Abstract
The abnormal expansion of a ≥36 CAG unit tract in the Huntingtin gene (HTT) leads to Huntington's disease (HD), but has also been associated with cancer: the incidence of cancer is lower in HD patients than in age-matched controls, but HD-causing variants of HTT accelerate the progression of breast tumors and the development of metastases in mouse models of breast cancer. To investigate the relationship between HTT CAGs and cancer, data concerning 2407 women with BRCA1 or BRCA2 mutations that predispose to breast and ovarian cancers and 431 patients with breast cancer without family histories were studied; the size of the CAG expansions on both HTT alleles was determined in each subject. The proportion of individuals carrying a CAG expansion in a pathological range for HD was 10 times more frequent than previously reported in the literature. In carriers of BRCA2 mutations, the length of the HTT CAG tract was correlated with lower incidence of ovarian cancer. Among carriers of BRCA1 mutations who developed a breast cancer, its onset occurred 2.4 years earlier in individuals with intermediate HTT alleles (≥27) than in those with a CAG tract <27. Finally, in patients with sporadic HER2 breast cancer, metastasis increased by a factor of 11.10 per 10 additional CAG repeats in HTT. We concluded that whereas long CAG length could be associated with lower cancer incidence, it could also be paradoxically associated with cancer severity (age of apparition and metastasis development).
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Acknowledgements
We thank Frédéric Saudou, Anne Vincent-Salomon, the members of the Humbert and Saudou laboratories for discussions and the GEMO study: National Cancer Genetics Network (UNICANCER Genetic Group, France) and the patients for the biological samples. We also thank all the collaborating GEMO groups for their contribution to this study (a list of collaborating GEMO Centers and their members follows). The coordinating centers, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon–Centre Léon Bérard and Equipe (Génétique du cancer du sein), Centre de Recherche en Cancérologie de Lyon: Olga Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Alain Calender, Sophie Giraud, Mélanie Léone; and Service de Génétique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Carole Tirapo, Antoine de Pauw. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron. Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona, Sandrine Handallou. Centre François Baclesse, Caen: Agnès Hardouin, Pascaline Berthet. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, François Eisinger. CHU Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Philippe Vennin, Claude Adenis. Hôpital René Huguenin/Institut Curie, St Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange, Catherine Nogues. Centre Paul Strauss, Strasbourg: Danièle Muller, Jean-Pierre Fricker. Institut Bergonié, Bordeaux: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU Grenoble: Dominique Leroux, Hélène Dreyfus, Christine Rebischung, Magalie Peysselon. CHU Dijon: Fanny Coron, Laurence Faivre. CHU St-Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz. Hôtel Dieu Centre Hospitalier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frénay. CHU Limoges: Laurence Vénat-Bouvet. CHU Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier. CHU Vandoeuvre-les-Nancy: Johanna Sokolowska, Myriam Bronner. CHU Besançon: Marie-Agnès Collonge-Rame, Alexandre Damette. Creighton University, Omaha, USA: Henry T Lynch, Carrie L Snyder. The study was supported by the Ligue National Contre le Cancer, the Association ‘Le cancer du sein, parlons-en!’ Award, and the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program. The EUROSCA Clinical study (EUROSCA/LSHM-CT-2004-503304) was supported in part by the European Union 6th framework program, and included the following principle investigators: J Berciano (Santander), Sylvia Boesch (Innsbruck), Alexis Brice (Paris), Alessandro Filla (Naples), Paola Giunti (London), Thomas Klockgether (Bonn), Ludger Schols and Olaf Riess (Tübingen), Maria Rakowicz (Warsaw), Caterina Mariotti (Milano), Bela Melegh (Budapest), Massimo Pandolfo (Brussels), Bart van de Warrenburg (Nijmegen).
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Thion, M., Tézenas du Montcel, S., Golmard, JL. et al. CAG repeat size in Huntingtin alleles is associated with cancer prognosis. Eur J Hum Genet 24, 1310–1315 (2016). https://doi.org/10.1038/ejhg.2016.13
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DOI: https://doi.org/10.1038/ejhg.2016.13
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