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Y disruption, autosomal hypomethylation and poor male lung cancer survival

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Title: Y disruption, autosomal hypomethylation and poor male lung cancer survival
Authors: Willis-Owen, S
Domingo Sabugo, C
Starren, E
Liang, L
Freidin, M
Arseneault, M
Zhang, Y
Kiong Lu, S
Popat, S
Lim, E
Nicholson, A
Riazalhosseini, Y
Lathrop, M
Cookson, W
Moffatt, M
Item Type: Journal Article
Abstract: 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.
Issue Date: 14-Jun-2021
Date of Acceptance: 26-May-2021
URI: http://hdl.handle.net/10044/1/90121
DOI: 10.1038/s41598-021-91907-8
ISSN: 2045-2322
Publisher: Nature Publishing Group
Journal / Book Title: Scientific Reports
Volume: 11
Copyright Statement: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 096964/Z/11/Z
Publication Status: Published online
Article Number: ARTN 12453
Appears in Collections:National Heart and Lung Institute



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