A field synopsis on low-penetrance variants in DNA repair genes and cancer susceptibility.

2.50
Hdl Handle:
http://hdl.handle.net/10146/113406
Title:
A field synopsis on low-penetrance variants in DNA repair genes and cancer susceptibility.
Authors:
Vineis, Paolo; Manuguerra, Maurizio; Kavvoura, Fotini K.; Guarrera, Simonetta; Allione, Alessandra; Rosa, Fabio; Di Gregorio, Alessandra; Polidoro, Silvia; Saletta, Federica; Ioannidis, John P.A.; Matullo, Giuseppe
Abstract:
BACKGROUND: Several genes encoding for DNA repair molecules implicated in maintaining genomic integrity have been proposed as cancer-susceptibility genes. Although efforts have been made to create synopses for specific fields that summarize the data from genetic association studies, such an overview is not available for genes involved in DNA repair. METHODS: We have created a regularly updated database of studies addressing associations between DNA repair gene variants (excluding highly penetrant mutations) and different types of cancer. Using 1087 datasets and publicly available data from genome-wide association platforms, meta-analyses using dominant and recessive models were performed on 241 associations between individual variants and specific cancer types that had been tested in two or more independent studies. The epidemiological strength of each association was graded with Venice criteria that assess amount of evidence, replication, and protection from bias. All statistical tests were two-sided. RESULTS: Thirty-one nominally statistically significant (ie, P < .05 without adjustment for multiple comparisons) associations were recorded for 16 genes in dominant and/or recessive model analyses (BRCA2, CCND1, ERCC1, ERCC2, ERCC4, ERCC5, MGMT, NBN, PARP1, POLI, TP53, XPA, XRCC1, XRCC2, XRCC3, and XRCC4). XRCC1, XRCC2, TP53, and ERCC2 variants were each nominally associated with several types of cancer. Three associations were graded as having "strong" credibility, another four had modest credibility, and 24 had weak credibility based on Venice criteria. Requiring more stringent P values to account for multiplicity of comparisons, only the associations of ERCC2 codon 751 (recessive model) and of XRCC1 -77 T>C (dominant model) with lung cancer had P <or= .0001 and retained P <or= .001 even when the first published studies on the respective associations were excluded. CONCLUSIONS: We have conducted meta-analyses of 241 associations between variants in DNA repair genes and cancer and have found sparse association signals with strong epidemiological credibility. This synopsis offers a model to survey the current status and gaps in evidence in the field of DNA repair genes and cancer susceptibility, may indicate potential pleiotropic activity of genes and gene pathways, and may offer mechanistic insights in carcinogenesis.
Citation:
J. Natl. Cancer Inst. 2009, 101 (1):24-36
Journal:
Journal of the National Cancer Institute
Issue Date:
7-Jan-2009
URI:
http://hdl.handle.net/10146/113406
DOI:
10.1093/jnci/djn437
PubMed ID:
19116388
Additional Links:
http://jnci.oxfordjournals.org/content/101/1/24.long
Type:
Article
Language:
en
ISSN:
1460-2105
Sponsors:
This work was made possible by a grant to ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (contract no. 513943), and by a grant of the compagnia di San Paolo, of the Italian Association for Cancer Research, Italy, and of the Piedmont Region Progetti di Ricerca Sanitaria Finalizzata. F. K. Kavvoura is supported by a PENED training grant cofi nanced by EU — European Social Fund (75%) and the Greek Ministry of Development – General Secretariat of Research and Technology (25%).
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Full metadata record

