title: p27 variant and corticotropinoma susceptibility: a genetic and in vitro study.
abstract: Germline mutations in p27(kip1) are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, n=252; pheochromocytomas, n=125; medullary thyroid carcinoma, n=51; and parathyroid adenomas, n=19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (P=0.01), particularly for those with ACTH-secreting pituitary adenomas (P=0.005). In contrast, no association was found with GH-secreting pituitary tumors alone or with the sporadic counterpart of MEN2-component neoplasias. Our in vitro analyses revealed increased colony formation and cell growth rate for an AtT20 corticotropin mouse cell line overexpressing the p27-V109G variant compared with cells transfected with the WT p27. However, the genotypic effects in genetic and in vitro approaches were divergent. In accordance with our genetic data showing specificity for ACTH-secreting pituitary tissues, the overexpression of p27-V109G in a GH3 somatotropin rat cell line resulted in no difference compared with the WT. Pituitary tumors are one of the major clinical components of syndromes associated with the p27 pathogenic mutations MENX and MEN4. Our genetic and in vitro data indicate that the common polymorphism rs2066827 may play a role in corticotropinoma susceptibility and tumorigenesis through a molecular mechanism not fully understood thus far.
authors.affiliation: Endocrine Genetics Unit LIM-25 Neuroendocrinology Unit Adrenal Unit (LIM-42) Experimental Oncology Laboratory (LIM-24), School of Medicine, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil Nursing School School of Public Health, University of Sao Paulo, Sao Paulo, Brazil Endocrinology Division, Santa Casa Hospital, Sao Paulo, Brazil Brigadeiro Hospital, Sao Paulo, Brazil Federal University of Sao Paulo, Sao Paulo, Brazil Human Genome Research Center Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil Instituto do Cérebro, Instituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, Brazil National Institute of Aging, National Institutes of Health (NIH), Bethesda, Maryland, USA Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sekiya
authors.forename: Marcello D
authors.initials: MD
authors.lastname: Bronstein
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Benfini
authors.forename: Viviane C
authors.initials: VC
authors.lastname: Longuini
authors.forename: Raquel S
authors.initials: RS
authors.lastname: Jallad
authors.forename: Marcio C
authors.initials: MC
authors.lastname: Machado
authors.forename: Tatiana D
authors.initials: TD
authors.lastname: Goncalves
authors.forename: Luciana H
authors.initials: LH
authors.lastname: Osaki
authors.forename: Leonardo
authors.initials: L
authors.lastname: Higashi
authors.forename: Jose
authors.initials: J
authors.lastname: Viana
authors.forename: Claudio
authors.initials: C
authors.lastname: Kater
authors.forename: Misu
authors.initials: M
authors.lastname: Lee
authors.forename: Sara
authors.initials: S
authors.lastname: Molatore
authors.forename: Guilherme
authors.initials: G
authors.lastname: Francisco
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.forename: Michel S
authors.initials: MS
authors.lastname: Naslavsky
authors.forename: David
authors.initials: D
authors.lastname: Schlesinger
authors.forename: Patricia
authors.initials: P
authors.lastname: Gama
authors.forename: Yeda A O
authors.initials: YA
authors.lastname: Duarte
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Lebrão
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
authors.forename: Osorio
authors.initials: O
authors.lastname: Meirelles
authors.forename: Bernardo
authors.initials: B
authors.lastname: Liberman
authors.forename: Maria Candida B V
authors.initials: MC
authors.lastname: Fragoso
authors.forename: Sergio P A
authors.initials: SP
authors.lastname: Toledo
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Pellegata
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Toledo
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018278:Carcinoma, Neuroendocrine; D016022:Case-Control Studies; D049109:Cell Proliferation; D015331:Cohort Studies; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008875:Middle Aged; D009377:Multiple Endocrine Neoplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: C436291:CDKN1B protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: corticotropinoma; endocrine tumor; p27; pituitary tumor