Y disruption, autosomal hypomethylation and poor male lung cancer survival

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 undergo...

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Autores principales:	Saffron A. G. Willis-Owen, Clara Domingo-Sabugo, Elizabeth Starren, Liming Liang, Maxim B. Freidin, Madeleine Arseneault, Youming Zhang, Shir Kiong Lu, Sanjay Popat, Eric Lim, Andrew G. Nicholson, Yasser Riazalhosseini, Mark Lathrop, William O. C. Cookson, Miriam F. Moffatt
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/984df0ae21224581b348c62efb1c4fcb
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spelling	oai:doaj.org-article:984df0ae21224581b348c62efb1c4fcb2021-12-02T17:23:03ZY disruption, autosomal hypomethylation and poor male lung cancer survival10.1038/s41598-021-91907-82045-2322https://doaj.org/article/984df0ae21224581b348c62efb1c4fcb2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91907-8https://doaj.org/toc/2045-2322Abstract 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.Saffron A. G. Willis-OwenClara Domingo-SabugoElizabeth StarrenLiming LiangMaxim B. FreidinMadeleine ArseneaultYouming ZhangShir Kiong LuSanjay PopatEric LimAndrew G. NicholsonYasser RiazalhosseiniMark LathropWilliam O. C. CooksonMiriam F. MoffattNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Saffron A. G. Willis-Owen Clara Domingo-Sabugo Elizabeth Starren Liming Liang Maxim B. Freidin Madeleine Arseneault Youming Zhang Shir Kiong Lu Sanjay Popat Eric Lim Andrew G. Nicholson Yasser Riazalhosseini Mark Lathrop William O. C. Cookson Miriam F. Moffatt Y disruption, autosomal hypomethylation and poor male lung cancer survival
description	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.
format	article
author	Saffron A. G. Willis-Owen Clara Domingo-Sabugo Elizabeth Starren Liming Liang Maxim B. Freidin Madeleine Arseneault Youming Zhang Shir Kiong Lu Sanjay Popat Eric Lim Andrew G. Nicholson Yasser Riazalhosseini Mark Lathrop William O. C. Cookson Miriam F. Moffatt
author_facet	Saffron A. G. Willis-Owen Clara Domingo-Sabugo Elizabeth Starren Liming Liang Maxim B. Freidin Madeleine Arseneault Youming Zhang Shir Kiong Lu Sanjay Popat Eric Lim Andrew G. Nicholson Yasser Riazalhosseini Mark Lathrop William O. C. Cookson Miriam F. Moffatt
author_sort	Saffron A. G. Willis-Owen
title	Y disruption, autosomal hypomethylation and poor male lung cancer survival
title_short	Y disruption, autosomal hypomethylation and poor male lung cancer survival
title_full	Y disruption, autosomal hypomethylation and poor male lung cancer survival
title_fullStr	Y disruption, autosomal hypomethylation and poor male lung cancer survival
title_full_unstemmed	Y disruption, autosomal hypomethylation and poor male lung cancer survival
title_sort	y disruption, autosomal hypomethylation and poor male lung cancer survival
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/984df0ae21224581b348c62efb1c4fcb
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Y disruption, autosomal hypomethylation and poor male lung cancer survival

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