Viviane C Longuini1, Delmar M Lourenço1, Tomoko Sekiya1, Osorio Meirelles1, Tatiana D Goncalves1, Flavia L Coutinho1, Guilherme Francisco1, Luciana H Osaki1, Roger Chammas1, Venancio A F Alves1, Sheila A C Siqueira1, David Schlesinger2, Michel S Naslavsky1, Mayana Zatz1, Yeda A O Duarte1, Maria Lucia Lebrão1, Patricia Gama1, Misu Lee1, Sara Molatore1, Maria Adelaide A Pereira1, Raquel S Jallad1, Marcello D Bronstein1, Malebranche B Cunha-Neto1, Bernardo Liberman1, Maria Candida B V Fragoso1, Sergio P A Toledo2, Natalia S Pellegata1, Rodrigo A Toledo3. 1. Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil. 2. Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, BrazilEndocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil. 3. Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil toledorodrigo@usp.br toledorodrigo79@gmail.com.
Abstract
OBJECTIVE: 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.
OBJECTIVE: 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 p27V109G 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 p27tumor 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.
Authors: Kate E Lines; Mahsa Javid; Anita A C Reed; Gerard V Walls; Mark Stevenson; Michelle Simon; Kreepa G Kooblall; Sian E Piret; Paul T Christie; Paul J Newey; Ann-Marie Mallon; Rajesh V Thakker Journal: Endocr Connect Date: 2020-05 Impact factor: 3.335