MTHFR Glu429Ala and ERCC5 His46His polymorphisms are associated with prognosis in colorectal cancer patients: analysis of two independent cohorts from Newfoundland
In this study, 27 genetic polymorphisms that were previously reported to be associated with clinical outcomes in colorectal cancer patients were investigated in relation to overall survival (OS) and disease free survival (DFS) in colorectal cancer patients from Newfoundland. The discovery and valida...
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| Veröffentlicht in: | PloS one 2013-04, Vol.8 (4), p.e61469 |
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| creator | Negandhi, Amit A Hyde, Angela Dicks, Elizabeth Pollett, William Younghusband, Banfield H Parfrey, Patrick Green, Roger C Savas, Sevtap |
| description | In this study, 27 genetic polymorphisms that were previously reported to be associated with clinical outcomes in colorectal cancer patients were investigated in relation to overall survival (OS) and disease free survival (DFS) in colorectal cancer patients from Newfoundland.
The discovery and validation cohorts comprised of 532 and 252 patients, respectively. Genotypes of 27 polymorphisms were first obtained in the discovery cohort and survival analyses were performed assuming the co-dominant genetic model. Polymorphisms associated with disease outcomes in the discovery cohort were then investigated in the validation cohort.
When adjusted for sex, age, tumor stage and microsatellite instability (MSI) status, four polymorphisms were independent predictors of OS in the discovery cohort MTHFR Glu429Ala (HR: 1.72, 95%CI: 1.04-2.84, p = 0.036), ERCC5 His46His (HR: 1.78, 95%CI: 1.15-2.76, p = 0.01), SERPINE1 -675indelG (HR: 0.52, 95%CI: 0.32-0.84, p = 0.008), and the homozygous deletion of GSTM1 gene (HR: 1.4, 95%CI: 1.03-1.92, p = 0.033). In the validation cohort, the MTHFR Glu429Ala polymorphism was associated with shorter OS (HR: 1.71, 95%CI: 1.18-2.49, p = 0.005), although with a different genotype than the discovery cohort (CC genotype in the discovery cohort and AC genotype in the validation cohort). When stratified based on treatment with 5-Fluorouracil (5-FU)-based regimens, this polymorphism was associated with reduced OS only in patients not treated with 5-FU. In the DFS analysis, when adjusted for other variables, the TT genotype of the ERCC5 His46His polymorphism was associated with shorter DFS in both cohorts (discovery cohort: HR: 1.54, 95%CI: 1.04-2.29, p = 0.032 and replication cohort: HR: 1.81, 95%CI: 1.11-2.94, p = 0.018).
In this study, associations of the MTHFR Glu429Ala polymorphism with OS and the ERCC5 His46His polymorphism with DFS were identified in two colorectal cancer patient cohorts. Our results also suggest that the MTHFR Glu429Ala polymorphism may be an adverse prognostic marker in patients not treated with 5-FU. |
| doi_str_mv | 10.1371/journal.pone.0061469 |
| format | Article |
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The discovery and validation cohorts comprised of 532 and 252 patients, respectively. Genotypes of 27 polymorphisms were first obtained in the discovery cohort and survival analyses were performed assuming the co-dominant genetic model. Polymorphisms associated with disease outcomes in the discovery cohort were then investigated in the validation cohort.
When adjusted for sex, age, tumor stage and microsatellite instability (MSI) status, four polymorphisms were independent predictors of OS in the discovery cohort MTHFR Glu429Ala (HR: 1.72, 95%CI: 1.04-2.84, p = 0.036), ERCC5 His46His (HR: 1.78, 95%CI: 1.15-2.76, p = 0.01), SERPINE1 -675indelG (HR: 0.52, 95%CI: 0.32-0.84, p = 0.008), and the homozygous deletion of GSTM1 gene (HR: 1.4, 95%CI: 1.03-1.92, p = 0.033). In the validation cohort, the MTHFR Glu429Ala polymorphism was associated with shorter OS (HR: 1.71, 95%CI: 1.18-2.49, p = 0.005), although with a different genotype than the discovery cohort (CC genotype in the discovery cohort and AC genotype in the validation cohort). When stratified based on treatment with 5-Fluorouracil (5-FU)-based regimens, this polymorphism was associated with reduced OS only in patients not treated with 5-FU. In the DFS analysis, when adjusted for other variables, the TT genotype of the ERCC5 His46His polymorphism was associated with shorter DFS in both cohorts (discovery cohort: HR: 1.54, 95%CI: 1.04-2.29, p = 0.032 and replication cohort: HR: 1.81, 95%CI: 1.11-2.94, p = 0.018).
