Open AccessMultiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer
Author(s) -
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,
L. Phuong,
Kate Lawrenson,
Michael D. Stutz,
Yi Lu,
Rod Karevan,
Nicholas T. Woods,
Rebecca L. Johnston,
Juliet D. French,
Xiaohong Chen,
Maren Weischer,
Sune F. Nielsen,
Melanie 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 GonzálezNeira,
Mary Anne Rossing,
Guillermo Pita,
Jennifer A. Doherty,
Núria Álvarez,
Melissa C. Larson,
Brooke L. Fridley,
Nils Schoof,
Jenny ChangClaude,
Mine 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,
Joaquín J. García,
Angela Cox,
Vijayalakshmi Shridhar,
Barbara Burwinkel,
Frederik Marmé,
Rebecca Hein,
Elinor J. Sawyer,
Christopher A. Haiman,
Shan WangGohrke,
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 J. Swerdlow,
Marc T. Goodman,
Hiltrud Brauch,
Montserrat GarcíaClosas,
Peter Hillemanns,
Robert Winqvist,
Matthias Dürst,
Peter Devilee,
Ingo B. Runnebaum,
Anna Jakubowska,
Jan Lubiński,
Graham J. Mann,
Ralf Bützow,
Natalia Bogdanova,
Thilo Dörk,
Liisa M. Pelttari,
Wei Zheng,
Arto Leminen,
Hoda AntonCulver,
Clareann H. Bunker,
Vessela N. Kristensen,
Roberta B. Ness,
Kenneth Muir,
Robert P. Edwards,
Alfons Meindl,
Florian Heitz,
Keitaro Matsuo,
Andreas du Bois,
Anna H. Wu,
Philipp Harter,
SooHwang Teo,
Ira Schwaab,
XiaoOu Shu,
William J. Blot,
Satoyo Hosono,
Daehee Kang,
Toru Nakanishi,
Mikael Hartman,
Yasushi Yatabe,
Ute Hamann,
Beth Y. Karlan,
Suleeporn Sangrajrang,
Susanne K. Kjær,
Valérie Gaborieau,
Allan Jensen,
Diana Eccles,
Estrid Høgdall,
ChenYang 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 M. Vachon,
Janet E. Olson,
Xianshu Wang,
Douglas A. Levine,
Anja Rudolph,
Rachel Palmieri Weber,
Dieter FleschJanys,
Edwin S. Iversen,
Stefan Nickels,
Joellen M. Schildkraut,
Isabel dosSantosSilva,
Daniel W. Cramer,
Lorna J. 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 Rodríguez-Rodríguez,
Kristiina Aittomäki,
Helga B. Salvesen,
Taru Muranen,
Elisabeth Wik,
Barbara Brouwers,
Camilla Krakstad,
Els Wauters,
Mari K. Halle,
Hans Wildiers,
Lambertus A. Kiemeney,
Claire Mulot,
Katja K.H. Aben,
Pierre LaurentPuig,
Anne Mvan Altena,
Thérèse Truong,
Leon F.A.G. Massuger,
Javier Benı́tez,
Tanja Pejović,
José Ignacio Arias Pérez,
Maureen E. Hoatlin,
M. Pilar Zamora,
Linda S. Cook,
Sabapathy P. Balasubramanian,
Linda E. Kelemen,
Andreas Schneeweiß,
Nhu D. Le,
Christof Sohn,
Angela BrooksWilson,
Ian Tomlinson,
Michael J. Kerin,
Nicola Miller,
Cezary Cybulski,
Brian E. Henderson,
Janusz Menkiszak,
Fredrick R. Schumacher,
Nicolas Wentzensen,
Loı̈c Le Marchand,
Hannah Yang,
Anna Marie Mulligan,
Gord Glendon,
Svend Aage Engelholm,
Julia A. Knight,
Claus Høgdall,
Carmel Apicella,
Martin Gore,
Helen Tsimiklis,
Honglin Song,
Melissa C. Southey,
Agnes Jager,
Ans M. W. den Van 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,
Esther M. John,
Arndt Hartmann,
Arif B. Ekici,
Matthias W. Beckmann,
Catherine M. Phelan,
Michael P. Lux,
Jenny PermuthWey,
Bernard Peissel,
Thomas A. Sellers,
Filomena Ficarazzi,
Monica Barile,
Argyrios Ziogas,
Alan Ashworth,
Aleksandra GentryMaharaj,
