NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma

Abstract Chromatin modifying enzymes are frequently mutated in cancer, resulting in widespread epigenetic deregulation. Recent reports indicate that inactivating mutations in the histone methyltransferase NSD1 define an intrinsic subtype of head and neck squamous cell carcinoma (HNSC) that features...

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Autores principales:	Kevin Brennan, June Ho Shin, Joshua K. Tay, Marcos Prunello, Andrew J. Gentles, John B. Sunwoo, Olivier Gevaert
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e80aabb014e14336a67aa59a1ef260a9
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spelling	oai:doaj.org-article:e80aabb014e14336a67aa59a1ef260a92021-12-02T15:05:57ZNSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma10.1038/s41598-017-17298-x2045-2322https://doaj.org/article/e80aabb014e14336a67aa59a1ef260a92017-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-17298-xhttps://doaj.org/toc/2045-2322Abstract Chromatin modifying enzymes are frequently mutated in cancer, resulting in widespread epigenetic deregulation. Recent reports indicate that inactivating mutations in the histone methyltransferase NSD1 define an intrinsic subtype of head and neck squamous cell carcinoma (HNSC) that features pronounced DNA hypomethylation. Here, we describe a similar hypomethylated subtype of lung squamous cell carcinoma (LUSC) that is enriched for both inactivating mutations and deletions in NSD1. The ‘NSD1 subtypes’ of HNSC and LUSC are highly correlated at the DNA methylation and gene expression levels, featuring ectopic expression of developmental transcription factors and genes that are also hypomethylated in Sotos syndrome, a congenital disorder caused by germline NSD1 mutations. Further, the NSD1 subtype of HNSC displays an ‘immune cold’ phenotype characterized by low infiltration of tumor-associated leukocytes, particularly macrophages and CD8+ T cells, as well as low expression of genes encoding the immunotherapy target PD-1 immune checkpoint receptor and its ligands. Using an in vivo model, we demonstrate that NSD1 inactivation results in reduced T cell infiltration into the tumor microenvironment, implicating NSD1 as a tumor cell-intrinsic driver of an immune cold phenotype. NSD1 inactivation therefore causes epigenetic deregulation across cancer sites, and has implications for immunotherapy.Kevin BrennanJune Ho ShinJoshua K. TayMarcos PrunelloAndrew J. GentlesJohn B. SunwooOlivier GevaertNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kevin Brennan June Ho Shin Joshua K. Tay Marcos Prunello Andrew J. Gentles John B. Sunwoo Olivier Gevaert NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma
description	Abstract Chromatin modifying enzymes are frequently mutated in cancer, resulting in widespread epigenetic deregulation. Recent reports indicate that inactivating mutations in the histone methyltransferase NSD1 define an intrinsic subtype of head and neck squamous cell carcinoma (HNSC) that features pronounced DNA hypomethylation. Here, we describe a similar hypomethylated subtype of lung squamous cell carcinoma (LUSC) that is enriched for both inactivating mutations and deletions in NSD1. The ‘NSD1 subtypes’ of HNSC and LUSC are highly correlated at the DNA methylation and gene expression levels, featuring ectopic expression of developmental transcription factors and genes that are also hypomethylated in Sotos syndrome, a congenital disorder caused by germline NSD1 mutations. Further, the NSD1 subtype of HNSC displays an ‘immune cold’ phenotype characterized by low infiltration of tumor-associated leukocytes, particularly macrophages and CD8+ T cells, as well as low expression of genes encoding the immunotherapy target PD-1 immune checkpoint receptor and its ligands. Using an in vivo model, we demonstrate that NSD1 inactivation results in reduced T cell infiltration into the tumor microenvironment, implicating NSD1 as a tumor cell-intrinsic driver of an immune cold phenotype. NSD1 inactivation therefore causes epigenetic deregulation across cancer sites, and has implications for immunotherapy.
format	article
author	Kevin Brennan June Ho Shin Joshua K. Tay Marcos Prunello Andrew J. Gentles John B. Sunwoo Olivier Gevaert
author_facet	Kevin Brennan June Ho Shin Joshua K. Tay Marcos Prunello Andrew J. Gentles John B. Sunwoo Olivier Gevaert
author_sort	Kevin Brennan
title	NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma
title_short	NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma
title_full	NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma
title_fullStr	NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma
title_full_unstemmed	NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma
title_sort	nsd1 inactivation defines an immune cold, dna hypomethylated subtype in squamous cell carcinoma
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e80aabb014e14336a67aa59a1ef260a9
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NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma

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