Molecular markers in diagnosis and prognosis of patients with tumors of the human thyroid: transition from basic to clinical research

• Grant number: 05/60330-8
• Support Opportunities: Research Projects - Thematic Grants
• Start date: June 01, 2006
• End date: May 31, 2011
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Janete Maria Cerutti
• Grantee: Janete Maria Cerutti
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Pesquisadores principais: Rui Monteiro de Barros Maciel
• Associated scholarship(s): 10/13833-2 - ABI3 and ABI3BP, characterization of in vitro interactions and investigation of the signaling pathway, BP.MS; 09/12211-0 - RET/PTC rearrangements: prevalence, clinical-pathologic correlation and gene expression profile in patients with papillary thyroid carcinoma, BP.MS

Abstract

Our long term goal is to address two important clinical problems related to patients with thyroid tumors. The first one is the incidental discovery of non-palpable thyroid nodules in general population, in an estimated 50% of general population. The increasing rate detection of non-palpable thyroid nodules demands a careful preoperative evaluation of a thyroid nodule, mainly because the treatment is based on cytological findings. Currently, fine-needle aspiration (FNA) cytology is the best non-surgical diagnostic tool for evaluate a thyroid nodule. However, approximately 30% of all nodules are classified as suspicious. To address this problem, we previously performed gene expression profile of a follicular thyroid adenoma (FT A), follicular thyroid carcinoma (FTC). This analysis using Serial Analysis of Gene Expression (SAGE) and subsequent validation of candidate genes through real time PCR (qPCR) and immunohistochemistry (IHC) revealed that four novel markers (DDIT3, ARG2, Clorf24 and ITMl) differed between the two and a linear combination of expression levels distinguish ITC from FIA with an estimated predictive accuracy of 0.83. Commercially available antibodies for DDIT3 and ARG2 were used for further validation in an independent set of FT A and FTC paraffin-embedded sections. Sensitivity and specificity were 85% and 91 % respectively for each antibody. Using the two in combination did not improve the estimates. We here propose improve the sensibility and specificity of our test and our hypothesis is that gene expression profile will locate novel diagnostic markers that can improve the accuracy of the test. We will use Serial Analysis of Gene Expression to profile the originally misclassified samples. Additionally, we will test the expression of our markers in other thyroid benign and malignant thyroid lesions, perform function analysis of ITM1md Clorf24 and to evaluate the effectiveness of antibody test in differentiate benign from malignant thyroid lesions in FNA material. Upon completion of this specific aims we will develop an innovative and more accurate preoperative diagnostic test for evaluating a thyroid nodule. The second clinical problem is that recurrence of thyroid tumors is high, ranging from 20-40% of patients with differentiated thyroid tumors. Lymph nodes account for 60-75% of all neck recurrences. This grant proposes in part to identify genes that are involved in lymph node metastases. Although much has been learned about the pathogenesis of thyroid carcinomas, the mechanism of metastasis is imperfectly understood. Therefore, monitoring the expression profile of normal, primary tumor and lymph node metastasis may help to identify genes involved in metastatic process. We believe that, beyond of understanding the mechanism of metastases, the molecular markers identified from gene expression profile must offer an alternative in the follow up of patients with thyroid carcinoma and ultimately may reveal a target gene for therapy. (AU)

Scientific publications

(17)

(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)

OLIVEIRA, DANIELA R.; SANADA, PRISCILA F.; SARAGOSSA, FILHO A. C.; INNOCENTI, L. R.; OLER, GISELE; CERUTTI, JANETE M.; CERUTTI, SUZETE M.. Neuromodulatory property of standardized extract Ginkgo biloba L. (EGb 761) on memory: Behavioral and molecular evidence. Brain Research, v. 1269, p. 68-89, MAY 7 2009. (05/60330-8)

CERUTTI, JANETE M.; OLER, GISELE; DELCELO, ROSANA; GERARDT, RENE; MICHALUART, JR., PEDRO; DE SOUZA, SANDRO J.; GALANTE, PEDRO A. F.; HUANG, PENG; RIGGINS, GREGORY J.. PVALB, a New Hurthle Adenoma Diagnostic Marker Identified through Gene Expression. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v. 96, n. 1, p. E151-E160, JAN 2011. (05/60330-8)

CAMACHO, CLEBER P.; LATINI, FLAVIA R. M.; OLER, GISELE; HOJAIJ, FLAVIO C.; MACIEL, RUI M. B.; RIGGINS, GREGORY J.; CERUTTI, JANETE M.. Down-regulation of NR4A1 in follicular thyroid carcinomas is restored following lithium treatment. CLINICAL ENDOCRINOLOGY, v. 70, n. 3, p. 475-483, MAR 2009. (05/60330-8)

OLER, GISELE; CERUTTI, JANETE M.. High Prevalence of BRAF Mutation in a Brazilian Cohort of Patients With Sporadic Papillary Thyroid Carcinomas Correlation With More Aggressive Phenotype and Decreased Expression of Iodide-Metabolizing Genes. Cancer, v. 115, n. 5, p. 972-980, MAR 1 2009. (05/60330-8)

HEMERLY, JEFFERSON PESSOA; BASTOS, ANDRE UCHIMURA; CERUTTI, JANETE M.. Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. EUROPEAN JOURNAL OF ENDOCRINOLOGY, v. 163, n. 5, p. 747-755, NOV 2010. (05/60330-8, 09/11257-7)

