Document Detail


Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
MedLine Citation:
PMID:  23535731     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
Authors:
Stig E Bojesen; Karen A Pooley; Sharon E Johnatty; Jonathan Beesley; Kyriaki Michailidou; Jonathan P Tyrer; Stacey L Edwards; Hilda A Pickett; Howard C Shen; Chanel E Smart; Kristine M Hillman; Phuong L Mai; Kate Lawrenson; Michael D Stutz; Yi Lu; Rod Karevan; Nicholas Woods; Rebecca L Johnston; Juliet D French; Xiaoqing Chen; Maren Weischer; Sune F Nielsen; Melanie J Maranian; Maya Ghoussaini; Shahana Ahmed; Caroline Baynes; Manjeet K Bolla; Qin Wang; Joe Dennis; Lesley McGuffog; Daniel Barrowdale; Andrew Lee; Sue Healey; Michael Lush; Daniel C Tessier; Daniel Vincent; Françis Bacot; ; ; ; ; ; ; ; ; Ignace Vergote; Sandrina Lambrechts; Evelyn Despierre; Harvey A Risch; Anna González-Neira; Mary Anne Rossing; Guillermo Pita; Jennifer A Doherty; Nuria Alvarez; Melissa C Larson; Brooke L Fridley; Nils Schoof; Jenny Chang-Claude; Mine S Cicek; Julian Peto; Kimberly R Kalli; Annegien Broeks; Sebastian M Armasu; Marjanka K Schmidt; Linde M Braaf; Boris Winterhoff; Heli Nevanlinna; Gottfried E Konecny; Diether Lambrechts; Lisa Rogmann; Pascal Guénel; Attila Teoman; Roger L Milne; Joaquin J Garcia; Angela Cox; Vijayalakshmi Shridhar; Barbara Burwinkel; Frederik Marme; Rebecca Hein; Elinor J Sawyer; Christopher A Haiman; Shan Wang-Gohrke; Irene L Andrulis; Kirsten B Moysich; John L Hopper; Kunle Odunsi; Annika Lindblom; Graham G Giles; Hermann Brenner; Jacques Simard; Galina Lurie; Peter A Fasching; Michael E Carney; Paolo Radice; Lynne R Wilkens; Anthony Swerdlow; Marc T Goodman; Hiltrud Brauch; Montserrat Garcia-Closas; Peter Hillemanns; Robert Winqvist; Matthias Dürst; Peter Devilee; Ingo Runnebaum; Anna Jakubowska; Jan Lubinski; Arto Mannermaa; Ralf Butzow; Natalia V Bogdanova; Thilo Dörk; Liisa M Pelttari; Wei Zheng; Arto Leminen; Hoda Anton-Culver; Clareann H Bunker; Vessela Kristensen; Roberta B Ness; Kenneth Muir; Robert Edwards; Alfons Meindl; Florian Heitz; Keitaro Matsuo; Andreas du Bois; Anna H Wu; Philipp Harter; Soo-Hwang Teo; Ira Schwaab; Xiao-Ou Shu; William Blot; Satoyo Hosono; Daehee Kang; Toru Nakanishi; Mikael Hartman; Yasushi Yatabe; Ute Hamann; Beth Y Karlan; Suleeporn Sangrajrang; Susanne Krüger Kjaer; Valerie Gaborieau; Allan Jensen; Diana Eccles; Estrid Høgdall; Chen-Yang Shen; Judith Brown; Yin Ling Woo; Mitul Shah; Mat Adenan Noor Azmi; Robert Luben; Siti Zawiah Omar; Kamila Czene; Robert A Vierkant; Børge G Nordestgaard; Henrik Flyger; Celine Vachon; Janet E Olson; Xianshu Wang; Douglas A Levine; Anja Rudolph; Rachel Palmieri Weber; Dieter Flesch-Janys; Edwin Iversen; Stefan Nickels; Joellen M Schildkraut; Isabel Dos Santos Silva; Daniel W Cramer; Lorna Gibson; Kathryn L Terry; Olivia Fletcher; Allison F Vitonis; C Ellen van der Schoot; Elizabeth M Poole; Frans B L Hogervorst; Shelley S Tworoger; Jianjun Liu; Elisa V Bandera; Jingmei Li; Sara H Olson; Keith Humphreys; Irene Orlow; Carl Blomqvist; Lorna Rodriguez-Rodriguez; Kristiina Aittomäki; Helga B Salvesen; Taru A Muranen; Elisabeth