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Article: Multigene pathway-based analyses identify nasopharyngeal carcinoma risk associations for cumulative adverse effects of TERT-CLPTM1L and DNA double-strand breaks repair

TitleMultigene pathway-based analyses identify nasopharyngeal carcinoma risk associations for cumulative adverse effects of TERT-CLPTM1L and DNA double-strand breaks repair
Authors
KeywordsPathway associations
Genetic susceptibility
NPC
TERT
DNA DSB repair
Familial NPC
BLM
CCDC170
NHEJ
Issue Date2014
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/journal/29331/home
Citation
International Journal of Cancer, 2014, v. 135 n. 7, p. 1634-1645 How to Cite?
AbstractThe genetic etiology of nasopharyngeal carcinoma (NPC) and mechanisms for inherited susceptibility remain unclear. To examine genetic risk factors for NPC, we hypothesized that heritable risk is attributable to cumulative effects of multiple common low‐risk variants. With the premise that individual SNPs only confer subtle effects for cancer risk, a multigenic pathway‐based approach was used to systematically examine associations between NPC genetic susceptibility with SNPs in genes in DNA repair pathways and from previously identified cancer genome‐wide association study analyses. This case–control study covers 161 genes/loci and focuses on pathway‐based analyses in 2,349 Hong Kong individuals, allowing stratification according to NPC familial status for meaningful association analysis. Three SNPs (rs401681, rs6774494 and rs3757318) corresponding to TERT/CLPTM1L (OR 95% CI = 0.77, 0.68–0.88), MDS1‐EVI1 (OR 95% CI=0.79 0.69–0.89) and CCDC170 (OR 95% CI = 0.76, 0.66–0.86) conferred modest protective effects individually for NPC risk by the logistic regression analysis after multiple testing adjustment (pBonferroni < 0.05). Stratification of NPC according to familial status identified rs2380165 in BLM (OR 95% CI = 1.49, 1.20–1.86, pBonferroni < 0.05) association with family history‐positive NPC (FH+ NPC) patients. Multiple SNPs pathway‐based analysis revealed that the combined gene dosage effects for increasing numbers of unfavorable genotypes in TERT‐CLPTM1L and double‐strand break repair (DSBR) conferred elevated risk in FH+ and sporadic NPC patients (ORs per allele, 95% CIs = 1.37, 1.22–1.55, pBonferroni = 5.00 × 10−6; 1.17, 1.09–1.26, pBonferroni = 4.58 × 10−4, respectively, in TERT/NHEJ pathways). Our data suggested cumulative increased NPC risk associations with TERT‐CLPTM1L and DSBR pathways contribute to genetic susceptibility to NPC and have potential translational relevance for patient stratification and therapeutics.
Persistent Identifierhttp://hdl.handle.net/10722/198010
ISSN
2019 Impact Factor: 5.145
2015 SCImago Journal Rankings: 2.657
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorKo, JMY-
dc.contributor.authorDai, W-
dc.contributor.authorWong, EHW-
dc.contributor.authorKwong, D-
dc.contributor.authorNg, WT-
dc.contributor.authorLee, AWM-
dc.contributor.authorNgan, RKC-
dc.contributor.authorYau, CC-
dc.contributor.authorTung, S-
dc.contributor.authorLung, ML-
dc.date.accessioned2014-06-25T02:39:52Z-
dc.date.available2014-06-25T02:39:52Z-
dc.date.issued2014-
dc.identifier.citationInternational Journal of Cancer, 2014, v. 135 n. 7, p. 1634-1645-
dc.identifier.issn0020-7136-
dc.identifier.urihttp://hdl.handle.net/10722/198010-
dc.description.abstractThe genetic etiology of nasopharyngeal carcinoma (NPC) and mechanisms for inherited susceptibility remain unclear. To examine genetic risk factors for NPC, we hypothesized that heritable risk is attributable to cumulative effects of multiple common low‐risk variants. With the premise that individual SNPs only confer subtle effects for cancer risk, a multigenic pathway‐based approach was used to systematically examine associations between NPC genetic susceptibility with SNPs in genes in DNA repair pathways and from previously identified cancer genome‐wide association study analyses. This case–control study covers 161 genes/loci and focuses on pathway‐based analyses in 2,349 Hong Kong individuals, allowing stratification according to NPC familial status for meaningful association analysis. Three SNPs (rs401681, rs6774494 and rs3757318) corresponding to TERT/CLPTM1L (OR 95% CI = 0.77, 0.68–0.88), MDS1‐EVI1 (OR 95% CI=0.79 0.69–0.89) and CCDC170 (OR 95% CI = 0.76, 0.66–0.86) conferred modest protective effects individually for NPC risk by the logistic regression analysis after multiple testing adjustment (pBonferroni < 0.05). Stratification of NPC according to familial status identified rs2380165 in BLM (OR 95% CI = 1.49, 1.20–1.86, pBonferroni < 0.05) association with family history‐positive NPC (FH+ NPC) patients. Multiple SNPs pathway‐based analysis revealed that the combined gene dosage effects for increasing numbers of unfavorable genotypes in TERT‐CLPTM1L and double‐strand break repair (DSBR) conferred elevated risk in FH+ and sporadic NPC patients (ORs per allele, 95% CIs = 1.37, 1.22–1.55, pBonferroni = 5.00 × 10−6; 1.17, 1.09–1.26, pBonferroni = 4.58 × 10−4, respectively, in TERT/NHEJ pathways). Our data suggested cumulative increased NPC risk associations with TERT‐CLPTM1L and DSBR pathways contribute to genetic susceptibility to NPC and have potential translational relevance for patient stratification and therapeutics.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/journal/29331/home-
dc.relation.ispartofInternational Journal of Cancer-
dc.subjectPathway associations-
dc.subjectGenetic susceptibility-
dc.subjectNPC-
dc.subjectTERT-
dc.subjectDNA DSB repair-
dc.subjectFamilial NPC-
dc.subjectBLM-
dc.subjectCCDC170-
dc.subjectNHEJ-
dc.titleMultigene pathway-based analyses identify nasopharyngeal carcinoma risk associations for cumulative adverse effects of TERT-CLPTM1L and DNA double-strand breaks repair-
dc.typeArticle-
dc.identifier.emailKo, JMY: joko@hku.hk-
dc.identifier.emailDai, W: weidai2@hku.hk-
dc.identifier.emailWong, EHW: elibe@hku.hk-
dc.identifier.emailKwong, D: dlwkwong@hku.hk-
dc.identifier.emailNg, WT: ngwt1@hkucc.hku.hk-
dc.identifier.emailLee, AWM: awmlee@hkucc.hku.hk-
dc.identifier.emailNgan, RKC: rkcngan@hkucc.hku.hk-
dc.identifier.emailLung, ML: mlilung@hku.hk-
dc.identifier.authorityKo, JMY=rp02011-
dc.identifier.authorityDai, W=rp02146-
dc.identifier.authorityKwong, D=rp00414-
dc.identifier.authorityNg, WT=rp02671-
dc.identifier.authorityLee, AWM=rp02056-
dc.identifier.authorityNgan, RKC=rp02371-
dc.identifier.authorityLung, ML=rp00300-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1002/ijc.28802-
dc.identifier.pmid24615621-
dc.identifier.scopuseid_2-s2.0-84904468367-
dc.identifier.hkuros229535-
dc.identifier.volume135-
dc.identifier.issue7-
dc.identifier.spage1634-
dc.identifier.epage1645-
dc.identifier.isiWOS:000340520800016-
dc.publisher.placeUnited States-
dc.identifier.issnl0020-7136-

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