Preprint: Loss of paternal KDM6A reshapes sperm epigenome and elevates cancer risk in wild-type offspring

A preprint posted to bioRxiv on 1 September 2026 describes a mechanistic study of how paternal epigenetic information transmitted through sperm can influence cancer susceptibility in offspring that do not themselves carry the causative mutation.

The researchers focused on KDM6A (also known as UTX), an X-linked histone demethylase and tumour suppressor. Using mouse models in which Kdm6a was knocked out specifically in the paternal germline, the team found that paternal loss of KDM6A increased cancer risk in genetically wild-type offspring — that is, offspring that did not inherit the knockout allele. The study identifies the mechanism: KDM6A functions during spermatogenesis to promote methylation of histone H3 at lysine 4 (H3K4) through selective interaction with the COMPASS complex, and this chromatin state is transmitted to the next generation in a way that influences tumour suppressor network activity.

The findings extend an emerging literature on intergenerational epigenetic inheritance in mammals and have potential relevance for understanding why cancer risk sometimes clusters in families beyond what Mendelian inheritance alone can explain. KDM6A is already implicated in several human cancers as a recurrently mutated gene.

This is a preprint that has not yet been peer-reviewed. The study is primarily of interest to researchers working in epigenetics, cancer genetics, and reproductive biology.