Analysis of copy number variation (CNV) in pacientes of a family with men 2A and P.G533C mutation in the RET gene: identification of CNV regions associated with genesis and progression of medullary thyroid carcinoma

• Grant number: 13/03867-5
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2014
• End date: September 30, 2016
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• 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
• Associated researchers: Diego Robles Mazzotti ; Rui Monteiro de Barros Maciel

Abstract

The medullary thyroid carcinoma (MTC) is a carcinoma that is originated from thyroid C cells and occurs either as a sporadic (SMTC) or hereditary (HMTC) form. The hereditary form can occurs as the only clinical feature (familial MTC) or as the thyroid manifestation of multiple endocrine neoplasia type 2 (MEN 2) syndromes (MEN 2A and MEN 2B). The hereditary form can be inherited in an autosomal dominant manner and is caused by germline mutation in the RET gene. Our group identified a new RET mutation (p.G533C) in a family with MEN 2A. Clinical heterogeneity was observed among the p.G533C-carries, mainly associated with tumor aggressiveness. The present work aim to investigate whether Loss of Heterozigosis (LOH), present in the constitutional DNA, is associated with higher predisposition to lymph node metastasis, one of the factors associated with worse prognosis and aggressiveness of MTC. To this end, constitutional DNA of fifteen p.G533C-carriers with MTC were divided into two groups according to presence of lymph node metastasis (n=8) and absence of lymph node metastasis (n=12). DNA from peripheral blood was extracted by phenol/chloroform method, and its integrity evaluated on agarose gel. In addition, we aim to investigate CNVs and LOH are associated with genesis of MTC and C-cell hyperplasia (CCH), a precursor lesion to hereditary MTC. To this end, we will evaluate DNA isolated from CCH (n=5) and MTC (n=5) samples and constitutional DNA form same patients (n=10) will be analyzed. DNA samples were independently analyzed by Genome-Wide Human SNP Array 6.0 platform and the result was evaluated using Nexus Copy Number, Tumor Aberration Prediction Suite (TAPS) e PennCNV. The CNV identified will be validated by quantitative PCR and correlated with clinical and pathological features. We believe that our findings can contribute to better understand the genesis and/or progression of hereditary MTC. (AU)

Scientific publications

(11)

(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)

NOZIMA, BRUNO HEIDI; MENDES, THAIS BIUDE; DA SILVA PEREIRA, GUSTAVO JOSE; ARALDI, RODRIGO PINHEIRO; MIAZATO IWAMURA, EDNA SADAYO; SMAILI, SORAYA SOUBHI; GRIZ CARVALHEIRA, GIANNA MARIA; CERUTTI, JANETE MARIA. FAM129A regulates autophagy in thyroid carcinomas in an oncogene-dependent manner. Endocrine-Related Cancer, v. 26, n. 1, p. 227-238, JAN 2019. (14/06570-6, 13/03867-5)

MORAES, LAIS; ZANCHIN, NILSON I. T.; CERUTTI, JANETE M.. ABI3, a component of the WAVE2 complex, is potentially regulated by PI3K/AKT pathway. ONCOTARGET, v. 8, n. 40, p. 67769-67781, SEP 15 2017. (13/03867-5)

MORAES, LAIS; GALRAO, ANA LUIZA R.; RUBIO, ILEANA; CERUTTI, JANETE M.. Transcriptional regulation of the potential tumor suppressor ABI3 gene in thyroid carcinomas: interplay between methylation and NKX2-1 availability. ONCOTARGET, v. 7, n. 18, p. 25960-25970, MAY 3 2016. (13/03867-5)

VIEIRA CORDIOLI, MARIA ISABEL C.; MORAES, LAIS; BASTOS, ANDRE U.; BESSON, PALOMA; DE SEIXAS ALVES, MARIA TERESA; DELCELO, ROSANA; MONTE, OSMAR; LONGUI, CARLOS; CURY, ADRIANO NAMO; CERUTTI, JANETE M.. Fusion Oncogenes Are the Main Genetic Events Found in Sporadic Papillary Thyroid Carcinomas from Children. THYROID, v. 27, n. 2, p. 182-188, FEB 2017. (13/03867-5)

