No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.
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Antoinette Hollestelle,
Frederieke H van der Baan,
Andrew Berchuck,
Sharon E Johnatty,
Katja K Aben,
Bjarni A Agnarsson,
Kristiina Aittomäki,
Elisa Alducci,
Irene L Andrulis,
Hoda Anton-Culver,
Natalia N Antonenkova,
Antonis C Antoniou,
Carmel Apicella,
Volker Arndt,
Norbert Arnold,
Banu K Arun,
Brita Arver,
Alan Ashworth,
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Laura Baglietto,
Rosemary Balleine,
Elisa V Bandera,
Daniel Barrowdale,
Yukie T Bean,
Lars Beckmann,
Matthias W Beckmann,
Javier Benitez,
Andreas Berger,
Raanan Berger,
Benoit Beuselinck,
Maria Bisogna,
Line Bjorge,
Carl Blomqvist,
Natalia V Bogdanova,
Anders Bojesen,
Stig E Bojesen,
Manjeet K Bolla,
Bernardo Bonanni,
Judith S Brand,
Hiltrud Brauch,
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Hermann Brenner,
Louise Brinton,
Angela Brooks-Wilson,
Fiona Bruinsma,
Joan Brunet,
Thomas Brüning,
Agnieszka Budzilowska,
Clareann H Bunker,
Barbara Burwinkel,
Ralf Butzow,
Saundra S Buys,
Maria A Caligo,
Ian Campbell,
Jonathan Carter,
Jenny Chang-Claude,
Stephen J Chanock,
Kathleen B M Claes,
J Margriet Collée,
Linda S Cook,
Fergus J Couch,
Angela Cox,
Daniel Cramer,
Simon S Cross,
Julie M Cunningham,
Cezary Cybulski,
Kamila Czene,
Francesca Damiola,
Agnieszka Dansonka-Mieszkowska,
Hatef Darabi,
Miguel de la Hoya,
Anna deFazio,
Joseph Dennis,
Peter Devilee,
Ed M Dicks,
Orland Diez,
Jennifer A Doherty,
Susan M Domchek,
Cecilia M Dorfling,
Thilo Dörk,
Isabel Dos Santos Silva,
Andreas du Bois,
Martine Dumont,
Alison M Dunning,
Mercedes Duran,
Douglas F Easton,
Diana Eccles,
Robert P Edwards,
Hans Ehrencrona,
Bent Ejlertsen,
Arif B Ekici,
Steve D Ellis,
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Christoph Engel,
Mikael Eriksson,
Peter A Fasching,
Lidia Feliubadalo,
Jonine Figueroa,
Dieter Flesch-Janys,
Olivia Fletcher,
Annette Fontaine,
Stefano Fortuzzi,
Florentia Fostira,
Brooke L Fridley,
Tara Friebel,
Eitan Friedman,
Grace Friel,
Debra Frost,
Judy Garber,
Montserrat García-Closas,
Simon A Gayther,
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Aleksandra Gentry-Maharaj,
Anne-Marie Gerdes,
Graham G Giles,
Rosalind Glasspool,
Gord Glendon,
Andrew K Godwin,
Marc T Goodman,
Martin Gore,
Mark H Greene,
Mervi Grip,
Jacek Gronwald,
Daphne Gschwantler Kaulich,
Pascal Guénel,
Starr R Guzman,
Lothar Haeberle,
Christopher A Haiman,
Per Hall,
Sandra L Halverson,
Ute Hamann,
Thomas V O Hansen,
Philipp Harter,
Jaana M Hartikainen,
Sue Healey,
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Alexander Hein,
Florian Heitz,
Brian E Henderson,
Josef Herzog,
Michelle A T Hildebrandt,
Claus K Høgdall,
Estrid Høgdall,
Frans B L Hogervorst,
John L Hopper,
Keith Humphreys,
Tomasz Huzarski,
Evgeny N Imyanitov,
Claudine Isaacs,
Anna Jakubowska,
Ramunas Janavicius,
Katarzyna Jaworska,
Allan Jensen,
Uffe Birk Jensen,
Nichola Johnson,
Arja Jukkola-Vuorinen,
Maria Kabisch,
Beth Y Karlan,
Vesa Kataja,
Noah Kauff,
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Linda E Kelemen,
Michael J Kerin,
Lambertus A Kiemeney,
Susanne K Kjaer,
Julia A Knight,
Jacoba P Knol-Bout,
Irene Konstantopoulou,
Veli-Matti Kosma,
Camilla Krakstad,
Vessela Kristensen,
Karoline B Kuchenbaecker,
Jolanta Kupryjanczyk,
Yael Laitman,
Diether Lambrechts,
Sandrina Lambrechts,
Melissa C Larson,
Adriana Lasa,
Pierre Laurent-Puig,
Conxi Lazaro,
Nhu D Le,
