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Lung cancer is the most frequent cause of cancer death worldwide1. It is male predominant and for reasons that are unknown also associated with significantly worse outcomes in men2. 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=1.2x10-10). 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.

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