Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations

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dc.contributor.authorLonguini, Viviane C.
dc.contributor.authorLourenco, Delmar M.
dc.contributor.authorSekiya, Tomoko
dc.contributor.authorMeirelles, Osorio
dc.contributor.authorGoncalves, Tatiana D.
dc.contributor.authorCoutinho, Flavia L.
dc.contributor.authorFrancisco, Guilherme
dc.contributor.authorOsaki, Luciana H.
dc.contributor.authorChammas, Roger
dc.contributor.authorAlves, Venancio A. F.
dc.contributor.authorSiqueira, Sheila A. C.
dc.contributor.authorSchlesinger, David
dc.contributor.authorNaslavsky, Michel S.
dc.contributor.authorZatz, Mayana
dc.contributor.authorDuarte, Yeda A. O.
dc.contributor.authorLebrao, Maria Lucia
dc.contributor.authorGama, Patricia
dc.contributor.authorLee, Misu
dc.contributor.authorMolatore, Sara
dc.contributor.authorPereira, Maria Adelaide A.
dc.contributor.authorJallad, Raquel S.
dc.contributor.authorBronstein, Marcello D.
dc.contributor.authorCunha-Neto, Malebranche B.
dc.contributor.authorLiberman, Bernardo
dc.contributor.authorFragoso, Maria Candida B. V.
dc.contributor.authorToledo, Sergio P. A. [UNIFESP]
dc.contributor.authorPellegata, Natalia S.
dc.contributor.authorToledo, Rodrigo A.
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionBrigadeiro Hosp
dc.contributor.institutionIsraelita Ensino & Pesquisa Albert Einstein
dc.contributor.institutionNIA
dc.contributor.institutionHelmholtz Zentrum Munchen
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.date.accessioned2016-01-24T14:37:46Z
dc.date.available2016-01-24T14:37:46Z
dc.date.issued2014-09-01
dc.description.abstractObjective: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for.Design: As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. the cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals.Methods: Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression.Results: There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR=2.55, P=0.019, CI=1.013-5.76). Among patients who are >= 30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P=0.002, CI=2.88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors.Conclusions: Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.en
dc.description.affiliationUniv São Paulo, Sch Med, Endocrine Genet Unit, Lab Invest Med LIM 25, São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Sch Med, Neuroendocrinol Unit, São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Sch Med, Neuroendocrinol Neurosurg Unit, São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Sch Med, Adrenal Unit LIM 42, São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Sch Med, Gen Endocrinol Unit, São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Sch Med, Expt Oncol Lab LIM 24, São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Sch Med, Dept Pathol, São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Sch Med, Sch Nursing, São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Sch Med, Hosp Clin, Sch Publ Hlth, São Paulo, Brazil
dc.description.affiliationBrigadeiro Hosp, São Paulo, Brazil
dc.description.affiliationUniv São Paulo, Human Genome Res Ctr, São Paulo, Brazil
dc.description.affiliationIsraelita Ensino & Pesquisa Albert Einstein, Inst Cerebro, São Paulo, Brazil
dc.description.affiliationNIA, NIH, Bethesda, MD 20892 USA
dc.description.affiliationHelmholtz Zentrum Munchen, Inst Pathol, Neuherberg, Germany
dc.description.affiliationUniv São Paulo, Inst Biomed Sci, São Paulo, Brazil
dc.description.affiliationFed Univ São Paulo UNIFESP, Div Endocrinol, São Paulo, Brazil
dc.description.affiliationUnifespFed Univ São Paulo UNIFESP, Div Endocrinol, São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.format.extent335-342
dc.identifierhttp://dx.doi.org/10.1530/EJE-14-0130
dc.identifier.citationEuropean Journal of Endocrinology. Bristol: Bioscientifica Ltd, v. 171, n. 3, p. 335-342, 2014.
dc.identifier.doi10.1530/EJE-14-0130
dc.identifier.issn0804-4643
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/38129
dc.identifier.wosWOS:000343670900011
dc.language.isoeng
dc.publisherBioscientifica Ltd
dc.relation.ispartofEuropean Journal of Endocrinology
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titleAssociation between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutationsen
dc.typeinfo:eu-repo/semantics/article
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