Y disruption, autosomal hypomethylation and poor male lung cancer survival

Summary Lung cancer is the most frequent cause of cancer death worldwide 1 . It is male predominant and for reasons that are unknown also associated with significantly worse outcomes in men 2 . Here we compared gene co-expression networks in affected and unaffected pulmonary tissue derived from 126 patients with Stage IA–IV lung cancer. We observed marked degradation of a sex-associated gene co-expression network in tumour tissue. The disturbance was linked to fractional loss of the Y chromosome and was detected in 28% of male tumours in the discovery dataset and 27% of male tumours in a 123 sample replication dataset. Depression of Y chromosome expression was accompanied by extensive autosomal DNA hypomethylation. The male specific H3K4 demethylase, KDM5D , was identified as an apex hub within this co-expression network. Male patients exhibiting relative tumour KDM5D deficiency had an increased risk of death in the discovery dataset (Hazard Ratio [HR] 3.80, 95% CI 1.40 – 10.3, P =0.009) and in an independent sample of 1,100 male lung tumours (HR 1.67, 95% CI 1.4-2.0, P =1.2⨯10 −10 ). Our findings identify tumour-specific weakening of male-specific expression, in particular deficiency of KDM5D , as a common replicable prognostic marker and credible mechanism underlying sex disparity in cancer.