The rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals
Glutathione S-transferases (GSTs) detoxify toxic molecules by conjugation with reduced glutathione and regulate cell signaling. Single nucleotide polymorphisms (SNPs) of GST genes have been suggested to affect GST functions and thus to increase the risk of human hepatocellular carcinoma (HCC). As GS...
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| description | Glutathione S-transferases (GSTs) detoxify toxic molecules by conjugation with reduced glutathione and regulate cell signaling. Single nucleotide polymorphisms (SNPs) of GST genes have been suggested to affect GST functions and thus to increase the risk of human hepatocellular carcinoma (HCC). As GSTA1 is expressed in hepatocytes and the rs3957357C>T (TT) SNP is known to downregulate GSTA1 mRNA expression, the aims of this study were: (i) to explore the relationship between the TT SNP in GSTA1 and the occurrence of HCC; (ii) to measure GSTA1 mRNA expression in HCCs. For that purpose, we genotyped non-tumor-tissue-derived DNA from 48 HCC patients and white-blood-cell-derived DNA from 37 healthy individuals by restriction fragment length polymorphism (RFLP). In addition, expression of GSTA1 mRNA was assessed by real-time PCR in 18 matching pairs of HCCs and non-tumor livers. Survival analysis was performed on an annotated microarray dataset containing 247 HCC patients (GSE14520). The GSTA1 TT genotype was more frequent in HCC than in non-HCC patients (27% versus 5%, respectively), suggesting that individuals carrying this genotype could be associated with 2-fold higher risk of developing HCCs (odds ratio = 2.1; p = 0.02). Also, we found that GSTA1 mRNA expression was lower in HCCs than in non-tumor livers. HCCs expressing the highest GSTA1 mRNA levels were the smallest in size (R = -0.67; p = 0.007), expressed the highest levels of liver-enriched genes such as ALB (albumin, R = -0.67; p = 0.007) and COL18A1 (procollagen type XVIII, R = -0.50; p = 0.03) and showed the most favorable disease-free (OR = 0.54; p |
| doi_str_mv | 10.1371/journal.pone.0167543 |
| format | Article |
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Single nucleotide polymorphisms (SNPs) of GST genes have been suggested to affect GST functions and thus to increase the risk of human hepatocellular carcinoma (HCC). As GSTA1 is expressed in hepatocytes and the rs3957357C>T (TT) SNP is known to downregulate GSTA1 mRNA expression, the aims of this study were: (i) to explore the relationship between the TT SNP in GSTA1 and the occurrence of HCC; (ii) to measure GSTA1 mRNA expression in HCCs. For that purpose, we genotyped non-tumor-tissue-derived DNA from 48 HCC patients and white-blood-cell-derived DNA from 37 healthy individuals by restriction fragment length polymorphism (RFLP). In addition, expression of GSTA1 mRNA was assessed by real-time PCR in 18 matching pairs of HCCs and non-tumor livers. Survival analysis was performed on an annotated microarray dataset containing 247 HCC patients (GSE14520). The GSTA1 TT genotype was more frequent in HCC than in non-HCC patients (27% versus 5%, respectively), suggesting that individuals carrying this genotype could be associated with 2-fold higher risk of developing HCCs (odds ratio = 2.1; p = 0.02). Also, we found that GSTA1 mRNA expression was lower in HCCs than in non-tumor livers. HCCs expressing the highest GSTA1 mRNA levels were the smallest in size (R = -0.67; p = 0.007), expressed the highest levels of liver-enriched genes such as ALB (albumin, R = -0.67; p = 0.007) and COL18A1 (procollagen type XVIII, R = -0.50; p = 0.03) and showed the most favorable disease-free (OR = 0.54; p<0.001) and overall (OR = 0.56; p = 0.006) outcomes. Moreover, GSTA1 was found within a 263-gene network involved in well-differentiated hepatocyte functions. In conclusion, HCCs are characterized by two GSTA1 features: the TT SNP and reduced GSTA1 gene expression in a context of hepatocyte de-differentiation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0167543</identifier><identifier>PMID: 27936036</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Bioinformatics ; Biology and Life Sciences ; Blood ; Cancer ; Carcinoma, Hepatocellular - ethnology ; Carcinoma, Hepatocellular - genetics ; Conjugation ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA microarrays ; Enzymes ; Europe ; European Continental Ancestry Group - genetics ; Gene expression ; Gene Expression Profiling - methods ; Gene Expression Profiling - statistics & numerical data ; Gene Expression Regulation, Neoplastic ; Gene Frequency ; Gene Ontology ; Genes ; Genetic Predisposition to Disease - ethnology ; Genetic Predisposition to Disease - genetics ; Genotype ; Genotypes ; Glutathione ; Glutathione Transferase - genetics ; Health sciences ; Hepatocellular carcinoma ; Hepatocytes ; Hepatocytes - metabolism ; Hepatology ; Human health and pathology ; Humans ; Hépatology and Gastroenterology ; Kaplan-Meier Estimate ; Kinases ; Life Sciences ; Linkage Disequilibrium ; Liver ; Liver - metabolism ; Liver cancer ; Liver Neoplasms - ethnology ; Liver Neoplasms - genetics ; Medical laboratories ; Medicine and Health Sciences ; Metabolism ; Patients ; Polymerase Chain Reaction ; Polymorphism ; Polymorphism, Restriction Fragment Length ; Polymorphism, Single