Association of SLC15A2 genomic variation with the response to sorafenib treatment: Whole-genome analysis in patients with hepatocellular carcinoma.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 308-308
Author(s):  
Bo Hyun Kim ◽  
Yeon-Su Lee ◽  
Byung Chul Kim ◽  
Aesun Shin ◽  
Jin Sook Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Functional Analysis ◽  
Genome Analysis ◽  
Whole Genome ◽  
Whole Genome Analysis ◽  
Single Nucleotide ◽  
Sorafenib Treatment ◽  
Genomic Variations ◽  
Validation Tests

308 Background: Reliable biomarkers are required to predict patient response to sorafenib. We attempted to investigate genomic variations associated with responsiveness to sorafenib treatment in patients with unresectable hepatocellular carcinoma (HCC) and their functional relevance. Methods: We obtained blood samples from 4 strong and 3 poor responders to sorafenib treatment and subjected these samples to whole-genome analysis. Next, we performed validation tests for candidate single-nucleotide polymorphisms (SNPs) in the samples of 174 HCC patients who were treated with sorafenib, followed by in vitro functional analysis and in silico analyses of candidate SNPs. Results: On average, 90 gigabases/sample was generated at ~34X sequencing depth. In total, 1813 genomic variations were perfectly matched to sorafenib responses in the clinical data; 708 were located within regions for sorafenib-target genes or drug absorption, distribution, metabolism, and excretion (ADME)-related genes—36 within the coding regions and 6 identified as non-synonymous single-nucleotide variants from 4 ADME-related genes (ABCB1, FMO3, MUSK, and SLC15A2), which potentially cause functional alterations. Validation tests of 174 patients confirmed sequencing results and revealed that patients with the C/C genotype for rs2257212 in SCL15A2 displayed higher risk for cancer progression than did patients with C/T or T/T genotypes (HR: 2.18; 95% CI, 1.15–4.15; P = 0.018). In vitro functional analysis revealed that cells harboring C/C genotype for this SNP displayed lower response to sorafenib treatment than did cells harboring the T/T genotype. Structural prediction analysis revealed change in protein phosphorylation levels, potentially affecting sorafenib-associated enzymatic activity. Conclusions: SLC15A2 could be a robust biomarker of response to sorafenib treatment in HCC patients.

Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance

Gut ◽  
2017 ◽  
Vol 67 (7) ◽  
pp. 1328-1341 ◽  
Author(s):  
Peter Dietrich ◽  
Andreas Koch ◽  
Valerie Fritz ◽  
Arndt Hartmann ◽  
Anja Katrin Bosserhoff ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Functional Analysis ◽  
Protein Kinase ◽  
Advanced Hepatocellular Carcinoma ◽  
Wild Type ◽  
Sorafenib Treatment ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Hcc Cells

ObjectiveSorafenib is the only effective therapy for advanced hepatocellular carcinoma (HCC). Combinatory approaches targeting mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)- and phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)/protein-kinase B(AKT) signalling yield major therapeutic improvements. RAS proteins regulate both RAF/MAPK and PI3K/AKT signalling. However, the most important RAS isoform in carcinogenesis, Kirsten rat sarcoma (KRAS), remains unexplored in HCC.DesignHuman HCC tissues and cell lines were used for expression and functional analysis. Sorafenib-resistant HCC cells were newly generated. RNA interference and the novel small molecule deltarasin were used for KRAS inhibition both in vitro and in a murine syngeneic orthotopic HCC model.ResultsExpression of wild type KRAS messenger RNA and protein was increased in HCC and correlated with extracellular-signal regulated kinase (ERK) activation, proliferation rate, advanced tumour size and poor patient survival. Bioinformatic analysis and reporter assays revealed that KRAS is a direct target of microRNA-622. This microRNA was downregulated in HCC, and functional analysis demonstrated that KRAS-suppression is the major mediator of its inhibitory effect on HCC proliferation. KRAS inhibition markedly suppressed RAF/ERK and PI3K/AKT signalling and proliferation and enhanced apoptosis of HCC cells in vitro and in vivo. Combinatory KRAS inhibition and sorafenib treatment revealed synergistic antitumorigenic effects in HCC. Sorafenib-resistant HCC cells showed elevated KRAS expression, and KRAS inhibition resensitised sorafenib-resistant cells to suppression of proliferation and induction of apoptosis.ConclusionsKRAS is dysregulated in HCC by loss of tumour-suppressive microRNA-622, contributing to tumour progression, sorafenib sensitivity and resistance. KRAS inhibition alone or in combination with sorafenib appears as novel promising therapeutic strategy for HCC.

scholarly journals In Vitro Whole-Genome Analysis Identifies a Susceptibility Locus for HIV-1

PLoS Biology ◽  
2008 ◽  
Vol 6 (2) ◽  
pp. e32 ◽  
Author(s):  
Corinne Loeuillet ◽  
Samuel Deutsch ◽  
Angela Ciuffi ◽  
Daniel Robyr ◽  
Patrick Taffé ◽  
...  
Keyword(s):  
Genome Analysis ◽  
Susceptibility Locus ◽  
Whole Genome ◽  
Whole Genome Analysis ◽  
Hiv 1

scholarly journals Defining the Yeast Resistome through in vitro Evolution and Whole Genome Sequencing

2021 ◽  
Author(s):  
Sabine Ottilie ◽  
Madeline R. Luth ◽  
Erich Hellemann ◽  
Gregory M. Goldgof ◽  
Eddy Vigil ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Transcription Factors ◽  
Enrichment Analysis ◽  
Neutral Evolution ◽  
Whole Genome ◽  
Genetic Determinants ◽  
Single Nucleotide Variants ◽  
Whole Genome Analysis ◽  
Single Nucleotide

SummaryIn vitro evolution and whole genome analysis were used to comprehensively identify the genetic determinants of chemical resistance in the model microbe, Saccharomyces cerevisiae. Analysis of 355 curated, laboratory-evolved clones, resistant to 80 different compounds, demonstrates differences in the types of mutations that are identified in selected versus neutral evolution and reveals numerous new, compound-target interactions. Through enrichment analysis we further identify a set of 137 genes strongly associated with or conferring drug resistance as indicated by CRISPR-Cas9 engineering. The set of 25 most frequently mutated genes was enriched for transcription factors and for almost 25 percent of the compounds, resistance was mediated by one of 100 independently derived, gain-of-function, single nucleotide variants found in 170-amino-acid domains in two Zn2C6 transcription factors, YRR1 and YRM1 (p < 1x 10 −100). This remarkable enrichment for transcription factors as drug resistance genes may explain why it is challenging to develop effective antifungal killing agents and highlights their important role in evolution.

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