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It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA\u2013IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression,\n                    <jats:italic>KDM5D<\/jats:italic>\n                    . After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour\n                    <jats:italic>KDM5D<\/jats:italic>\n                    deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40\u201310.3,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.009).\n                    <jats:italic>KDM5D<\/jats:italic>\n                    deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4\u20132.0,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20091.2\u2009\u00d7\u200910\n                    <jats:sup>\u201310<\/jats:sup>\n                    ). Our findings identify tumour deficiency of\n                    <jats:italic>KDM5D<\/jats:italic>\n                    as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-91907-8","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T06:03:10Z","timestamp":1623650590000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Y disruption, autosomal hypomethylation and poor male lung cancer survival"],"prefix":"10.1038","volume":"11","author":[{"given":"Saffron A. 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