In this study, associations of the MTHFR Glu429Ala polymorphism with OS and the ERCC5 His46His polymorphism with DFS were identified in two colorectal cancer patient cohorts. Our results also suggest that the MTHFR Glu429Ala polymorphism may be an adverse prognostic marker in patients not treated with 5-FU.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0061469</identifier><identifier>PMID: 23626689</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>5-Fluorouracil ; Adult ; Aged ; Amino Acid Substitution ; Analysis ; Antimetabolites, Antineoplastic - therapeutic use ; Binding sites ; Biology ; Cancer ; Cancer patients ; Cancer research ; Chemotherapy ; Cohort Studies ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - diagnosis ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - mortality ; Committees ; Deoxyribonucleic acid ; DNA ; DNA-Binding Proteins - genetics ; Endonucleases - genetics ; Epidemiology ; Female ; Fluorouracil - therapeutic use ; Gene deletion ; Gene expression ; Gene polymorphism ; Genes ; Genetic aspects ; Genetic polymorphisms ; Genetics ; Genotype ; Genotypes ; GSTM1 gene ; GSTM1 protein ; Humans ; Lung cancer ; Male ; Medical prognosis ; Medicine ; Metastasis ; Methylenetetrahydrofolate reductase ; Methylenetetrahydrofolate Reductase (NADPH2) - genetics ; Microsatellite instability ; Middle Aged ; Mortality ; Mutation ; Neoplasm Proteins - genetics ; Newfoundland and Labrador ; Nuclear Proteins - genetics ; Patients ; Polymorphism ; Polymorphism, Genetic ; Prognosis ; Stability ; Survival ; Survival Analysis ; Transcription Factors - genetics ; Tumors ; Vascular endothelial growth factor</subject><ispartof>PloS one, 2013-04, Vol.8 (4), p.e61469</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Negandhi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://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>2013 Negandhi et al 2013 Negandhi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-a153d352b185a1eeb5654bfebc5afbf672f604f3c0d47f740b3c630123ae90de3</citedby><cites>FETCH-LOGICAL-c692t-a153d352b185a1eeb5654bfebc5afbf672f604f3c0d47f740b3c630123ae90de3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634085/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634085/$$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/23626689$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Negandhi, Amit A</creatorcontrib><creatorcontrib>Hyde, Angela</creatorcontrib><creatorcontrib>Dicks, Elizabeth</creatorcontrib><creatorcontrib>Pollett, William</creatorcontrib><creatorcontrib>Younghusband, Banfield H</creatorcontrib><creatorcontrib>Parfrey, Patrick</creatorcontrib><creatorcontrib>Green, Roger C</creatorcontrib><creatorcontrib>Savas, Sevtap</creatorcontrib><title>MTHFR Glu429Ala and ERCC5 His46His polymorphisms are associated with prognosis in colorectal cancer patients: analysis of two independent cohorts from Newfoundland</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>In this study, 27 genetic polymorphisms that were previously reported to be associated with clinical outcomes in colorectal cancer patients were investigated in relation to overall survival (OS) and disease free survival (DFS) in colorectal cancer patients from Newfoundland.
The discovery and validation cohorts comprised of 532 and 252 patients, respectively. Genotypes of 27 polymorphisms were first obtained in the discovery cohort and survival analyses were performed assuming the co-dominant genetic model. Polymorphisms associated with disease outcomes in the discovery cohort were then investigated in the validation cohort.
