Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants
Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivo...
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| Veröffentlicht in: | European journal of cancer (1990) 2020-01, Vol.124, p.56-63 |
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| creator | Summers, Matthew G. Maughan, Timothy S. Kaplan, Richard Law, Philip J. Houlston, Richard S. Escott-Price, Valentina Cheadle, Jeremy P. |
| description | Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship.
For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN–B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10−4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival.
Univariate analysis identified six SNPs associated with overall survival (OS) (P |
| doi_str_mv | 10.1016/j.ejca.2019.09.024 |
| format | Article |
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For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN–B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10−4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival.
Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21–1.71, P = 5.0 × 10−5). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13–1.34, P = 1.9 × 10−6). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42–0.87, P = 6.6 × 10−3). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses.
The CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker.
•Analysed 83 colorectal cancer (CRC)-risk loci in 1948 patients with advanced CRC for prognostic outcome.•CDH1 variants were highly associated with overall survival in multivariate analysis.•Patients with rs12597188 minor alleles had a decrease in life expectancy of 5 months.•rs12597188 was also associated with poor response to therapy.•CDH1 (E-cadherin) involved in epithelial to mesenchymal transition during metastasis.</description><identifier>ISSN: 0959-8049</identifier><identifier>EISSN: 1879-0852</identifier><identifier>DOI: 10.1016/j.ejca.2019.09.024</identifier><identifier>PMID: 31734605</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Aged ; Aged, 80 and over ; Antigens, CD - genetics ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biomarkers ; Biomarkers, Tumor - genetics ; Cadherins - genetics ; Cancer ; CDH1 ; Chemotherapy ; Clinical trials ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - mortality ; Confidence intervals ; Design of experiments ; Drug Resistance ; Drug Resistance, Neoplasm - genetics ; E-cadherin ; Experimental design ; Female ; Follow-Up Studies ; Gene mapping ; Genetic Loci ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Health risks ; Humans ; Loci ; Male ; Mapping ; Medical prognosis ; Middle Aged ; Monoclonal antibodies ; Nucleotides ; Oxaliplatin ; Polymorphism, Single Nucleotide ; Prognosis ; Prognostic biomarker ; Progression-Free Survival ; Risk Assessment ; Risk loci ; Single-nucleotide polymorphism ; Survival ; Survival Analysis ; Targeted cancer therapy</subject><ispartof>European journal of cancer (1990), 2020-01, Vol.124, p.56-63</ispartof><rights>2019 Elsevier Ltd</rights><rights>Copyright © 2019 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Science Ltd. Jan 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-c5ff7aca663fca82747c7e41201c09ab2a77869c2c3c9aff16aa4dc74468734d3</citedby><cites>FETCH-LOGICAL-c428t-c5ff7aca663fca82747c7e41201c09ab2a77869c2c3c9aff16aa4dc74468734d3</cites><orcidid>0000-0001-6387-124X ; 0000-0001-9453-8458</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0959804919307476$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31734605$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Summers, Matthew G.</creatorcontrib><creatorcontrib>Maughan, Timothy S.</creatorcontrib><creatorcontrib>Kaplan, Richard</creatorcontrib><creatorcontrib>Law, Philip J.</creatorcontrib><creatorcontrib>Houlston, Richard S.</creatorcontrib><creatorcontrib>Escott-Price, Valentina</creatorcontrib><creatorcontrib>Cheadle, Jeremy P.</creatorcontrib><title>Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants</title><title>European journal of cancer (1990)</title><addtitle>Eur J Cancer</addtitle><description>Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship.
For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN–B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10−4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival.
Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21–1.71, P = 5.0 × 10−5). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13–1.34, P = 1.9 × 10−6). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42–0.87, P = 6.6 × 10−3). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses.
The CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker.
•Analysed 83 colorectal cancer (CRC)-risk loci in 1948 patients with advanced CRC for prognostic outcome.•CDH1 variants were highly associated with overall survival in multivariate analysis.•Patients with rs12597188 minor alleles had a decrease in life expectancy of 5 months.•rs12597188 was also associated with poor response to therapy.•CDH1 (E-cadherin) involved in epithelial to mesenchymal transition during metastasis.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antigens, CD - genetics</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Cadherins - genetics</subject><subject>Cancer</subject><subject>CDH1</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - mortality</subject><subject>Confidence intervals</subject><subject>Design of experiments</subject><subject>Drug Resistance</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>E-cadherin</subject><subject>Experimental design</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gene mapping</subject><subject>Genetic Loci</subject><subject>Genetic Predisposition to Disease</subject><subject>Germ-Line Mutation</subject><subject>Health risks</subject><subject>Humans</subject><subject>Loci</subject><subject>Male</subject><subject>Mapping</subject><subject>Medical prognosis</subject><subject>Middle Aged</subject><subject>Monoclonal antibodies</subject><subject>Nucleotides</subject><subject>Oxaliplatin</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Prognosis</subject><subject>Prognostic biomarker</subject><subject>Progression-Free Survival</subject><subject>Risk Assessment</subject><subject>Risk loci</subject><subject>Single-nucleotide polymorphism</subject><subject>Survival</subject><subject>Survival Analysis</subject><subject>Targeted cancer therapy</subject><issn>0959-8049</issn><issn>1879-0852</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtv1TAQhS0Eope2f4AFssSmm1z8SuwgNtXl0UqV2MDacidjcEjii51E6r_H0S0sWFQaaRbzzdHMOYS85mzPGW_e9Xvswe0F4-2elRLqGdlxo9uKmVo8JzvW1m1lmGrPyKuce8aYNoq9JGeSa6kaVu9IPMTxmPAnTjmsSN3khoccMo2eQhxiQpjdQMFNgKlKIf-iQ4RQuI7mJa1hLdO4zBBHfE-v6THFH1PMcwCa4oDUx0QPH284XV0KbprzBXnh3ZDx8rGfk--fP3073FR3X7_cHq7vKlDCzBXU3msHrmmkB2eEVho0Kl5-Bda6e-G0Nk0LAiS0znveOKc60Eo1przWyXNyddItF_1eMM92DBlwGNyEcclWSF7XkvPGFPTtf2gfl1SM2ChlJDfCyEKJEwUp5pzQ22MKo0sPljO7xWF7u8VhtzgsKyVUWXrzKL3cj9j9W_nrfwE-nAAsXqwBk80QsJjdhc1628XwlP4flbGcAQ</recordid><startdate>202001</startdate><enddate>202001</enddate><creator>Summers, Matthew G.