Wik; Barbara Brouwers; Camilla Krakstad; Els Wauters; Mari K Halle; Hans Wildiers; Lambertus A Kiemeney; Claire Mulot; Katja K Aben; Pierre Laurent-Puig; Anne Mvan Altena; Thérèse Truong; Leon F A G Massuger; Javier Benitez; Tanja Pejovic; Jose Ignacio Arias Perez; Maureen Hoatlin; M Pilar Zamora; Linda S Cook; Sabapathy P Balasubramanian; Linda E Kelemen; Andreas Schneeweiss; Nhu D Le; Christof Sohn; Angela Brooks-Wilson; Ian Tomlinson; Michael J Kerin; Nicola Miller; Cezary Cybulski; Brian E Henderson; Janusz Menkiszak; Fredrick Schumacher; Nicolas Wentzensen; Loic Le Marchand; Hannah P Yang; Anna Marie Mulligan; Gord Glendon; Svend Aage Engelholm; Julia A Knight; Claus K Høgdall; Carmel Apicella; Martin Gore; Helen Tsimiklis; Honglin Song; Melissa C Southey; Agnes Jager; Ans M Wvan den Ouweland; Robert Brown; John W M Martens; James M Flanagan; Mieke Kriege; James Paul; Sara Margolin; Nadeem Siddiqui; Gianluca Severi; Alice S Whittemore; Laura Baglietto; Valerie McGuire; Christa Stegmaier; Weiva Sieh; Heiko Müller; Volker Arndt; France Labrèche; Yu-Tang Gao; Mark S Goldberg; Gong Yang; Martine Dumont; John R McLaughlin; Arndt Hartmann; Arif B Ekici; Matthias W Beckmann; Catherine M Phelan; Michael P Lux; Jenny Permuth-Wey; Bernard Peissel; Thomas A Sellers; Filomena Ficarazzi; Monica Barile; Argyrios Ziogas; Alan Ashworth; Aleksandra Gentry-Maharaj; Michael Jones; Susan J Ramus; Nick Orr; Usha Menon; Celeste L Pearce; Thomas Brüning; Malcolm C Pike; Yon-Dschun Ko; Jolanta Lissowska; Jonine Figueroa; Jolanta Kupryjanczyk; Stephen J Chanock; Agnieszka Dansonka-Mieszkowska; Arja Jukkola-Vuorinen; Iwona K Rzepecka; Katri Pylkäs; Mariusz Bidzinski; Saila Kauppila; Antoinette Hollestelle; Caroline Seynaeve; Rob A E M Tollenaar; Katarzyna Durda; Katarzyna Jaworska; Jaana M Hartikainen; Veli-Matti Kosma; Vesa Kataja; Natalia N Antonenkova; Jirong Long; Martha Shrubsole; Sandra Deming-Halverson; Artitaya Lophatananon; Pornthep Siriwanarangsan; Sarah Stewart-Brown; Nina Ditsch; Peter Lichtner; Rita K Schmutzler; Hidemi Ito; Hiroji Iwata; Kazuo Tajima; Chiu-Chen Tseng; Daniel O Stram; David van den Berg; Cheng Har Yip; M Kamran Ikram; Yew-Ching Teh; Hui Cai; Wei Lu; Lisa B Signorello; Qiuyin Cai; Dong-Young Noh; Keun-Young Yoo; Hui Miao; Philip Tsau-Choong Iau; Yik Ying Teo; James McKay; Charles Shapiro; Foluso Ademuyiwa; George Fountzilas; Chia-Ni Hsiung; Jyh-Cherng Yu; Ming-Feng Hou; Catherine S Healey; Craig Luccarini; Susan Peock; Dominique Stoppa-Lyonnet; Paolo Peterlongo; Timothy R Rebbeck; Marion Piedmonte; Christian F Singer; Eitan Friedman; Mads Thomassen; Kenneth Offit; Thomas V O Hansen; Susan L Neuhausen; Csilla I Szabo; Ignacio Blanco; Judy Garber; Steven A Narod; Jeffrey N Weitzel; Marco Montagna; Edith Olah; Andrew K Godwin; Drakoulis Yannoukakos; David E Goldgar; Trinidad Caldes; Evgeny N Imyanitov; Laima Tihomirova; Banu K Arun; Ian Campbell; Arjen R Mensenkamp; Christi J van Asperen; Kees E P van Roozendaal; Hanne Meijers-Heijboer; J Margriet Collée; Jan C Oosterwijk; Maartje J Hooning; Matti A Rookus; Rob B van der Luijt; Theo A Mvan Os; D Gareth Evans; Debra Frost; Elena