Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.

Authors:
Dr. Jonine Figueroa, PhD
Dr. Jonine Figueroa, PhD
Usher Institute of Population Health Sciences and Informatics
Chancellor's Fellow
Molecular epidemiology
Edinburgh, Scotland | United Kingdom
Dr. Keun-Young Yoo, MD, PhD
Dr. Keun-Young Yoo, MD, PhD
Seoul National University College of Medicine
Professor
Cancer Epidemiology
Seoul | South Korea
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 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 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

Nat Genet 2013 Apr;45(4):371-84, 384e1-2

Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.

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.

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http://dx.doi.org/10.1038/ng.2566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670748PMC
April 2013
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