title: SLC15A2 genomic variation is associated with the extraordinary response of sorafenib treatment: whole-genome analysis in patients with hepatocellular carcinoma.
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 ~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.
authors.affiliation: Cancer Genomics Branch, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Yeon-Su
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Center for Liver Cancer, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Bo Hyun
authors.initials: BH
authors.lastname: Kim
authors.affiliation: The Genomics Institute, Biomedical Engineering, UNIST, Ulsan, Republic of Korea.
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Kim
authors.affiliation: Molecular Epidemiology Branch, National Cancer Center, Goyang, Republic of Korea.|Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Aesun
authors.initials: A
authors.lastname: Shin
authors.affiliation: Liver and Pancreatobiliary Cancer Branch, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Cancer Genomics Branch, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Cancer Genomics Branch, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Jung-Ah
authors.initials: JA
authors.lastname: Hwang
authors.affiliation: Liver and Pancreatobiliary Cancer Branch, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Jung Ahn
authors.initials: JA
authors.lastname: Lee
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Seungyoon
authors.initials: S
authors.lastname: Nam
authors.affiliation: Personal Genomics Institute, Genome Research Foundation, TheragenEtex, Suwon, Republic of Korea.|Theragen Bio Institute, TheragenEtex, Suwon, Republic of Korea.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: The Genomics Institute, Biomedical Engineering, UNIST, Ulsan, Republic of Korea.|Personal Genomics Institute, Genome Research Foundation, TheragenEtex, Suwon, Republic of Korea.
authors.forename: Jong
authors.initials: J
authors.lastname: Bhak
authors.affiliation: Center for Liver Cancer, National Cancer Center, Goyang, Republic of Korea.|Liver and Pancreatobiliary Cancer Branch, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Joong-Won
authors.initials: JW
authors.lastname: Park
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015894:Genome, Human / Q000235:genetics; D005838:Genotype; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D000077157:Sorafenib; D027981:Symporters / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010671:Phenylurea Compounds; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; D009536:Niacinamide; D000077157:Sorafenib
keywords: extraordinary response; genome variations; hepatocellular carcinoma; sorafenib; whole-genome sequencing