Michael E. Jones,
Susan J. Ramus,
Nick Orr,
Usha Me,
Celeste Leigh Pearce,
Thomas Brüning,
Malcolm C. Pike,
YonDschun Ko,
Jolanta Lissowska,
Jonine D. Figueroa,
Jolanta Kupryjańczyk,
Stephen J. Chanock,
Agnieszka DansonkaMieszkowska,
Arja JukkolaVuorinen,
Iwona K. Rzepecka,
Katri Pylkäs,
Mariusz Bidziński,
Saila Kauppila,
Antoinette Hollestelle,
Caroline Seynaeve,
Rob A.�E.�M. Tollenaar,
Katarzyna Durda,
Katarzyna Jaworska,
Jaana M. Hartikainen,
Veli-Matti Kosma,
Vesa Kataja,
Natalia Antonenkova,
Jirong Long,
Martha J. Shrubsole,
Sandra Deming-Halverson,
Artitaya Lophatana,
Pornthep Siriwanarangsan,
Sarah StewartBrown,
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,
DongYoung Noh,
Keun-Young Yoo,
Hui Miao,
Philip Tsau-Choong Iau,
Yik Ying Teo,
James McKay,
Charles L. Shapiro,
Foluso O. Ademuyiwa,
George Fountzilas,
Chia-Ni Hsiung,
Jyh-Cherng Yu,
MingFeng Hou,
Catherine S. Healey,
Craig Luccarini,
Susan Peock,
Dominique StoppaLyonnet,
Paolo Peterlongo,
Timothy R. Rebbeck,
Marion Piedmonte,
Christian F. Singer,
Eitan Friedman,
Mads Thomassen,
Kenneth Offit,
Thomas van Overeem Hansen,
Susan L. Neuhausen,
Csilla I. Szabo,
Ignacio Blanco,
Judy E. Garber,
Steven A. Narod,
Jeffrey N. Weitzel,
Marco Montagna,
Edith Oláh,
Andrew K. Godwin,
Drakoulis Yannoukakos,
David E. Goldgar,
Trinidad Caldés,
Evgeny N. Imyanitov,
Laima Tihomirova,
Banu K. Arun,
Ian Campbell,
Arjen R. Mensenkamp,
Christi J. van Asperen,
Kees E. P. van Roozendaal,
Hanne MeijersHeijboer,
J. Margriet Collée,
Jan C. Oosterwijk,
Maartje J. Hooning,
Matti A. Rookus,
Rob B. van der Luijt,
Theo A.M. van Os,
D. Gareth Evans,
Debra Frost,
Elena Fineberg,
Julian Barwell,
Lisa Walker,
Michael J. Kennedy,
Radka Platte,
Rosemarie Davidson,
Steve D. Ellis,
Trevor Cole,
Brigitte Bressac–de Paillerets,
Bruno Buecher,
Francesca Damiola,
Laurence Faivre,
Marc Frénay,
Olga M. Sinilnikova,
Olivier Caron,
Sophie Giraud,
Sylvie Mazoyer,
Valérie Bonadona,
Virginie CauxMoncoutier,
Aleksandra TołoczkoGrabarek,
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,
Åke Borg,
Beatrice Melin,
Johanna Rantala,
Maria Soller,
Katherine L. Nathanson,
Susan M. Domchek,
Gustavo C. Rodriguez,
Ritu Salani,
Daphne Gschwantler Kaulich,
Muy-Kheng M. Tea,
Shani Shimon Paluch,
Yael Laitman,
AnneBine Skytte,
Torben A. Kruse,
Uffe Birk Jensen,
Mark E. Robson,
Anne–Marie Gerdes,
Bent Ejlertsen,
Lenka Foretová,
Sharon A. Savage,
Jenny Lester,
Penny Soucy,
Karoline Kuchenbaecker,
Curtis Olswold,
Julie M. Cunningham,
Susan Slager,
V. Shane Pankratz,
Ed Dicks,
Sunil R. Lakhani,
Fergus J. Couch,
Per Hall,
Álvaro 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 ChenevixTrench,
Alison M. Dunning
Publication year - 2013
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/ng.2566
Subject(s) - breast cancer , ovarian cancer , biology , telomere , single nucleotide polymorphism , minor allele frequency , locus (genetics) , allele , snp , genotyping , genotype , genetics , cancer , oncology , cancer research , medicine , gene
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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