title: Multiple HABP2 variants in familial papillary thyroid carcinoma: Contribution of a group of "thyroid-checked" controls.
abstract: A heterozygous germline variant in the HABP2 gene c.1601G > A (p.Gly534Glu), which negatively impacts its tumor suppressive activity in vitro, has been described in 4-14% of kindreds of European-American ancestry with familial papillary thyroid carcinoma (fPTC). But it is also found in ≈4% of Europeans and European/Americans from public databases that, however, did not provide information on the thyroid function of the controls. To get unbiased results, we decided to compare HABP2 genotypes of patients with fPTC with those of "thyroid-checked" controls. A control group consisting of 136 European patients who were thyroidectomised for medullary thyroid carcinoma and devoid of any histologically detectable PTC or follicular-deriving carcinoma was built. In parallel we recruited 20 patients with fPTC from eleven independent European kindreds. The entire coding region of HABP2 was analyzed by Sanger sequencing the germline DNAs of patients. Nucleotide variants were searched for by Snap Shot analysis in the controls. Two variants, c.1601G > A (p.Gly534Glu) and c.364C > T (p.Arg122Trp), were found in 2 and 3 patients at the heterozygous level respectively (minor allele frequency (MAF): 5.0% and 7.5%, respectively). In controls, the MAF was either similar for the c.1601G > A HABP2 variant (2.94%, ns) or significantly lower for the c.364C > T variant (0.73%, p = 0.016). The Arg122 residue lies in the EGF-3 domain of HABP2 which is important for its activation but, however, superposition of the predicted 3D structures of the wild type and mutated proteins suggests that this variant is tolerated at the protein level. In conclusion, our data do not support the pathogenicity of the HABP2 c.1601G > A variant but highlight the existence of a new one that should be more extensively searched for in fPTC patients and its pathogenicity more carefully evaluated.
authors.affiliation: Service de Biochimie « Hormonologie-Métabolisme-Nutrition & Oncologie », Centre de Biologie Pathologie, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kern
authors.affiliation: Service de Biochimie « Hormonologie-Métabolisme-Nutrition & Oncologie », Centre de Biologie Pathologie, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Coppin
authors.affiliation: Laboratoire de Biologie Moléculaire, Hôpital de la Conception, AP-HM, 13385 Marseille Cedex 05, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Romanet
authors.affiliation: Service de Biochimie « Hormonologie-Métabolisme-Nutrition & Oncologie », Centre de Biologie Pathologie, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Crépin
authors.affiliation: Service de Biochimie « Hormonologie-Métabolisme-Nutrition & Oncologie », Centre de Biologie Pathologie, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Szuster
authors.affiliation: Service d'Anatomie Pathologique, Centre de Biologie Pathologie, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Renaud
authors.affiliation: Service d'Anatomie Pathologique, Centre de Biologie Pathologie, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Leteurtre
authors.affiliation: Université de Lille 2, CHRU, Equipe RADEME, EA 7364, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Frénois
authors.affiliation: Service d'Endocrinologie, Hôpital Claude Huriez, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Wemeau
authors.affiliation: Service de Chirurgie Endocrinienne, Hôpital Claude Huriez, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Carnaille
authors.affiliation: Service d'Endocrinologie, Hôpital Claude Huriez, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cardot-Bauters
authors.affiliation: Service d'Endocrinologie, Hôpital Claude Huriez, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Do Cao
authors.affiliation: Service de Biochimie « Hormonologie-Métabolisme-Nutrition & Oncologie », Centre de Biologie Pathologie, Centre Hospitalier Régional & Universitaire, F-59037 Lille Cedex, France. Electronic address: pascal.pigny@chru-lille.fr.
authors.forename: Pascal
authors.initials: P
authors.lastname: Pigny
mesh_terms: D000368:Aged; D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D018278:Carcinoma, Neuroendocrine / Q000235:genetics*; D002291:Carcinoma, Papillary; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000502:physiology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C433550:HABP2 protein, human; D012697:Serine Endopeptidases
keywords: Familial cancer; HABP2; Novel variant; Papillary; Thyroid cancer