Fineberg; Julian Barwell; Lisa Walker; M John Kennedy; Radka Platte; Rosemarie Davidson; Steve D Ellis; Trevor Cole; Brigitte Bressac-de Paillerets; Bruno Buecher; Francesca Damiola; Laurence Faivre; Marc Frenay; Olga M Sinilnikova; Olivier Caron; Sophie Giraud; Sylvie Mazoyer; Valérie Bonadona; Virginie Caux-Moncoutier; Aleksandra Toloczko-Grabarek; Jacek Gronwald; Tomasz Byrski; Amanda B Spurdle; Bernardo Bonanni; Daniela Zaffaroni; Giuseppe Giannini; Loris Bernard; Riccardo Dolcetti; Siranoush Manoukian; Norbert Arnold; Christoph Engel; Helmut Deissler; Kerstin Rhiem; Dieter Niederacher; Hansjoerg Plendl; Christian Sutter; Barbara Wappenschmidt; Ake Borg; Beatrice Melin; Johanna Rantala; Maria Soller; Katherine L Nathanson; Susan M Domchek; Gustavo C Rodriguez; Ritu Salani; Daphne Gschwantler Kaulich; Muy-Kheng Tea; Shani Shimon Paluch; Yael Laitman; Anne-Bine Skytte; Torben A Kruse; Uffe Birk Jensen; Mark Robson; Anne-Marie Gerdes; Bent Ejlertsen; Lenka Foretova; Sharon A Savage; Jenny Lester; Penny Soucy; Karoline B Kuchenbaecker; Curtis Olswold; Julie M Cunningham; Susan Slager; Vernon S Pankratz; Ed Dicks; Sunil R Lakhani; Fergus J Couch; Per Hall; Alvaro N A Monteiro; Simon A Gayther; Paul D P Pharoah; Roger R Reddel; Ellen L Goode; Mark H Greene; Douglas F Easton; Andrew Berchuck; Antonis C Antoniou; Georgia Chenevix-Trench; Alison M Dunning
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Nature genetics     Volume:  45     ISSN:  1546-1718     ISO Abbreviation:  Nat. Genet.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-28     Completed Date:  2013-05-21     Revised Date:  2014-04-07    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  371-84, 384e1-2     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alternative Splicing
Breast Neoplasms / etiology*,  pathology
Case-Control Studies
Chromatin / genetics
DNA Methylation
Female
Gene Expression Profiling
Genetic Loci / genetics*
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Luciferases / metabolism
Oligonucleotide Array Sequence Analysis
Ovarian Neoplasms / etiology*,  pathology
Polymorphism, Single Nucleotide / genetics*
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Risk Factors
Telomerase / genetics*
Telomere / genetics*
Tumor Markers, Biological / genetics*
Grant Support
ID/Acronym/Agency:
076113//Wellcome Trust; C12292/A11174//Cancer Research UK; C1287/A10118//Cancer Research UK; C1287/A10710//Cancer Research UK; C1287/A12014//Cancer Research UK; C1287/A9540//Cancer Research UK; CA116201/CA/NCI NIH HHS; CA128978/CA/NCI NIH HHS; P30 CA008748/CA/NCI NIH HHS; P30 CA016520/CA/NCI NIH HHS; P30 ES013508/ES/NIEHS NIH HHS; P50 CA116201/CA/NCI NIH HHS; P50 CA136393/CA/NCI NIH HHS; R01 CA122443/CA/NCI NIH HHS; R01 CA128978/CA/NCI NIH HHS; R01 CA149429/CA/NCI NIH HHS; R37 CA070867/CA/NCI NIH HHS; RC4 CA153828/CA/NCI NIH HHS; //Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Chromatin; 0/RNA, Messenger; 0/Tumor Markers, Biological; EC 1.13.12.-/Luciferases; EC 2.7.7.49/TERT protein, human; EC 2.7.7.49/Telomerase
Comments/Corrections

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