Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate of <8%. Unsupervised clustering of 76 PDAC patients based on intron retention (IR) events resulted in two clusters of tumors (IR-1 and IR-2). While gene expression-based clusters are not predictiv...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Daniel J. Tan, Mithun Mitra, Alec M. Chiu, Hilary A. Coller
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/fc3a0c8629c1439484ba57658f1cc672
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:fc3a0c8629c1439484ba57658f1cc672
record_format	dspace
spelling	oai:doaj.org-article:fc3a0c8629c1439484ba57658f1cc6722021-12-02T15:11:55ZIntron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma10.1038/s41525-020-00159-42056-7944https://doaj.org/article/fc3a0c8629c1439484ba57658f1cc6722020-12-01T00:00:00Zhttps://doi.org/10.1038/s41525-020-00159-4https://doaj.org/toc/2056-7944Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate of <8%. Unsupervised clustering of 76 PDAC patients based on intron retention (IR) events resulted in two clusters of tumors (IR-1 and IR-2). While gene expression-based clusters are not predictive of patient outcome in this cohort, the clusters we developed based on intron retention were associated with differences in progression-free interval. IR levels are lower and clinical outcome is worse in IR-1 compared with IR-2. Oncogenes were significantly enriched in the set of 262 differentially retained introns between the two IR clusters. Higher IR levels in IR-2 correlate with higher gene expression, consistent with detention of intron-containing transcripts in the nucleus in IR-2. Out of 258 genes encoding RNA-binding proteins (RBP) that were differentially expressed between IR-1 and IR-2, the motifs for seven RBPs were significantly enriched in the 262-intron set, and the expression of 25 RBPs were highly correlated with retention levels of 139 introns. Network analysis suggested that retention of introns in IR-2 could result from disruption of an RBP protein−protein interaction network previously linked to efficient intron removal. Finally, IR-based clusters developed for the majority of the 20 cancer types surveyed had two clusters with asymmetrical distributions of IR events like PDAC, with one cluster containing mostly intron loss events. Taken together, our findings suggest IR may be an important biomarker for subclassifying tumors.Daniel J. TanMithun MitraAlec M. ChiuHilary A. CollerNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 5, Iss 1, Pp 1-17 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Daniel J. Tan Mithun Mitra Alec M. Chiu Hilary A. Coller Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma
description	Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate of <8%. Unsupervised clustering of 76 PDAC patients based on intron retention (IR) events resulted in two clusters of tumors (IR-1 and IR-2). While gene expression-based clusters are not predictive of patient outcome in this cohort, the clusters we developed based on intron retention were associated with differences in progression-free interval. IR levels are lower and clinical outcome is worse in IR-1 compared with IR-2. Oncogenes were significantly enriched in the set of 262 differentially retained introns between the two IR clusters. Higher IR levels in IR-2 correlate with higher gene expression, consistent with detention of intron-containing transcripts in the nucleus in IR-2. Out of 258 genes encoding RNA-binding proteins (RBP) that were differentially expressed between IR-1 and IR-2, the motifs for seven RBPs were significantly enriched in the 262-intron set, and the expression of 25 RBPs were highly correlated with retention levels of 139 introns. Network analysis suggested that retention of introns in IR-2 could result from disruption of an RBP protein−protein interaction network previously linked to efficient intron removal. Finally, IR-based clusters developed for the majority of the 20 cancer types surveyed had two clusters with asymmetrical distributions of IR events like PDAC, with one cluster containing mostly intron loss events. Taken together, our findings suggest IR may be an important biomarker for subclassifying tumors.
format	article
author	Daniel J. Tan Mithun Mitra Alec M. Chiu Hilary A. Coller
author_facet	Daniel J. Tan Mithun Mitra Alec M. Chiu Hilary A. Coller
author_sort	Daniel J. Tan
title	Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma
title_short	Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma
title_full	Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma
title_fullStr	Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma
title_full_unstemmed	Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma
title_sort	intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/fc3a0c8629c1439484ba57658f1cc672
work_keys_str_mv	AT danieljtan intronretentionisarobustmarkerofintertumoralheterogeneityinpancreaticductaladenocarcinoma AT mithunmitra intronretentionisarobustmarkerofintertumoralheterogeneityinpancreaticductaladenocarcinoma AT alecmchiu intronretentionisarobustmarkerofintertumoralheterogeneityinpancreaticductaladenocarcinoma AT hilaryacoller intronretentionisarobustmarkerofintertumoralheterogeneityinpancreaticductaladenocarcinoma
_version_	1718387669479718912

Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma

Ejemplares similares