title: CAG repeat size in Huntingtin alleles is associated with cancer prognosis.
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).
authors.affiliation: Institut Curie, Paris, France.|CNRS UMR 3306, Orsay, France.|INSERM U1005, Orsay, France.|University Paris Sud 11, Orsay, France.
authors.forename: Morgane Sonia
authors.initials: MS
authors.lastname: Thion
authors.affiliation: Department of Biostatistics and Medical Informatics, Assistance Publique-Hôpitaux de Paris, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.|INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Tézenas du Montcel
authors.affiliation: Department of Biostatistics and Medical Informatics, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Golmard
authors.affiliation: Institut Curie, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.affiliation: INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Barjhoux
authors.affiliation: INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Sornin
authors.affiliation: Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM U975, CNRS UMR7225, UPMC Paris VI UMR S975, Paris, France.|Assistance Publique-Hôpitaux de Paris, Département de Génétique, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Cazeneuve
authors.affiliation: Institut Curie, Paris, France.|University Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon, Centre Léon Bérard, Lyon, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Sinilnikova
authors.affiliation: Institut Curie, Paris, France.|Department of Tumour Biology, INSERM U830, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.affiliation: Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM U975, CNRS UMR7225, UPMC Paris VI UMR S975, Paris, France.|Assistance Publique-Hôpitaux de Paris, Département de Génétique, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: University of Grenoble Alpes, Grenoble Institut des Neurosciences, INSERM U1216, Grenoble, France.|INSERM, U1216, Grenoble, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
mesh_terms: D000328:Adult; D000483:Alleles; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics*; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; D000071058:Huntingtin Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; C492913:BRCA1 protein, human; C551750:BRCA2 protein, human; C086055:HTT protein, human; C508053:ERBB2 protein, human