When adjusted for sex, age, tumor stage and microsatellite instability (MSI) status, four polymorphisms were independent predictors of OS in the discovery cohort MTHFR Glu429Ala (HR: 1.72, 95%CI: 1.04-2.84, p = 0.036), ERCC5 His46His (HR: 1.78, 95%CI: 1.15-2.76, p = 0.01), SERPINE1 -675indelG (HR: 0.52, 95%CI: 0.32-0.84, p = 0.008), and the homozygous deletion of GSTM1 gene (HR: 1.4, 95%CI: 1.03-1.92, p = 0.033). In the validation cohort, the MTHFR Glu429Ala polymorphism was associated with shorter OS (HR: 1.71, 95%CI: 1.18-2.49, p = 0.005), although with a different genotype than the discovery cohort (CC genotype in the discovery cohort and AC genotype in the validation cohort). When stratified based on treatment with 5-Fluorouracil (5-FU)-based regimens, this polymorphism was associated with reduced OS only in patients not treated with 5-FU. In the DFS analysis, when adjusted for other variables, the TT genotype of the ERCC5 His46His polymorphism was associated with shorter DFS in both cohorts (discovery cohort: HR: 1.54, 95%CI: 1.04-2.29, p = 0.032 and replication cohort: HR: 1.81, 95%CI: 1.11-2.94, p = 0.018).
In this study, associations of the MTHFR Glu429Ala polymorphism with OS and the ERCC5 His46His polymorphism with DFS were identified in two colorectal cancer patient cohorts. Our results also suggest that the MTHFR Glu429Ala polymorphism may be an adverse prognostic marker in patients not treated with 5-FU.</description><subject>5-Fluorouracil</subject><subject>Adult</subject><subject>Aged</subject><subject>Amino Acid Substitution</subject><subject>Analysis</subject><subject>Antimetabolites, Antineoplastic - therapeutic use</subject><subject>Binding sites</subject><subject>Biology</subject><subject>Cancer</subject><subject>Cancer patients</subject><subject>Cancer research</subject><subject>Chemotherapy</subject><subject>Cohort Studies</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - diagnosis</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - mortality</subject><subject>Committees</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Endonucleases - genetics</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Fluorouracil - therapeutic use</subject><subject>Gene deletion</subject><subject>Gene expression</subject><subject>Gene polymorphism</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic polymorphisms</subject><subject>Genetics</subject><subject>Genotype</subject><subject>Genotypes</subject><subject>GSTM1 gene</subject><subject>GSTM1 protein</subject><subject>Humans</subject><subject>Lung cancer</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Metastasis</subject><subject>Methylenetetrahydrofolate reductase</subject><subject>Methylenetetrahydrofolate Reductase (NADPH2) - genetics</subject><subject>Microsatellite instability</subject><subject>Middle Aged</subject><subject>Mortality</subject><subject>Mutation</subject><subject>Neoplasm Proteins - genetics</subject><subject>Newfoundland and Labrador</subject><subject>Nuclear Proteins - genetics</subject><subject>Patients</subject><subject>Polymorphism</subject><subject>Polymorphism, Genetic</subject><subject>Prognosis</subject><subject>Stability</subject><subject>Survival</subject><subject>Survival Analysis</subject><subject>Transcription Factors - genetics</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk-1qFDEYhQdRbK3egWhAEPyxazL5mB1_CMvSj4VqoVb_hncyyW5KZjImGddejzdq1m5LFxQkkITkOScvh7xF8ZLgKaEVeX_tx9CDmw6-11OMBWGiflQckpqWE1Fi-vjB_qB4FuM1xpzOhHhaHJRUlELM6sPi16ers5NLdOpGVtZzBwj6Fh1fLhYcndnIRJ7Q4N1N58OwtrGLCIJGEKNXFpJu0camNRqCX_U-Ztb2SHnng1YJHFLQKx3QAMnqPsUP2R3czZbzBqWNz3irB52nPmXd2ocUkQm-Q5_1xvixb12u53nxxICL-sVuPSq-nhxfLc4m5xeny8X8fKJEXaYJEE5bysuGzDgQrRsuOGuMbhQH0xhRlUZgZqjCLatMxXBDlaCYlBR0jVtNj4rXt76D81Hu8o2SUCZ4zepaZGJ5S7QeruUQbAfhRnqw8s-BDysJIVnltMRYk1JXDeGMMpjRmmgMFXDVVqbBjGSvj7vXxqbTrcoRBHB7pvs3vV3Llf8hqaAMz3g2eLMzCP77qGP6R8k7agW5Ktsbn81UZ6OSc1bNCC8Z23pN_0Ll0erOqvzDjM3ne4J3e4LMJP0zrWCMUS6_XP4_e_Ftn337gF1rcGkdvRuT9X3cB9ktqIKPMWhznxzBctsgd2nIbYPIXYNk2auHqd-L7jqC_gbW4w1q</recordid><startdate>20130423</startdate><enddate>20130423</enddate><creator>Negandhi, Amit