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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Autor*in:	Saffron A. G. Willis-Owen [verfasserIn] Clara Domingo-Sabugo [verfasserIn] Elizabeth Starren [verfasserIn] Liming Liang [verfasserIn] Maxim B. Freidin [verfasserIn] Madeleine Arseneault [verfasserIn] Youming Zhang [verfasserIn] Shir Kiong Lu [verfasserIn] Sanjay Popat [verfasserIn] Eric Lim [verfasserIn] Andrew G. Nicholson [verfasserIn] Yasser Riazalhosseini [verfasserIn] Mark Lathrop [verfasserIn] William O. C. Cookson [verfasserIn] Miriam F. Moffatt [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Übergeordnetes Werk:	In: Scientific Reports - Nature Portfolio, 2011, 11(2021), 1, Seite 12
Übergeordnetes Werk:	volume:11 ; year:2021 ; number:1 ; pages:12

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41598-021-91907-8

Katalog-ID:	DOAJ004564820

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author_variant	s a g w o sagwo c d s cds e s es l l ll m b f mbf m a ma y z yz s k l skl s p sp e l el a g n agn y r yr m l ml w o c c wocc m f m mfm
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allfields	10.1038/s41598-021-91907-8 doi (DE-627)DOAJ004564820 (DE-599)DOAJ984df0ae21224581b348c62efb1c4fcb DE-627 ger DE-627 rakwb eng Saffron A. G. Willis-Owen verfasserin aut Y disruption, autosomal hypomethylation and poor male lung cancer survival 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Clara Domingo-Sabugo verfasserin aut Elizabeth Starren verfasserin aut Liming Liang verfasserin aut Maxim B. Freidin verfasserin aut Madeleine Arseneault verfasserin aut Youming Zhang verfasserin aut Shir Kiong Lu verfasserin aut Sanjay Popat verfasserin aut Eric Lim verfasserin aut Andrew G. Nicholson verfasserin aut Yasser Riazalhosseini verfasserin aut Mark Lathrop verfasserin aut William O. C. Cookson verfasserin aut Miriam F. Moffatt verfasserin aut In Scientific Reports Nature Portfolio, 2011 11(2021), 1, Seite 12 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:11 year:2021 number:1 pages:12 https://doi.org/10.1038/s41598-021-91907-8 kostenfrei https://doaj.org/article/984df0ae21224581b348c62efb1c4fcb kostenfrei https://doi.org/10.1038/s41598-021-91907-8 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 12
spelling	10.1038/s41598-021-91907-8 doi (DE-627)DOAJ004564820 (DE-599)DOAJ984df0ae21224581b348c62efb1c4fcb DE-627 ger DE-627 rakwb eng Saffron A. G. Willis-Owen verfasserin aut Y disruption, autosomal hypomethylation and poor male lung cancer survival 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Clara Domingo-Sabugo verfasserin aut Elizabeth Starren verfasserin aut Liming Liang verfasserin aut Maxim B. Freidin verfasserin aut Madeleine Arseneault verfasserin aut Youming Zhang verfasserin aut Shir Kiong Lu verfasserin aut Sanjay Popat verfasserin aut Eric Lim verfasserin aut Andrew G. Nicholson verfasserin aut Yasser Riazalhosseini verfasserin aut Mark Lathrop verfasserin aut William O. C. Cookson verfasserin aut Miriam F. Moffatt verfasserin aut In Scientific Reports Nature Portfolio, 2011 11(2021), 1, Seite 12 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:11 year:2021 number:1 pages:12 https://doi.org/10.1038/s41598-021-91907-8 kostenfrei https://doaj.org/article/984df0ae21224581b348c62efb1c4fcb kostenfrei https://doi.org/10.1038/s41598-021-91907-8 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 12
allfields_unstemmed	10.1038/s41598-021-91907-8 doi (DE-627)DOAJ004564820 (DE-599)DOAJ984df0ae21224581b348c62efb1c4fcb DE-627 ger DE-627 rakwb eng Saffron A. G. Willis-Owen verfasserin aut Y disruption, autosomal hypomethylation and poor male lung cancer survival 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Clara Domingo-Sabugo verfasserin aut Elizabeth Starren verfasserin aut Liming Liang verfasserin aut Maxim B. Freidin verfasserin aut Madeleine Arseneault verfasserin aut Youming Zhang verfasserin aut Shir Kiong Lu verfasserin aut Sanjay Popat verfasserin aut Eric Lim verfasserin aut Andrew G. Nicholson verfasserin aut Yasser Riazalhosseini verfasserin aut Mark Lathrop verfasserin aut William O. C. Cookson verfasserin aut Miriam F. Moffatt verfasserin aut In Scientific Reports Nature Portfolio, 2011 11(2021), 1, Seite 12 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:11 year:2021 number:1 pages:12 https://doi.org/10.1038/s41598-021-91907-8 kostenfrei https://doaj.org/article/984df0ae21224581b348c62efb1c4fcb kostenfrei https://doi.org/10.1038/s41598-021-91907-8 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 12