Loic Le Marchand,
Arto Leminen,
Jenny Lester,
Douglas A Levine,
Jingmei Li,
Dong Liang,
Annika Lindblom,
Noralane Lindor,
Jolanta Lissowska,
Jirong Long,
Karen H Lu,
Jan Lubinski,
Lene Lundvall,
Galina Lurie,
Phuong L Mai,
Arto Mannermaa,
Sara Margolin,
Frederique Mariette,
Frederik Marme,
John W M Martens,
Leon F A G Massuger,
Christine Maugard,
Sylvie Mazoyer,
Lesley McGuffog,
Valerie McGuire,
Catriona McLean,
Iain McNeish,
Alfons Meindl,
Florence Menegaux,
Primitiva Menéndez,
Janusz Menkiszak,
Usha Menon,
Arjen R Mensenkamp,
Nicola Miller,
Roger L Milne,
Francesmary Modugno,
Marco Montagna,
Kirsten B Moysich,
Heiko Müller,
Anna Marie Mulligan,
Taru A Muranen,
Steven A Narod,
Katherine L Nathanson,
Roberta B Ness,
Susan L Neuhausen,
Heli Nevanlinna,
Patrick Neven,
Finn C Nielsen,
Sune F Nielsen,
Børge G Nordestgaard,
Robert L Nussbaum,
Kunle Odunsi,
Kenneth Offit,
Edith Olah,
Olufunmilayo I Olopade,
Janet E Olson,
Sara H Olson,
Jan C Oosterwijk,
Irene Orlow,
Nick Orr,
Sandra Orsulic,
Ana Osorio,
Laura Ottini,
James Paul,
Celeste L Pearce,
Inge Sokilde Pedersen,
Bernard Peissel,
Tanja Pejovic,
Liisa M Pelttari,
Jo Perkins,
Jenny Permuth-Wey,
Paolo Peterlongo,
Julian Peto,
Catherine M Phelan,
Kelly-Anne Phillips,
Marion Piedmonte,
Malcolm C Pike,
Radka Platte,
Joanna Plisiecka-Halasa,
Elizabeth M Poole,
Bruce Poppe,
Katri Pylkäs,
Paolo Radice,
Susan J Ramus,
Timothy R Rebbeck,
Malcolm W R Reed,
Gad Rennert,
Harvey A Risch,
Mark Robson,
Gustavo C Rodriguez,
Atocha Romero,
Mary Anne Rossing,
Joseph H Rothstein,
Anja Rudolph,
Ingo Runnebaum,
Ritu Salani,
Helga B Salvesen,
Elinor J Sawyer,
Joellen M Schildkraut,
Marjanka K Schmidt,
Rita K Schmutzler,
Andreas Schneeweiss,
Minouk J Schoemaker,
Michael G Schrauder,
Fredrick Schumacher,
Ira Schwaab,
Giulietta Scuvera,
Thomas A Sellers,
Gianluca Severi,
Caroline M Seynaeve,
Mitul Shah,
Martha Shrubsole,
Nadeem Siddiqui,
Weiva Sieh,
Jacques Simard,
Christian F Singer,
Olga M Sinilnikova,
Dominiek Smeets,
Christof Sohn,
Maria Soller,
Honglin Song,
Penny Soucy,
Melissa C Southey,
Christa Stegmaier,
Dominique Stoppa-Lyonnet,
Lara Sucheston,
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Anthony Swerdlow,
Ingvild L Tangen,
Muy-Kheng Tea,
Manuel R Teixeira,
Kathryn L Terry,
Mary Beth Terry,
Mads Thomassen,
Pamela J Thompson,
Laima Tihomirova,
Marc Tischkowitz,
Amanda Ewart Toland,
Rob A E M Tollenaar,
Ian Tomlinson,
Diana Torres,
Thérèse Truong,
Helen Tsimiklis,
Nadine Tung,
Shelley S Tworoger,
Jonathan P Tyrer,
Celine M Vachon,
Laura J Van 't Veer,
Anne M van Altena,
C J Van Asperen,
David van den Berg,
Ans M W van den Ouweland,
Helena C van Doorn,
Els Van Nieuwenhuysen,
Elizabeth J van Rensburg,
Ignace Vergote,
Senno Verhoef,
Robert A Vierkant,
Joseph Vijai,
Allison F Vitonis,
Anna von Wachenfeldt,
Christine Walsh,
Qin Wang,
Shan Wang-Gohrke,
Barbara Wappenschmidt,
Maren Weischer,
Jeffrey N Weitzel,
Caroline Weltens,
Nicolas Wentzensen,
Alice S Whittemore,
Lynne R Wilkens,
Robert Winqvist,
Anna H Wu,
Xifeng Wu,
Hannah P Yang,
Daniela Zaffaroni,
M Pilar Zamora,
Wei Zheng,
Argyrios Ziogas,
Georgia Chenevix-Trench,
Paul D P Pharoah,
Matti A Rookus,
Maartje J Hooning,
Ellen L Goode
Abstract
METHODS
Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers).
CONCLUSIONS
rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
RESULTS
We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations.
OBJECTIVE
Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.