Y disruption, autosomal hypomethylation and poor male lung cancer survival.

Autor:	Willis-Owen SAG; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK., Domingo-Sabugo C; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK., Starren E; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK., Liang L; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA., Freidin MB; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK.; Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, Lambeth Palace Road, London, SE1 7EH, UK., Arseneault M; McGill Genome Centre, Montréal, QC, H3A 0G1, Canada., Zhang Y; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK., Lu SK; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK., Popat S; Royal Marsden Hospital NHS Foundation Trust, London and Surrey, UK.; The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK., Lim E; Department of Thoracic Surgery, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK., Nicholson AG; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK.; Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, London, UK., Riazalhosseini Y; McGill Genome Centre, Montréal, QC, H3A 0G1, Canada.; Department of Human Genetics, McGill University, Montréal, QC, Canada., Lathrop M; McGill Genome Centre, Montréal, QC, H3A 0G1, Canada., Cookson WOC; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK. w.cookson@imperial.ac.uk., Moffatt MF; National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK. m.moffatt@imperial.ac.uk.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2021 Jun 14; Vol. 11 (1), pp. 12453. Date of Electronic Publication: 2021 Jun 14.
DOI:	10.1038/s41598-021-91907-8
Abstrakt:	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.
Databáze:	MEDLINE
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