Nucleotide ; Procollagen ; Proportional Hazards Models ; Research and Analysis Methods ; Restriction fragment length polymorphism ; Reverse Transcriptase Polymerase Chain Reaction ; Risk ; Risk Factors ; Signaling ; Single-nucleotide polymorphism ; Studies</subject><ispartof>PloS one, 2016-12, Vol.11 (12), p.e0167543</ispartof><rights>2016 Akhdar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2016 Akhdar et al 2016 Akhdar et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5083-b18e0103612c04c596e3927fbe6b69bed9ff6e22116d3d231d98c17d941eac7c3</citedby><cites>FETCH-LOGICAL-c5083-b18e0103612c04c596e3927fbe6b69bed9ff6e22116d3d231d98c17d941eac7c3</cites><orcidid>0000-0001-8786-5741 ; 0000-0002-8522-0445</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147914/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147914/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27936036$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://univ-rennes.hal.science/hal-01439220$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Akhdar, Hanane</creatorcontrib><creatorcontrib>El Shamieh, Said</creatorcontrib><creatorcontrib>Musso, Orlando</creatorcontrib><creatorcontrib>Désert, Romain</creatorcontrib><creatorcontrib>Joumaa, Wissam</creatorcontrib><creatorcontrib>Guyader, Dominique</creatorcontrib><creatorcontrib>Aninat, Caroline</creatorcontrib><creatorcontrib>Corlu, Anne</creatorcontrib><creatorcontrib>Morel, Fabrice</creatorcontrib><title>The rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Glutathione S-transferases (GSTs) detoxify toxic molecules by conjugation with reduced glutathione and regulate cell signaling. Single nucleotide polymorphisms (SNPs) of GST genes have been suggested to affect GST functions and thus to increase the risk of human hepatocellular carcinoma (HCC). As GSTA1 is expressed in hepatocytes and the rs3957357C>T (TT) SNP is known to downregulate GSTA1 mRNA expression, the aims of this study were: (i) to explore the relationship between the TT SNP in GSTA1 and the occurrence of HCC; (ii) to measure GSTA1 mRNA expression in HCCs. For that purpose, we genotyped non-tumor-tissue-derived DNA from 48 HCC patients and white-blood-cell-derived DNA from 37 healthy individuals by restriction fragment length polymorphism (RFLP). In addition, expression of GSTA1 mRNA was assessed by real-time PCR in 18 matching pairs of HCCs and non-tumor livers. Survival analysis was performed on an annotated microarray dataset containing 247 HCC patients (GSE14520). The GSTA1 TT genotype was more frequent in HCC than in non-HCC patients (27% versus 5%, respectively), suggesting that individuals carrying this genotype could be associated with 2-fold higher risk of developing HCCs (odds ratio = 2.1; p = 0.02). Also, we found that GSTA1 mRNA expression was lower in HCCs than in non-tumor livers. HCCs expressing the highest GSTA1 mRNA levels were the smallest in size (R = -0.67; p = 0.007), expressed the highest levels of liver-enriched genes such as ALB (albumin, R = -0.67; p = 0.007) and COL18A1 (procollagen type XVIII, R = -0.50; p = 0.03) and showed the most favorable disease-free (OR = 0.54; p<0.001) and overall (OR = 0.56; p = 0.006) outcomes. Moreover, GSTA1 was found within a 263-gene network involved in well-differentiated hepatocyte functions. In conclusion, HCCs are characterized by two GSTA1 features: the TT SNP and reduced GSTA1 gene expression in a context of hepatocyte de-differentiation.</description><subject>Bioinformatics</subject><subject>Biology and Life Sciences</subject><subject>Blood</subject><subject>Cancer</subject><subject>Carcinoma, Hepatocellular - ethnology</subject><subject>Carcinoma, Hepatocellular - genetics</subject><subject>Conjugation</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA microarrays</subject><subject>Enzymes</subject><subject>Europe</subject><subject>European Continental Ancestry Group - genetics</subject><subject>Gene expression</subject><subject>Gene Expression Profiling - methods</subject><subject>Gene Expression Profiling - statistics & numerical data</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Frequency</subject><subject>Gene Ontology</subject><subject>Genes</subject><subject>Genetic Predisposition to Disease - ethnology</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Genotype</subject><subject>Genotypes</subject><subject>Glutathione</subject><subject>Glutathione Transferase - genetics</subject><subject>Health sciences</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatocytes</subject><subject>Hepatocytes - metabolism</subject><subject>Hepatology</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>Hépatology and Gastroenterology</subject><subject>Kaplan-Meier Estimate</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Linkage Disequilibrium</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - ethnology</subject><subject>Liver Neoplasms - genetics</subject><subject>Medical laboratories</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Patients</subject><subject>Polymerase Chain Reaction</subject><subject>Polymorphism</subject><subject>Polymorphism, Restriction Fragment Length</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Procollagen</subject><subject>Proportional Hazards Models</subject><subject>Research and Analysis