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Author

Bhak, Jong
The Genomics Institute of UNIST (TGI)
Research Interests
  • Geromics, genomics, bioinformatics, protein Engineering, OMICS

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SLC15A2 genomic variation is associated with the extraordinary response of sorafenib treatment: whole-genome analysis in patients with hepatocellular carcinoma

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Title
SLC15A2 genomic variation is associated with the extraordinary response of sorafenib treatment: whole-genome analysis in patients with hepatocellular carcinoma
Author
Lee, Yeon-SuKim, Bo HyunKim, Byung ChulShin, AesunKim, Jin SookHong, Seung-HyunHwang, Jung-AhLee, Jung AhnNam, SeungyoonLee, Sung HoonBhak, Jong HwaPark, Joong-Won
Keywords
hepatocellular carcinoma; extraordinary response; sorafenib; whole-genome sequencing; genome variations
Issue Date
201506
Publisher
IMPACT JOURNALS LLC
Citation
ONCOTARGET, v.6, no.18, pp.16449 - 16460
Abstract
Reliable biomarkers are required to predict the response to sorafenib. We investigated genomic variations associated with responsiveness to sorafenib for patients with unresectable hepatocellular carcinoma (HCC). Blood samples from 2 extreme, 2 strong and 3 poor responders to sorafenib were subjected to whole-genome analysis. Then, we validated candidate genomic variations with another 174 HCC patients, and performed in vitro functional analysis and in silico analyses. Genomic data of > 96 gigabases/sample was generated at average of similar to 34X sequencing depth. In total, 1813 genomic variations were matched to sorafenib responses in clinical data; 708 were located within regions for sorafenib-target genes or drug absorption, distribution, metabolism, and excretion (ADME)-related genes. From them, 36 variants were within the coding regions and 6 identified as non-synonymous single-nucleotide variants from 4 ADME-related genes (ABCB1, FMO3, MUSK, and SLC15A2). Validation genotyping confirmed sequencing results and revealed patients genotype for rs2257212 in SLC15A2 showed longer progression-free survival (HR = 2.18). In vitro study displayed different response to sorafenib depending on the genotype of SLC15A2. Structural prediction analysis revealed changes of the phosphorylation levels in protein, potentially affecting sorafenib-associated enzymatic activity. Our finding using extreme responder seems to generate robust biomarker to predict the response of sorafenib treatment for HCC
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DOI
http://dx.doi.org/10.18632/oncotarget.3758
ISSN
1949-2553
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SLS_Journal Papers
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