Y disruption, autosomal hypomethylation and poor male lung cancer survival

Sci Rep. 2021 Jun 14;11(1):12453. doi: 10.1038/s41598-021-91907-8.


Lung cancer is the most frequent cause of cancer death worldwide. 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-IV 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, KDM5D. After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40-10.3, P = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4-2.0, P = 1.2 × 10-10). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / deficiency
  • Biomarkers, Tumor / genetics*
  • Chromosome Deletion*
  • Chromosomes, Human, Y / genetics*
  • DNA Methylation
  • Datasets as Topic
  • Epigenesis, Genetic
  • Exome Sequencing
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Health Status Disparities
  • Histone Demethylases / deficiency
  • Histone Demethylases / genetics*
  • Humans
  • Kaplan-Meier Estimate
  • Lung / pathology
  • Lung / surgery
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / surgery
  • Male
  • Middle Aged
  • Minor Histocompatibility Antigens / genetics*
  • Neoplasm Staging
  • Pneumonectomy
  • Prognosis
  • Risk Assessment / statistics & numerical data
  • Sex Factors


  • Biomarkers, Tumor
  • Minor Histocompatibility Antigens
  • Histone Demethylases
  • KDM5D protein, human