SHI, XIAOGUANG; LIU, RENGYUN; BASOLO, FULVIO; GIANNINI, RICCARDO; SHEN, XIAOPEI; TENG, DI; GUAN, HAIXIA; SHAN, ZHONGYAN; TENG, WEIPING; MUSHOLT, THOMAS J.; et al. Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v. 101, n. 1, p. 263-273, JAN 2016. (12/02902-9, 13/03867-5)

CUNHA VIEIRA CORDIOLI, MARIA ISABEL; MORAES, LAIS; DE SEIXAS ALVES, MARIA TERESA; DELCELO, ROSANA; MONTE, OSMAR; LONGUI, CARLOS ALBERTO; CURY, ADRIANO NAMO; CERUTTI, JANETE MARIA. Thyroid-Specific Genes Expression Uncovered Age-Related Differences in Pediatric Thyroid Carcinomas. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY, 2016. (12/02902-9, 13/03867-5)

BASTOS, ANDRE UCHIMURA; OLER, GISELE; NAKANO NOZIMA, BRUNO HEIDI; MOYSES, RAQUEL AJUB; CERUTTI, JANETE MARIA. BRAF V600E and decreased NIS and TPO expression are associated with aggressiveness of a subgroup of papillary thyroid microcarcinoma. EUROPEAN JOURNAL OF ENDOCRINOLOGY, v. 173, n. 4, p. 525-540, OCT 2015. (12/02902-9, 13/03867-5, 11/10787-2)

CORDIOLI, MARIA ISABEL C. V.; MORAES, LAIS; CARVALHEIRA, GIANNA; SISDELLI, LUIZA; ALVES, MARIA TERESA S.; DELCELO, ROSANA; MONTE, OSMAR; LONGUI, CARLOS A.; CURY, ADRIANO N.; CERUTTI, JANETE M.. AGK-BRAF gene fusion is a recurrent event in sporadic pediatric thyroid carcinoma. CANCER MEDICINE, v. 5, n. 7, p. 1535-1541, JUL 2016. (12/02902-9, 13/03867-5, 14/06570-6)

BASTOS, ANDRE UCHIMURA; DE JESUS, ANA CAROLINA; CERUTTI, JANETE MARIA. ETV6-NTRK3 and STRN-ALK kinase fusions are recurrent events in papillary thyroid cancer of adult population. EUROPEAN JOURNAL OF ENDOCRINOLOGY, v. 178, n. 1, p. 83-91, JAN 2018. (12/06221-6, 13/03867-5)

MENDES, THAIS BIUDE; NOZIMA, BRUNO HEIDI; BUDU, ALEXANDRE; DE SOUZA, RODRIGO BARBOSA; BRAGA CATROXO, MARCIA HELENA; DELCELO, ROSANA; GAZARINI, MARCOS LEONI; CERUTTI, JANETE MARIA. PVALB diminishes [Ca2+] and alters mitochondrial features in follicular thyroid carcinoma cells through AKT/GSK3 beta pathway. Endocrine-Related Cancer, v. 23, n. 9, p. 769-782, SEP 2016. (14/06570-6, 13/03867-5)

CUNHA VIEIRA CORDIOLI, MARIA ISABEL; MORAES, LAIS; DE SEIXAS ALVES, MARIA TERESA; DELCELO, ROSANA; MONTE, OSMAR; LONGUI, CARLOS ALBERTO; CURY, ADRIANO NAMO; CERUTTI, JANETE MARIA. Thyroid-Specific Genes Expression Uncovered Age-Related Differences in Pediatric Thyroid Carcinomas. INTERNATIONAL JOURNAL OF ENDOCRINOLOGY, v. 2016, p. 9-pg., 2016-01-01. (13/03867-5, 12/02902-9)