title: Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.
abstract: Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
authors.affiliation: Division of Cancer Epidemiology and Genetics, Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
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authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, St Andrew's Place, East Melbourne, VIC, Australia.
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authors.affiliation: Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK.
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authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.
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authors.affiliation: Division of Cancer Epidemiology and Genetics.
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authors.affiliation: Division of Cancer Epidemiology and Genetics.
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authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
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authors.affiliation: Division of Cancer Epidemiology and Genetics.
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authors.affiliation: Department of Pulmonary Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
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authors.affiliation: Division of Cancer Epidemiology and Genetics.
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authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
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authors.affiliation: Imperial College, London, UK, Human Genetics Foundation (HuGeF), Torino Italy.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA, Department of Biochemistry and Centre for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Junwen
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authors.affiliation: Division of Cancer Etiology, Department of Population Sciences, City of Hope and the Beckman Research Institute, Duarte, CA, USA.
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authors.affiliation: Division of Cancer Epidemiology and Genetics.
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authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padua, Italy.
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authors.affiliation: Department of Epidemiology.
authors.forename: Xifeng
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authors.affiliation: Guangdong Lung Cancer Institute, Medical Research Center and Cancer Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Yi-Long
authors.initials: YL
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authors.affiliation: Division of Urologic Surgery, Washington University School of Medicine, St Louis, MO, USA.
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authors.affiliation: Division of Cancer Epidemiology and Genetics.
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authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
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authors.affiliation: Division of Cancer Epidemiology and Genetics.
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authors.affiliation: Division of Cancer Epidemiology and Genetics.
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authors.affiliation: Division of Cancer Epidemiology and Genetics.
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authors.affiliation: Division of Cancer Epidemiology and Genetics.
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mesh_terms: D000483:Alleles; D002895:Chromosomes, Human, Pair 5 / Q000737:chemistry*; D019295:Computational Biology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D019098:Telomerase / Q000235:genetics*
chemical_list: C422445:CLPTM1L protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C509186:TERT protein, human; D019098:Telomerase