Methods</subject><subject>Restriction fragment length polymorphism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Risk</subject><subject>Risk Factors</subject><subject>Signaling</subject><subject>Single-nucleotide 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rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals</title><author>Akhdar, Hanane ; El Shamieh, Said ; Musso, Orlando ; Désert, Romain ; Joumaa, Wissam ; Guyader, Dominique ; Aninat, Caroline ; Corlu, Anne ; Morel, Fabrice</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5083-b18e0103612c04c596e3927fbe6b69bed9ff6e22116d3d231d98c17d941eac7c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Bioinformatics</topic><topic>Biology and Life Sciences</topic><topic>Blood</topic><topic>Cancer</topic><topic>Carcinoma, Hepatocellular - ethnology</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Conjugation</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>DNA microarrays</topic><topic>Enzymes</topic><topic>Europe</topic><topic>European Continental 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Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Akhdar, Hanane</au><au>El Shamieh, Said</au><au>Musso, Orlando</au><au>Désert, Romain</au><au>Joumaa, Wissam</au><au>Guyader, Dominique</au><au>Aninat, Caroline</au><au>Corlu, Anne</au><au>Morel, Fabrice</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-12-01</date><risdate>2016</risdate><volume>11</volume><issue>12</issue><spage>e0167543</spage><pages>e0167543-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Glutathione S-transferases (GSTs) detoxify toxic molecules by conjugation with reduced glutathione and regulate cell signaling. Single nucleotide polymorphisms (SNPs) of GST genes have been suggested to affect GST functions and thus to increase the risk of human hepatocellular carcinoma (HCC). As GSTA1 is expressed in hepatocytes and the rs3957357C>T (TT) SNP is known to downregulate GSTA1 mRNA expression, the aims of this study were: (i) to explore the relationship between the TT SNP in GSTA1 and the occurrence of HCC; (ii) to measure GSTA1 mRNA expression in HCCs. For that purpose, we genotyped non-tumor-tissue-derived DNA from 48 HCC patients and white-blood-cell-derived DNA from 37 healthy individuals by restriction fragment length polymorphism (RFLP). In addition, expression of GSTA1 mRNA was assessed by real-time PCR in 18 matching pairs of HCCs and non-tumor livers. Survival analysis was performed on an annotated microarray dataset containing 247 HCC patients (GSE14520). The GSTA1 TT genotype was more frequent in HCC than in non-HCC patients (27% versus 5%, respectively), suggesting that individuals carrying this genotype could be associated with 2-fold higher risk of developing HCCs (odds ratio = 2.1; p = 0.02). Also, we found that GSTA1 mRNA expression was lower in HCCs than in non-tumor livers. HCCs expressing the highest GSTA1 mRNA levels were the smallest in size (R = -0.67; p = 0.007), expressed the highest levels of liver-enriched genes such as ALB (albumin, R = -0.67; p = 0.007) and COL18A1 (procollagen type XVIII, R = -0.50; p = 0.03) and showed the most favorable disease-free (OR = 0.54; p<0.001) and overall (OR = 0.56; p = 0.006) outcomes. Moreover, GSTA1 was found within a 263-gene network involved in well-differentiated hepatocyte functions. In conclusion, HCCs are characterized by two GSTA1 features: the TT SNP and reduced GSTA1 gene expression in a context of hepatocyte de-differentiation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27936036</pmid><doi>10.1371/journal.pone.0167543</doi><orcidid>https://orcid.org/0000-0001-8786-5741</orcidid><orcidid>https://orcid.org/0000-0002-8522-0445</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-12, Vol.11 (12), p.e0167543 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1847562464 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Bioinformatics Biology and Life Sciences Blood Cancer Carcinoma, Hepatocellular - ethnology Carcinoma, Hepatocellular - genetics Conjugation Deoxyribonucleic acid DNA DNA methylation DNA microarrays Enzymes Europe European Continental Ancestry Group - genetics Gene expression Gene Expression Profiling - methods Gene Expression Profiling - statistics & numerical data Gene Expression Regulation, Neoplastic Gene Frequency Gene Ontology Genes Genetic Predisposition to Disease - ethnology Genetic Predisposition to Disease - genetics Genotype Genotypes Glutathione Glutathione Transferase - genetics Health sciences Hepatocellular carcinoma Hepatocytes Hepatocytes - metabolism Hepatology Human health and pathology Humans Hépatology and Gastroenterology Kaplan-Meier Estimate Kinases Life Sciences Linkage Disequilibrium Liver Liver - metabolism Liver cancer Liver Neoplasms - ethnology Liver Neoplasms - genetics Medical laboratories Medicine and Health Sciences Metabolism Patients Polymerase Chain Reaction Polymorphism Polymorphism, Restriction Fragment Length Polymorphism, Single Nucleotide Procollagen Proportional Hazards Models Research and Analysis Methods Restriction fragment length polymorphism Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Signaling Single-nucleotide polymorphism Studies |
| title | The rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals |
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