</creator><creator>Maughan, Timothy S.</creator><creator>Kaplan, Richard</creator><creator>Law, Philip J.</creator><creator>Houlston, Richard S.</creator><creator>Escott-Price, Valentina</creator><creator>Cheadle, Jeremy P.</creator><general>Elsevier Ltd</general><general>Elsevier Science Ltd</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>7TO</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6387-124X</orcidid><orcidid>https://orcid.org/0000-0001-9453-8458</orcidid></search><sort><creationdate>202001</creationdate><title>Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants</title><author>Summers, Matthew G. ; Maughan, Timothy S. ; Kaplan, Richard ; Law, Philip J. ; Houlston, Richard S. ; Escott-Price, Valentina ; Cheadle, Jeremy P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c428t-c5ff7aca663fca82747c7e41201c09ab2a77869c2c3c9aff16aa4dc74468734d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antigens, CD - genetics</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Biomarkers</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Cadherins - genetics</topic><topic>Cancer</topic><topic>CDH1</topic><topic>Chemotherapy</topic><topic>Clinical trials</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - mortality</topic><topic>Confidence intervals</topic><topic>Design of experiments</topic><topic>Drug Resistance</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>E-cadherin</topic><topic>Experimental design</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Gene mapping</topic><topic>Genetic Loci</topic><topic>Genetic Predisposition to Disease</topic><topic>Germ-Line Mutation</topic><topic>Health risks</topic><topic>Humans</topic><topic>Loci</topic><topic>Male</topic><topic>Mapping</topic><topic>Medical prognosis</topic><topic>Middle Aged</topic><topic>Monoclonal antibodies</topic><topic>Nucleotides</topic><topic>Oxaliplatin</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Prognosis</topic><topic>Prognostic biomarker</topic><topic>Progression-Free Survival</topic><topic>Risk Assessment</topic><topic>Risk loci</topic><topic>Single-nucleotide polymorphism</topic><topic>Survival</topic><topic>Survival Analysis</topic><topic>Targeted cancer therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Summers, Matthew G.</creatorcontrib><creatorcontrib>Maughan, Timothy S.</creatorcontrib><creatorcontrib>Kaplan, Richard</creatorcontrib><creatorcontrib>Law, Philip J.</creatorcontrib><creatorcontrib>Houlston, Richard S.</creatorcontrib><creatorcontrib>Escott-Price, Valentina</creatorcontrib><creatorcontrib>Cheadle, Jeremy P.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of cancer (1990)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Summers, Matthew G.</au><au>Maughan, Timothy S.</au><au>Kaplan, Richard</au><au>Law, Philip J.</au><au>Houlston, Richard S.</au><au>Escott-Price, Valentina</au><au>Cheadle, Jeremy P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants</atitle><jtitle>European journal of cancer (1990)</jtitle><addtitle>Eur J Cancer</addtitle><date>2020-01</date><risdate>2020</risdate><volume>124</volume><spage>56</spage><epage>63</epage><pages>56-63</pages><issn>0959-8049</issn><eissn>1879-0852</eissn><abstract>Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship.
For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN–B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10−4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival.
Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21–1.71, P = 5.0 × 10−5). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13–1.34, P = 1.9 × 10−6). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42–0.87, P = 6.6 × 10−3). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses.
The CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker.
•Analysed 83 colorectal cancer (CRC)-risk loci in 1948 patients with advanced CRC for prognostic outcome.•CDH1 variants were highly associated with overall survival in multivariate analysis.•Patients with rs12597188 minor alleles had a decrease in life expectancy of 5 months.•rs12597188 was also associated with poor response to therapy.•CDH1 (E-cadherin) involved in epithelial to mesenchymal transition during metastasis.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>31734605</pmid><doi>10.1016/j.ejca.2019.09.024</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-6387-124X</orcidid><orcidid>https://orcid.org/0000-0001-9453-8458</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Aged, 80 and over Antigens, CD - genetics Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biomarkers Biomarkers, Tumor - genetics Cadherins - genetics Cancer CDH1 Chemotherapy Clinical trials Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - mortality Confidence intervals Design of experiments Drug Resistance Drug Resistance, Neoplasm - genetics E-cadherin Experimental design Female Follow-Up Studies Gene mapping Genetic Loci Genetic Predisposition to Disease Germ-Line Mutation Health risks Humans Loci Male Mapping Medical prognosis Middle Aged Monoclonal antibodies Nucleotides Oxaliplatin Polymorphism, Single Nucleotide Prognosis Prognostic biomarker Progression-Free Survival Risk Assessment Risk loci Single-nucleotide polymorphism Survival Survival Analysis Targeted cancer therapy |
| title | Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants |
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