follicular lymphoma and is common in diffuse large B-cell lymphoma, bladder cancer, lung squamous cell carcinoma, head and neck cancer and medulloblastoma. KMT2C is recurrently mutated in breast, prostate and other cancers.

The mutations are usually truncating and distributed across the gene, consistent with a tumour-suppressor loss-of-function pattern rather than a hotspot oncogenic change.

Interpretation Notes

Because KMT2C and KMT2D are very large genes, they accumulate passenger mutations, and not every truncating variant is a driver in a given tumour. Germline KMT2D variants cause Kabuki syndrome, a developmental disorder, which is a distinct context from somatic loss in cancer.

There is no approved therapy that directly targets KMT2C or KMT2D loss, though restoring enhancer activity, for example by modulating the opposing H3K27 methylation, is an area of research.

What It Adds to a Tumour Profile

A KMT2C or KMT2D loss rarely changes treatment on its own, but it contributes context. Enhancer-regulator loss is associated with a less differentiated tumour phenotype, and in bladder and lung squamous cancers these mutations are part of the broad chromatin-remodeller disruption that characterises those diseases.

There is preliminary laboratory evidence that KMT2D-deficient tumours may be more sensitive to certain agents, including KDM demethylase inhibitors, but nothing clinical. For now the value is mainly in explaining tumour biology and in flagging a possible Kabuki-syndrome context when a variant looks germline.

Key Takeaways

• ·KMT2D and KMT2C write the H3K4me1 mark that flags active enhancers.
• ·Truncating loss-of-function mutations are frequent across lymphoma and many epithelial cancers.
• ·Their large size means passenger mutations are common and driver status is context-dependent.