Decoding complex patterns of genomic rearrangement in hepatocellular carcinoma.
Elucidating the molecular basis of hepatocellular carcinoma (HCC) is crucial to developing targeted diagnostics and therapies for this deadly disease. The landscape of somatic genomic rearrangements (GRs), which can lead to oncogenic gene fusions, remains poorly characterized in HCC. We have predicted 4314 GRs including large-scale insertions, deletions, inversions and translocations based on the whole-genome sequencing data for 88 primary HCC tumor/non-tumor tissues. We identified chromothripsis in 5 HCC genomes (5.7%) recurrently affecting chromosomal arms 1q and 8q. Albumin (ALB) was found to harbor GRs, deactivating mutations and deletions in 10% of cohort. Integrative analysis identified a pattern of paired intra-chromosomal translocations flanking focal amplifications and asymmetrical patterns of copy number variation flanking breakpoints of translocations. Furthermore, we predicted 260 gene fusions which frequently result in aberrant over-expression of the 3' genes in tumors and validated 18 gene fusions, including recurrent fusion (2/88) of ABCB11 and LRP2.
Pfizer Oncology, San Diego, CA, USA.
Julio
J
Fernandez-Banet
Department of Surgery, University of Hong Kong, Hong Kong, China.
Nikki P
NP
Lee
Department of Surgery, University of Hong Kong, Hong Kong, China.
Kin Tak
KT
Chan
BGI-Shenzhen, Shenzhen, China.
Huan
H
Gao
BGI-Shenzhen, Shenzhen, China; Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Xiao
X
Liu
School of Computing, National University of Singapore, Singapore; Computational and Systems Biology, Genome Institute of Singapore, Singapore.
Wing-Kin
WK
Sung
Department of Surgery, University of Hong Kong, Hong Kong, China.
Winnie
W
Tan
Department of Surgery, University of Hong Kong, Hong Kong, China.
Sheung Tat
ST
Fan
Department of Surgery, University of Hong Kong, Hong Kong, China.
Ronnie T
RT
Poon
BGI-Shenzhen, Shenzhen, China.
Shiyong
S
Li
Pfizer Oncology, San Diego, CA, USA.
Keith
K
Ching
Pfizer Oncology, San Diego, CA, USA.
Paul A
PA
Rejto
Pfizer Oncology, San Diego, CA, USA; Asian Cancer Research Group, Inc., Wilmington, DE, USA.
Mao
M
Mao
Pfizer Oncology, San Diego, CA, USA. Electronic address: zhengyan.kan@pfizer.com.
Zhengyan
Z
Kan
D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D015321:Gene Rearrangement; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D014178:Translocation, Genetic
Copy number variation; Genomic rearrangement; Hepatocellular carcinoma; Whole-genome sequencing