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Conference Paper: Case-control association studies of DNA damage repair genes associated with genetic susceptibility of nasopharyngeal carcinoma

TitleCase-control association studies of DNA damage repair genes associated with genetic susceptibility of nasopharyngeal carcinoma
Authors
Issue Date2014
Citation
The 2014 Gorden Research Conference (GRC) on Genomic Instability, The Hong Kong University of Science and Technology, Hong Kong, 6-11 July 2014. How to Cite?
AbstractNasopharyngeal carcinoma (NPC) has a distinctive racial and geographical distribution and is especially prevalent in Southern Chinese. Its genetic etiology and the mechanisms responsible for inherited genetic susceptibility are complex and unclear. We hypothesized that heritable risk for NPC is attributable to cumulative effects of multiple common low-risk variants, especially those of the DNA damage repair (DDR) genes. To score the harmful effects of multiple common variants together conferring 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 other cancer-linked loci. This case - control association study covers 161 genes/loci with a focus on DDR pathway-based analyses in 2,349 Hong Kong individuals. Three SNPs (rs401681, rs6774494, rs3757318) corresponding to TERT/CLPTM1L, MDS1-EVI1, and CCDC170 conferred modest protective effects individually for NPC risk by the logistic regression analysis after multiple testing adjustment. Stratification of NPC according to familial status identified rs2380165 in BLM association with family history-positive (FH+) NPC patients. FH+ NPC patients carrying higher numbers of unfavorable genotypes in different DDR pathways, including homologous recombination (HR), Fanconi Anemia (FA)-HR, FA-BLM, non-homologous end-joining (NHEJ), double-strand break repair (DSBR) - (HR+NHEJ), exhibited elevated NPC risk, while similar pathway-based analysis was not observed in sporadic NPC patients. The combined effects of TERT-CLPTM1L and DSB repairs for NPC risk were examined, since shortened telomeres are recognized as DSBs and DNA repair and recombination machineries are crucial for maintaining normal telomere function. Both FH+ and sporadic patients exhibited progressively significantly elevated NPC risk; a similar but less pronounced risk elevation was observed in sporadic NPC patients with regards to the cumulative effects in the DSBR pathways and TERT-CLPTM1L. The data suggested increasing NPC risk associated with TERT-CLPTM1L and DSBR signaling pathways correlate with NPC genetic susceptibility. This suggested a potential translational relevance for patient stratification and therapeutics.
DescriptionConference Theme: Mechanisms That Cause DNA Damage and Related Diseases
Persistent Identifierhttp://hdl.handle.net/10722/201330

 

DC FieldValueLanguage
dc.contributor.authorKo, JMYen_US
dc.contributor.authorDai, Wen_US
dc.contributor.authorWong, EHWen_US
dc.contributor.authorKwong, DLWen_US
dc.contributor.authorNg, WTen_US
dc.contributor.authorLee, Aen_US
dc.contributor.authorNgan, RKCen_US
dc.contributor.authorYau, CCen_US
dc.contributor.authorTung, Sen_US
dc.contributor.authorLung, MLen_US
dc.date.accessioned2014-08-21T07:24:10Z-
dc.date.available2014-08-21T07:24:10Z-
dc.date.issued2014en_US
dc.identifier.citationThe 2014 Gorden Research Conference (GRC) on Genomic Instability, The Hong Kong University of Science and Technology, Hong Kong, 6-11 July 2014.en_US
dc.identifier.urihttp://hdl.handle.net/10722/201330-
dc.descriptionConference Theme: Mechanisms That Cause DNA Damage and Related Diseases-
dc.description.abstractNasopharyngeal carcinoma (NPC) has a distinctive racial and geographical distribution and is especially prevalent in Southern Chinese. Its genetic etiology and the mechanisms responsible for inherited genetic susceptibility are complex and unclear. We hypothesized that heritable risk for NPC is attributable to cumulative effects of multiple common low-risk variants, especially those of the DNA damage repair (DDR) genes. To score the harmful effects of multiple common variants together conferring 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 other cancer-linked loci. This case - control association study covers 161 genes/loci with a focus on DDR pathway-based analyses in 2,349 Hong Kong individuals. Three SNPs (rs401681, rs6774494, rs3757318) corresponding to TERT/CLPTM1L, MDS1-EVI1, and CCDC170 conferred modest protective effects individually for NPC risk by the logistic regression analysis after multiple testing adjustment. Stratification of NPC according to familial status identified rs2380165 in BLM association with family history-positive (FH+) NPC patients. FH+ NPC patients carrying higher numbers of unfavorable genotypes in different DDR pathways, including homologous recombination (HR), Fanconi Anemia (FA)-HR, FA-BLM, non-homologous end-joining (NHEJ), double-strand break repair (DSBR) - (HR+NHEJ), exhibited elevated NPC risk, while similar pathway-based analysis was not observed in sporadic NPC patients. The combined effects of TERT-CLPTM1L and DSB repairs for NPC risk were examined, since shortened telomeres are recognized as DSBs and DNA repair and recombination machineries are crucial for maintaining normal telomere function. Both FH+ and sporadic patients exhibited progressively significantly elevated NPC risk; a similar but less pronounced risk elevation was observed in sporadic NPC patients with regards to the cumulative effects in the DSBR pathways and TERT-CLPTM1L. The data suggested increasing NPC risk associated with TERT-CLPTM1L and DSBR signaling pathways correlate with NPC genetic susceptibility. This suggested a potential translational relevance for patient stratification and therapeutics.en_US
dc.languageengen_US
dc.relation.ispartofGRC on Genomic Instabilityen_US
dc.titleCase-control association studies of DNA damage repair genes associated with genetic susceptibility of nasopharyngeal carcinomaen_US
dc.typeConference_Paperen_US
dc.identifier.emailKo, JMY: joko@hku.hken_US
dc.identifier.emailDai, W: weidai2@hku.hken_US
dc.identifier.emailKwong, DLW: dlwkwong@hku.hken_US
dc.identifier.emailNg, WT: ngwt1@hkucc.hku.hken_US
dc.identifier.emailNgan, RKC: rkcngan@hkucc.hku.hk-
dc.identifier.emailYau, CC: yaucc@hkucc.hku.hk-
dc.identifier.emailLung, ML: mlilung@hku.hk-
dc.identifier.authorityKwong, DLW=rp00414en_US
dc.identifier.authorityLung, ML=rp00300en_US
dc.identifier.hkuros235181en_US

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