A</creator><creator>Hyde, Angela</creator><creator>Dicks, Elizabeth</creator><creator>Pollett, William</creator><creator>Younghusband, Banfield H</creator><creator>Parfrey, Patrick</creator><creator>Green, Roger C</creator><creator>Savas, Sevtap</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130423</creationdate><title>MTHFR Glu429Ala and ERCC5 His46His polymorphisms are associated with prognosis in colorectal cancer patients: analysis of two independent cohorts from Newfoundland</title><author>Negandhi, Amit A ; Hyde, Angela ; Dicks, Elizabeth ; Pollett, William ; Younghusband, Banfield H ; Parfrey, Patrick ; Green, Roger C ; Savas, Sevtap</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-a153d352b185a1eeb5654bfebc5afbf672f604f3c0d47f740b3c630123ae90de3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>5-Fluorouracil</topic><topic>Adult</topic><topic>Aged</topic><topic>Amino Acid Substitution</topic><topic>Analysis</topic><topic>Antimetabolites, Antineoplastic - therapeutic use</topic><topic>Binding sites</topic><topic>Biology</topic><topic>Cancer</topic><topic>Cancer patients</topic><topic>Cancer research</topic><topic>Chemotherapy</topic><topic>Cohort Studies</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms - diagnosis</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - mortality</topic><topic>Committees</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA-Binding Proteins - genetics</topic><topic>Endonucleases - genetics</topic><topic>Epidemiology</topic><topic>Female</topic><topic>Fluorouracil - therapeutic use</topic><topic>Gene deletion</topic><topic>Gene expression</topic><topic>Gene polymorphism</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic polymorphisms</topic><topic>Genetics</topic><topic>Genotype</topic><topic>Genotypes</topic><topic>GSTM1 gene</topic><topic>GSTM1 protein</topic><topic>Humans</topic><topic>Lung cancer</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Metastasis</topic><topic>Methylenetetrahydrofolate reductase</topic><topic>Methylenetetrahydrofolate Reductase (NADPH2) - genetics</topic><topic>Microsatellite instability</topic><topic>Middle Aged</topic><topic>Mortality</topic><topic>Mutation</topic><topic>Neoplasm Proteins - genetics</topic><topic>Newfoundland and Labrador</topic><topic>Nuclear Proteins - genetics</topic><topic>Patients</topic><topic>Polymorphism</topic><topic>Polymorphism, Genetic</topic><topic>Prognosis</topic><topic>Stability</topic><topic>Survival</topic><topic>Survival Analysis</topic><topic>Transcription Factors - genetics</topic><topic>Tumors</topic><topic>Vascular endothelial growth factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Negandhi, Amit A</creatorcontrib><creatorcontrib>Hyde, Angela</creatorcontrib><creatorcontrib>Dicks, Elizabeth</creatorcontrib><creatorcontrib>Pollett, William</creatorcontrib><creatorcontrib>Younghusband, Banfield H</creatorcontrib><creatorcontrib>Parfrey, Patrick</creatorcontrib><creatorcontrib>Green, Roger C</creatorcontrib><creatorcontrib>Savas, Sevtap</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</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>Negandhi, Amit A</au><au>Hyde, Angela</au><au>Dicks, Elizabeth</au><au>Pollett, William</au><au>Younghusband, Banfield H</au><au>Parfrey, Patrick</au><au>Green, Roger C</au><au>Savas, Sevtap</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MTHFR Glu429Ala and ERCC5 His46His polymorphisms are associated with prognosis in colorectal cancer patients: analysis of two independent cohorts from Newfoundland</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-04-23</date><risdate>2013</risdate><volume>8</volume><issue>4</issue><spage>e61469</spage><pages>e61469-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>In this study, 27 genetic polymorphisms that were previously reported to be associated with clinical outcomes in colorectal cancer patients were investigated in relation to overall survival (OS) and disease free survival (DFS) in colorectal cancer patients from Newfoundland.
