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Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma

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Autor(es):
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Araujo, Aline Neves [1] ; Camacho, Cleber Pinto [2] ; Mendes, Thais Biude [1] ; Lindsey, Susan Chow [2] ; Moraes, Lais [1] ; Miyazawa, Marta [1] ; Delcelo, Rosana [3] ; Pellegrino, Renata [4] ; Mazzotti, Diego Robles [5] ; Maciel, Rui Monteiro de Barros [2] ; Cerutti, Janete Maria [1]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Univ Fed Sao Paulo, Genet Bases Thyroid Tumors Lab, Div Genet, Dept Morphol & Genet, Escola Paulista Med, Pedro de Toledo 669, 11 Andar, BR-04039032 Sao Paulo - Brazil
[2] Univ Fed Sao Paulo, Lab Mol & Translat Endocrinol, Div Endocrinol, Dept Med, Escola Paulista Medicina, Pedro de Toledo 669, 11 Andar, BR-04039032 Sao Paulo - Brazil
[3] Univ Fed Sao Paulo, Dept Pathol, Escola Paulista Med, Rua Botucatu 740, BR-04023900 Sao Paulo - Brazil
[4] Childrens Hosp Philadelphia, Ctr Appl Genom, Res Inst, 3401 Civ Ctr Blvd, Philadelphia, PA 19101 - USA
[5] Univ Penn, Dept Med, Div Sleep Med, Perelman Sch Med, Philadelphia, PA 19104 - USA
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: CANCERS; v. 13, n. 2 JAN 2021.
Citações Web of Science: 0
Resumo

Simple Summary Medullary thyroid cancer (MTC) is often discovered in its advanced stage. Although a rare disease, advanced MTC cases have poor prognosis and the treatment is often palliative. Several studies have reported the existence of an association between copy number alterations (CNAs) burden and cancer progression. Moreover, the accumulation of broad CNAs, which contribute to intra-tumor heterogeneity, might be required for immune evasion. The identification of the recurrent CNAs associated with tumor phenotype aided in discovering new therapeutics options in several cancer types. To our knowledge, CNA is not well characterized in MTC. We analyzed recurrent focal CNAs on MTC. Our analysis provides a novel insight on MTC biology and may help in uncovering novel potential therapeutic targets. Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C-cells that can occur either in sporadic (70-80%) or hereditary (20-30%) form. In this study we aimed to identify recurrent copy number alterations (CNA) that might be related to the pathogenesis or progression of MTC. We used Affymetrix SNP array 6.0 on MTC and paired-blood samples to identify CNA using PennCNV and Genotyping Console software. The algorithms identified recurrent copy number gains in chromosomes 15q, 10q, 14q and 22q in MTC, whereas 4q cumulated losses. Coding genes were identified within CNA regions. The quantitative PCR analysis performed in an independent series of MTCs (n = 51) confirmed focal recurrent copy number gains encompassing the DLK1 (14q32.2) and AIFM3 (22q11.21) genes. Immunohistochemistry confirmed AIFM3 and DLK1 expression in MTC cases, while no expression was found in normal thyroid tissues and few MTC samples were found with normal copy numbers. The functional relevance of CNA was also assessed by in silico analysis. CNA status correlated with protein expression (DLK1, p = 0.01), tumor size (DLK1, p = 0.04) and AJCC staging (AIFM3 p = 0.01 and DLK1 p = 0.05). These data provide a novel insight into MTC biology, and suggest a common CNA landscape, regardless of if it is sporadic or hereditary MTC. (AU)

Processo FAPESP: 10/13833-2 - ABI3 e ABI3BP, caracterização das interações in vitro e investigação da via de sinalização
Beneficiário:Lais Moraes de Godoy
Linha de fomento: Bolsas no Brasil - Mestrado
Processo FAPESP: 14/06570-6 - Sequenciamento completo do exoma, Paired-end RNA e genoma: novos insights sobre a natureza genética do câncer de tiróide na idade adulta e na faixa etária pediátrica e aplicações na prática clínica
Beneficiário:Janete Maria Cerutti
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 17/06487-0 - Identificação do perfil metabólico das células com expressão ectópica de PVALB e investigação do mecanismo molecular associado sua expressão nos adenomas de células de Hürthle
Beneficiário:Thais Biude Mendes
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 12/02248-7 - Avaliação da relação entre os processos de angiogênese e linfangiogênese tumorais e o carcinoma medular de tiroide
Beneficiário:Marta Miyazawa
Linha de fomento: Bolsas no Brasil - Pós-Doutorado