allfieldsGer	10.1038/s41598-021-91907-8 doi (DE-627)DOAJ004564820 (DE-599)DOAJ984df0ae21224581b348c62efb1c4fcb DE-627 ger DE-627 rakwb eng Saffron A. G. Willis-Owen verfasserin aut Y disruption, autosomal hypomethylation and poor male lung cancer survival 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Clara Domingo-Sabugo verfasserin aut Elizabeth Starren verfasserin aut Liming Liang verfasserin aut Maxim B. Freidin verfasserin aut Madeleine Arseneault verfasserin aut Youming Zhang verfasserin aut Shir Kiong Lu verfasserin aut Sanjay Popat verfasserin aut Eric Lim verfasserin aut Andrew G. Nicholson verfasserin aut Yasser Riazalhosseini verfasserin aut Mark Lathrop verfasserin aut William O. C. Cookson verfasserin aut Miriam F. Moffatt verfasserin aut In Scientific Reports Nature Portfolio, 2011 11(2021), 1, Seite 12 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:11 year:2021 number:1 pages:12 https://doi.org/10.1038/s41598-021-91907-8 kostenfrei https://doaj.org/article/984df0ae21224581b348c62efb1c4fcb kostenfrei https://doi.org/10.1038/s41598-021-91907-8 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 12
allfieldsSound	10.1038/s41598-021-91907-8 doi (DE-627)DOAJ004564820 (DE-599)DOAJ984df0ae21224581b348c62efb1c4fcb DE-627 ger DE-627 rakwb eng Saffron A. G. Willis-Owen verfasserin aut Y disruption, autosomal hypomethylation and poor male lung cancer survival 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Clara Domingo-Sabugo verfasserin aut Elizabeth Starren verfasserin aut Liming Liang verfasserin aut Maxim B. Freidin verfasserin aut Madeleine Arseneault verfasserin aut Youming Zhang verfasserin aut Shir Kiong Lu verfasserin aut Sanjay Popat verfasserin aut Eric Lim verfasserin aut Andrew G. Nicholson verfasserin aut Yasser Riazalhosseini verfasserin aut Mark Lathrop verfasserin aut William O. C. Cookson verfasserin aut Miriam F. Moffatt verfasserin aut In Scientific Reports Nature Portfolio, 2011 11(2021), 1, Seite 12 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:11 year:2021 number:1 pages:12 https://doi.org/10.1038/s41598-021-91907-8 kostenfrei https://doaj.org/article/984df0ae21224581b348c62efb1c4fcb kostenfrei https://doi.org/10.1038/s41598-021-91907-8 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 12
language	English
source	In Scientific Reports 11(2021), 1, Seite 12 volume:11 year:2021 number:1 pages:12
sourceStr	In Scientific Reports 11(2021), 1, Seite 12 volume:11 year:2021 number:1 pages:12
format_phy_str_mv	Article
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container_title	Scientific Reports
authorswithroles_txt_mv	Saffron A. G. Willis-Owen @@aut@@ Clara Domingo-Sabugo @@aut@@ Elizabeth Starren @@aut@@ Liming Liang @@aut@@ Maxim B. Freidin @@aut@@ Madeleine Arseneault @@aut@@ Youming Zhang @@aut@@ Shir Kiong Lu @@aut@@ Sanjay Popat @@aut@@ Eric Lim @@aut@@ Andrew G. Nicholson @@aut@@ Yasser Riazalhosseini @@aut@@ Mark Lathrop @@aut@@ William O. C. Cookson @@aut@@ Miriam F. Moffatt @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
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author	Saffron A. G. Willis-Owen
spellingShingle	Saffron A. G. Willis-Owen misc Medicine misc R misc Science misc Q Y disruption, autosomal hypomethylation and poor male lung cancer survival
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topic_title	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
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title_full	Y disruption, autosomal hypomethylation and poor male lung cancer survival
author_sort	Saffron A. G. Willis-Owen
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author_browse	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
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author-letter	Saffron A. G. Willis-Owen
doi_str_mv	10.1038/s41598-021-91907-8
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title_sort	disruption, autosomal hypomethylation and poor male lung cancer survival
title_auth	Y disruption, autosomal hypomethylation and poor male lung cancer survival
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	Y disruption, autosomal hypomethylation and poor male lung cancer survival
url	https://doi.org/10.1038/s41598-021-91907-8 https://doaj.org/article/984df0ae21224581b348c62efb1c4fcb https://doaj.org/toc/2045-2322
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author2	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
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up_date	2024-07-04T00:13:52.834Z
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Vorhandene Bände

Nicht das Richtige dabei?