CERUTTI, JANETE M.; OLER, GISELE; MICHALUART JÚNIOR, PEDRO; DELCELO, ROSANA; BEATY, ROBERT M.; SHOEMAKER, JENNIFER; RIGGINS, GREGORY J.. Molecular profiling of matched samples identifies biomarkers of papillary thyroid carcinoma lymph node metastasis. Cancer Research, v. 67, n. 16, p. 7885-7892, Aug. 2007. (05/60330-8)

JANETE M. CERUTTI. Nódulos com diagnóstico de padrão folicular: marcadores biológicos são o futuro?. Arquivos Brasileiros de Endocrinologia e Metabologia, v. 51, n. 5, p. 832-842, 2007-07-00. (05/60330-8)

FREITAS, BEATRIZ C. G.; CERUTTI, JANETE M.. Genetic markers differentiating follicular thyroid carcinoma from benign lesions. Molecular and Cellular Endocrinology, v. 321, n. 1, p. 9-pg., 2010-05-28. (05/60330-8)

GISELE OLER; CLAUDIA D. NAKABASHI; ROSA PAULA M. BISCOLLA; JANETE M. CERUTTI. Sete anos de seguimento de uma paciente jovem com carcinoma papílfero de tireóide e mutação de BRAF e perda de expressão de genes do metabolismo de iodo. Arquivos Brasileiros de Endocrinologia e Metabologia, v. 52, n. 8, p. 1313-1316, 2008-11-00. (05/60330-8)

FREITAS, BEATRIZ C. G.; CERUTTI, JANETE M.. Genetic markers differentiating follicular thyroid carcinoma from benign lesions. Molecular and Cellular Endocrinology, v. 321, n. 1, SI, p. 77-85, MAY 28 2010. (05/60330-8)

SOUSA, MARIA SHARMILA A.; LATINI, FLAVIA R. M.; MONTEIRO, HUGO P.; CERUTTI, JANETE M.. Arginase 2 and nitric oxide synthase: Pathways associated with the pathogenesis of thyroid tumors. Free Radical Biology and Medicine, v. 49, n. 6, p. 997-1007, SEP 15 2010. (05/60330-8, 09/11257-7)

CAMACHO, CLEBER P.; HOFF, ANA O.; LINDSEY, SUSAN C.; SIGNORINI, PRISCILA S.; VALENTE, FLAVIA O. F.; OLIVEIRA, MARIANA N. L.; KUNII, ILDA S.; BISCOLLA, ROSA PAULA M.; CERUTTI, JANETE M.; MACIEL, RUI M. B.. Diagnóstico precoce de neoplasia endócrina múltipla tipo 2B: um desafio para os médicos. Arquivos Brasileiros de Endocrinologia e Metabologia, v. 52, n. 8, p. 1393-1398, NOV 2008. (05/60330-8, 06/60402-1)

LATINI, FLAVIA R. M.; HEMERLY, JEFFERSON P.; FREITAS, BEATRIZ C. G.; OLER, GISELE; RIGGINS, GREGORY J.; CERUTTI, JANETE M.. ABI3 ectopic expression reduces in vitro and in vivo cell growth properties while inducing senescence. BMC CANCER, v. 11, JAN 11 2011. (05/60330-8)

CERUTTI, JANETE M.. Employing Genetic Markers to Improve Diagnosis of Thyroid Tumor Fine Needle Biopsy. CURRENT GENOMICS, v. 12, n. 8, p. 589-596, DEC 2011. (05/60330-8, 09/11257-7)

TAMANAHA, ROSANA; CAMACHO, CLEBER P.; PEREIRA, ALEXANDRE C.; ALVARES DA SILVA, ADRIANA M.; MACIEL, RUI M. B.; CERUTTI, JANETE M.. Evaluation of RET polymorphisms in a six-generation family with G533C RET mutation: specific RET variants may modulate age at onset and clinical presentation. CLINICAL ENDOCRINOLOGY, v. 71, n. 1, p. 56-64, JUL 2009. (05/60330-8, 06/60402-1)

OLIVEIRA, MARIANA N. L.; HEMERLY, JEFFERSON P.; BASTOS, ANDRE U.; TAMANAHA, ROSANA; LATINI, FLAVIA R. M.; CAMACHO, CLEBER P.; IMPELLIZZERI, ANELISE; MACIEL, RUI M. B.; CERUTTI, JANETE M.. The RET p.G533C Mutation Confers Predisposition to Multiple Endocrine Neoplasia Type 2A in a Brazilian Kindred and Is Able to Induce a Malignant Phenotype In Vitro and In Vivo. THYROID, v. 21, n. 9, p. 975-985, SEP 2011. (05/60330-8, 06/60402-1, 09/11257-7)

LATINI, FLAVIA R. M.; HEMERLY, JEFFERSON P.; OLER, GISELE; RIGGINS, GREGORY J.; CERUTTI, JANETE M.. Re-expression of ABI3-binding protein suppresses thyroid tumor growth by promoting senescence and inhibiting invasion. Endocrine-Related Cancer, v. 15, n. 3, p. 787-799, SEP 2008. (05/60330-8)