TY - JOUR
T1 - High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations
AU - Zhang, Yiqun
AU - Chen, Fengju
AU - Fonseca, Nuno A.
AU - He, Yao
AU - Fujita, Masashi
AU - Nakagawa, Hidewaki
AU - Zhang, Zemin
AU - Brazma, Alvis
AU - Amin, Samirkumar B.
AU - Awadalla, Philip
AU - Bailey, Peter J.
AU - Brazma, Alvis
AU - Brooks, Angela N.
AU - Calabrese, Claudia
AU - Chateigner, Aurélien
AU - Cortés-Ciriano, Isidro
AU - Craft, Brian
AU - Craft, David
AU - Creighton, Chad J.
AU - Davidson, Natalie R.
AU - Demircioğlu, Deniz
AU - Erkek, Serap
AU - Fonseca, Nuno A.
AU - Frenkel-Morgenstern, Milana
AU - Goldman, Mary J.
AU - Greger, Liliana
AU - Göke, Jonathan
AU - He, Yao
AU - Hoadley, Katherine A.
AU - Hou, Yong
AU - Huska, Matthew R.
AU - Kahles, Andre
AU - Khurana, Ekta
AU - Kilpinen, Helena
AU - Korbel, Jan O.
AU - Lamaze, Fabien C.
AU - Lehmann, Kjong Van
AU - Li, Chang
AU - Li, Siliang
AU - Li, Xiaobo
AU - Li, Xinyue
AU - Liu, Dongbing
AU - Liu, Fenglin
AU - Liu, Xingmin
AU - Marin, Maximillian G.
AU - Markowski, Julia
AU - Meyerson, Matthew
AU - Nandi, Tannistha
AU - Nielsen, Morten Muhlig
AU - Ojesina, Akinyemi I.
AU - Maruvka, Yosef E.
N1 - Publisher Copyright: © 2020, The Author(s).
PY - 2020/2/5
Y1 - 2020/2/5
N2 - The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.
AB - The impact of somatic structural variants (SVs) on gene expression in cancer is largely unknown. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data and RNA sequencing from a common set of 1220 cancer cases, we report hundreds of genes for which the presence within 100 kb of an SV breakpoint associates with altered expression. For the majority of these genes, expression increases rather than decreases with corresponding breakpoint events. Up-regulated cancer-associated genes impacted by this phenomenon include TERT, MDM2, CDK4, ERBB2, CD274, PDCD1LG2, and IGF2. TERT-associated breakpoints involve ~3% of cases, most frequently in liver biliary, melanoma, sarcoma, stomach, and kidney cancers. SVs associated with up-regulation of PD1 and PDL1 genes involve ~1% of non-amplified cases. For many genes, SVs are significantly associated with increased numbers or greater proximity of enhancer regulatory elements near the gene. DNA methylation near the promoter is often increased with nearby SV breakpoint, which may involve inactivation of repressor elements.
UR - http://www.scopus.com/inward/record.url?scp=85079031729&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-019-13885-w
DO - https://doi.org/10.1038/s41467-019-13885-w
M3 - مقالة
C2 - 32024823
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 736
ER -