TY - JOUR
T1 - High-coverage whole-genome analysis of 1220 cancers reveals hundreds of genes deregulated by rearrangement-mediated cis-regulatory alterations
AU - PCAWG Transcriptome Working Group
AU - PCAWG-Structural Variation Working Group
AU - PCAWG Consortium
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 - Frenkel-Morgenstern, Milana
AU - Akdemir, Kadir C.
AU - Chen, Ken
AU - Akbani, Rehan
AU - Chakravarty, Dimple
AU - Chen, Yiwen
AU - Chong, Zechen
AU - Czerniak, Bogdan
AU - El-Naggar, Adel
AU - Fan, Yu
AU - Futreal, P. Andrew
AU - Gershenwald, Jeffrey E.
AU - Han, Leng
AU - Huse, Jason
AU - von Kalle, Christof
AU - Krishnamurthy, Savitri
AU - Lazar, Alexander J.
AU - Liang, Han
AU - Lu, Yiling
AU - Mills, Gordon B.
AU - Park, Keunchil
AU - Sothi, Sharmila
AU - Sun, Ren X.
AU - Umbricht, Christopher
AU - Van Meir, Erwin G.
AU - Wang, Qi
AU - Wang, Yumeng
AU - Weischenfeldt, Joachim
AU - Yuan, Yuan
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
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.
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U2 - 10.1038/s41467-019-13885-w
DO - 10.1038/s41467-019-13885-w
M3 - Article
C2 - 32024823
AN - SCOPUS:85079031729
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 736
ER -