DC FieldValue Language
dc.contributor.authorVineis, Paoloen
dc.contributor.authorManuguerra, Maurizioen
dc.contributor.authorKavvoura, Fotini K.en
dc.contributor.authorGuarrera, Simonettaen
dc.contributor.authorAllione, Alessandraen
dc.contributor.authorRosa, Fabioen
dc.contributor.authorDi Gregorio, Alessandraen
dc.contributor.authorPolidoro, Silviaen
dc.contributor.authorSaletta, Federicaen
dc.contributor.authorIoannidis, John P.A.en
dc.contributor.authorMatullo, Giuseppeen
dc.date.accessioned2010-10-18T13:08:50Z-
dc.date.available2010-10-18T13:08:50Z-
dc.date.issued2009-01-07-
dc.identifier.citationJ. Natl. Cancer Inst. 2009, 101 (1):24-36en
dc.identifier.issn1460-2105-
dc.identifier.pmid19116388-
dc.identifier.doi10.1093/jnci/djn437-
dc.identifier.urihttp://hdl.handle.net/10146/113406-
dc.description.abstractBACKGROUND: Several genes encoding for DNA repair molecules implicated in maintaining genomic integrity have been proposed as cancer-susceptibility genes. Although efforts have been made to create synopses for specific fields that summarize the data from genetic association studies, such an overview is not available for genes involved in DNA repair. METHODS: We have created a regularly updated database of studies addressing associations between DNA repair gene variants (excluding highly penetrant mutations) and different types of cancer. Using 1087 datasets and publicly available data from genome-wide association platforms, meta-analyses using dominant and recessive models were performed on 241 associations between individual variants and specific cancer types that had been tested in two or more independent studies. The epidemiological strength of each association was graded with Venice criteria that assess amount of evidence, replication, and protection from bias. All statistical tests were two-sided. RESULTS: Thirty-one nominally statistically significant (ie, P < .05 without adjustment for multiple comparisons) associations were recorded for 16 genes in dominant and/or recessive model analyses (BRCA2, CCND1, ERCC1, ERCC2, ERCC4, ERCC5, MGMT, NBN, PARP1, POLI, TP53, XPA, XRCC1, XRCC2, XRCC3, and XRCC4). XRCC1, XRCC2, TP53, and ERCC2 variants were each nominally associated with several types of cancer. Three associations were graded as having "strong" credibility, another four had modest credibility, and 24 had weak credibility based on Venice criteria. Requiring more stringent P values to account for multiplicity of comparisons, only the associations of ERCC2 codon 751 (recessive model) and of XRCC1 -77 T>C (dominant model) with lung cancer had P <or= .0001 and retained P <or= .001 even when the first published studies on the respective associations were excluded. CONCLUSIONS: We have conducted meta-analyses of 241 associations between variants in DNA repair genes and cancer and have found sparse association signals with strong epidemiological credibility. This synopsis offers a model to survey the current status and gaps in evidence in the field of DNA repair genes and cancer susceptibility, may indicate potential pleiotropic activity of genes and gene pathways, and may offer mechanistic insights in carcinogenesis.en
dc.description.sponsorshipThis work was made possible by a grant to ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (contract no. 513943), and by a grant of the compagnia di San Paolo, of the Italian Association for Cancer Research, Italy, and of the Piedmont Region Progetti di Ricerca Sanitaria Finalizzata. F. K. Kavvoura is supported by a PENED training grant cofi nanced by EU — European Social Fund (75%) and the Greek Ministry of Development – General Secretariat of Research and Technology (25%).en
dc.language.isoenen
dc.relation.urlhttp://jnci.oxfordjournals.org/content/101/1/24.longen
dc.subjectDNA Repairen
dc.subjectGenetic Predisposition to Diseaseen
dc.subjectHumansen
dc.subjectMutationen
dc.subjectNeoplasmsen
dc.subjectRetrospective Studiesen
dc.subjectOdds Ratioen
dc.subjectBias (Epidemiology)en
dc.subject.meshBias (Epidemiology)-
dc.subject.meshDNA Repair-
dc.subject.meshGenetic Predisposition to Disease-
dc.subject.meshHumans-
dc.subject.meshMutation-
dc.subject.meshNeoplasms-
dc.subject.meshOdds Ratio-
dc.subject.meshPenetrance-
dc.subject.meshPolymorphism, Genetic-
dc.subject.meshRetrospective Studies-
dc.titleA field synopsis on low-penetrance variants in DNA repair genes and cancer susceptibility.en
dc.typeArticleen
dc.identifier.journalJournal of the National Cancer Instituteen

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