SLC15A2 genomic variation is associated with the extraordinary response of sorafenib treatment: whole-genome analysis in patients with hepatocellular carcinoma
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Yeon-Su Lee1,*, Bo Hyun Kim2,*, Byung Chul Kim3,*, Aesun Shin4,9, Jin Sook Kim5, Seung-Hyun Hong1, Jung-Ah Hwang1, Jung Ahn Lee5, Seungyoon Nam6, Sung Hoon Lee7,8, Jong Bhak3,7, Joong-Won Park2,5
1Cancer Genomics Branch, National Cancer Center, Goyang, Republic of Korea
2Center for Liver Cancer, National Cancer Center, Goyang, Republic of Korea
3The Genomics Institute, Biomedical Engineering, UNIST, Ulsan, Republic of Korea
4Molecular Epidemiology Branch, National Cancer Center, Goyang, Republic of Korea
5Liver and Pancreatobiliary Cancer Branch, National Cancer Center, Goyang, Republic of Korea
6New Experimental Therapeutics Branch, National Cancer Center, Goyang, Republic of Korea
7Personal Genomics Institute, Genome Research Foundation, TheragenEtex, Suwon, Republic of Korea
8Theragen Bio Institute, TheragenEtex, Suwon, Republic of Korea
9Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
*These authors have contributed equally to this work
Joong-Won Park, e-mail: email@example.com
Keywords: hepatocellular carcinoma, extraordinary response, sorafenib, whole-genome sequencing, genome variations
Received: December 10, 2014 Accepted: April 10, 2015 Published: April 22, 2015
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 ~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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