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Clinical impact of the use of genetic panels through next generation sequencing in patients with potential risk of multiple endocrine neoplasia type 1

Grant number: 16/07965-0
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): August 01, 2016
Effective date (End): January 31, 2018
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Delmar Muniz Lourenço Jr
Grantee:Betsaida Urtremari
Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil


The multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant genetic disease caused by germline mutations in the MEN1 gene or, more rarely, by germline mutations in other genes (CDKN2B/CDKN2C/CDKN1A/CDKN1B/AIP). MEN1 is associated with high predisposition to the development of endocrine and non-endocrine tumors, mainly, involving tumors in parathyroid and pituitary glands and endocrine cells of duodenum/pancreas. Consensus on MEN1 (2012) suggests the analysis of these genes in a growing number of phenotypes as MEN1-suspected or atypical MEN1 cases, primary hyperparathyroidism (HPT) by adenoma (<30 years) or hyperplasia (age-independent) or recurrent HPT, gastrinoma, multifocal pancreatic neuroendocrine tumors (PNETs), etc. However, genetic analysis has been focused, mainly, to patients with clinical diagnosis of classical familial MEN1. This is due to the unfamiliarity of indication of genetic analysis in these at-risk groups, the need of sequencing of multiple genes, absence of mutational "hotspots" and, the high cost-effectiveness of the Sanger Sequencing (SS). The genetic diagnosis recognizes the asymptomatic mutation carriers, allows early diagnosis and treatment and reduces the mortality. Thus, it is important that the genetic analysis can be offered to these potential at-risk groups of MEN1. Thus, we intend to incorporate into medical practice a genetic panel based on next generation sequencing (NGS) which was validated in our Service recently. This panel, which includes the sequencing of the all MEN1-related genes, showed a high accuracy in the integrated analysis of these genes and detection of mutations beyond satisfactory cost-effectiveness. With this genetic panel is intended to establish conditions to provide the genetic diagnosis of familial MEN1, sporadic MEN1 cases, MEN1-suspected or atypical MEN1 cases and, of individuals with apparently sporadic endocrine tumors occurring in MEN1-related endocrine glands. Other objective of this study is defining the efficiency and cost-effectiveness of the genetic panel in the different subgroups of patients suggested for "Guidelines and, not fully evaluated yet. Also, this study intend to identify the patients to be targeted for genetic analysis by MLPA to the MEN1, AIP and CDKN1B genes. The achievement of these objectives has the potential to improve and expand the genetic diagnosis of MEN1 in our Service, to define better the subgroups of patients that benefit from genetic panel, to modify the clinical management, treatment and genetic counseling of potential at-risk groups of MEN1. There will be analyzed, initially, 90 patients with sporadic MEN1 or MEN1-suspected cases, 80 patients with apparently sporadic PNETs and, 20 patients with primary HPT diagnosed in young age (hyperplasia or adenoma) or for recurrent HPT. After, other Services/Centers that follow these patients, potentially, will be invited to participate of this study. It is estimated that, at the end, 500 patients will be selected to genetic analysis by NGS.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CARVALHO, RAFAEL A.; URTREMARI, BETSAIDA; JORGE, ALEXANDER A. L.; SANTANA, LUCAS S.; QUEDAS, ELISANGELA P. S.; SEKIYA, TOMOKO; LONGUINI, VIVIANE C.; MONTENEGRO, FABIO L. M.; LERARIO, ANTONIO M.; TOLEDO, SERGIO P. A.; et al. Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing. EUROPEAN JOURNAL OF ENDOCRINOLOGY, v. 179, n. 6, p. 391-407, . (15/25444-4, 13/19810-2, 16/07504-2, 16/07965-0, 13/15388-4)

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