The discovery and validation cohorts comprised of 532 and 252 patients, respectively. Genotypes of 27 polymorphisms were first obtained in the discovery cohort and survival analyses were performed assuming the co-dominant genetic model. Polymorphisms associated with disease outcomes in the discovery cohort were then investigated in the validation cohort.
When adjusted for sex, age, tumor stage and microsatellite instability (MSI) status, four polymorphisms were independent predictors of OS in the discovery cohort MTHFR Glu429Ala (HR: 1.72, 95%CI: 1.04-2.84, p = 0.036), ERCC5 His46His (HR: 1.78, 95%CI: 1.15-2.76, p = 0.01), SERPINE1 -675indelG (HR: 0.52, 95%CI: 0.32-0.84, p = 0.008), and the homozygous deletion of GSTM1 gene (HR: 1.4, 95%CI: 1.03-1.92, p = 0.033). In the validation cohort, the MTHFR Glu429Ala polymorphism was associated with shorter OS (HR: 1.71, 95%CI: 1.18-2.49, p = 0.005), although with a different genotype than the discovery cohort (CC genotype in the discovery cohort and AC genotype in the validation cohort). When stratified based on treatment with 5-Fluorouracil (5-FU)-based regimens, this polymorphism was associated with reduced OS only in patients not treated with 5-FU. In the DFS analysis, when adjusted for other variables, the TT genotype of the ERCC5 His46His polymorphism was associated with shorter DFS in both cohorts (discovery cohort: HR: 1.54, 95%CI: 1.04-2.29, p = 0.032 and replication cohort: HR: 1.81, 95%CI: 1.11-2.94, p = 0.018).
In this study, associations of the MTHFR Glu429Ala polymorphism with OS and the ERCC5 His46His polymorphism with DFS were identified in two colorectal cancer patient cohorts. Our results also suggest that the MTHFR Glu429Ala polymorphism may be an adverse prognostic marker in patients not treated with 5-FU.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23626689</pmid><doi>10.1371/journal.pone.0061469</doi><tpages>e61469</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-04, Vol.8 (4), p.e61469 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1346594996 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 5-Fluorouracil Adult Aged Amino Acid Substitution Analysis Antimetabolites, Antineoplastic - therapeutic use Binding sites Biology Cancer Cancer patients Cancer research Chemotherapy Cohort Studies Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - diagnosis Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - mortality Committees Deoxyribonucleic acid DNA DNA-Binding Proteins - genetics Endonucleases - genetics Epidemiology Female Fluorouracil - therapeutic use Gene deletion Gene expression Gene polymorphism Genes Genetic aspects Genetic polymorphisms Genetics Genotype Genotypes GSTM1 gene GSTM1 protein Humans Lung cancer Male Medical prognosis Medicine Metastasis Methylenetetrahydrofolate reductase Methylenetetrahydrofolate Reductase (NADPH2) - genetics Microsatellite instability Middle Aged Mortality Mutation Neoplasm Proteins - genetics Newfoundland and Labrador Nuclear Proteins - genetics Patients Polymorphism Polymorphism, Genetic Prognosis Stability Survival Survival Analysis Transcription Factors - genetics Tumors Vascular endothelial growth factor |
| title | MTHFR Glu429Ala and ERCC5 His46His polymorphisms are associated with prognosis in colorectal cancer patients: analysis of two independent cohorts from Newfoundland |
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