Evaluation of RET polymorphisms in a six-generation family with G533C RET mutation: specific RET variants may modulate age at onset and clinical presentation

Author(s)

Tamanaha, Rosana ^{[1, 2]} ; Camacho, Cleber P. ^[1] ; Pereira, Alexandre C. ^[3] ; Alvares da Silva, Adriana M. ^[4] ; Maciel, Rui M. B. ^[2] ; Cerutti, Janete M. ^{[1, 2]}

Affiliation

^[1] Univ Fed Sao Paulo, Genet Bases Thyroid Tumors Lab, Div Genet, BR-04039032 Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Div Endocrinol, BR-04039032 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Sch Med, Heart Inst InCor, Sao Paulo - Brazil

^[4] Heliopolis Hosp, Head & Neck Serv, Sao Paulo - Brazil

• Document type: Journal article
• Source: CLINICAL ENDOCRINOLOGY; v. 71, n. 1, p. 56-64, JUL 2009.
• Web of Science Citations: 20

Abstract

P>Context We previously described a six-generation family with G533C RET mutation and medullary thyroid carcinoma, in the largest family reported do date. Of particular interest, phenotype variability regarding the age of onset and clinical presentation of the disease, was observed. Objective We evaluate whether single SNPs within RET oncogene or haplotype comprising the RET variants (defined by Haploview) could predispose to early development of MTC in this family and influence the clinical manifestation. Design Eight SNPs were selected based on their previous association with the clinical course of hereditary or sporadic MTC, in particular promoting an early onset of disease. The variants were initially tested in 77 G533C-carriers and 100 controls using either PCR-direct sequencing or PCR-RFLP. Association between a SNP or haplotype and age at diagnosis or presence of lymph node metastasis was tested in 34 G533C-carries with MTC. Different bioinformatic tools were used to evaluate the potential effects on RNA splicing. Results An association was found between IVS1-126G > T and age at diagnosis. The variant {[}IVS8 +82A > G; 85-86 insC] was associated with the presence of lymph node metastases at diagnosis. In silico analysis suggested that this variant may induce abnormal splicing. This in silico analysis predicted that the {[}IVS8 +82A > G; 85-86 insC] could alter the splicing by disrupting and/or creating exonic splicing enhancer motifs. Conclusions We here identified two RET variants that were associated with phenotype variability in G533C-carriers, which highlights the fact that the modifier effect of a variant might depend on the type of mutation. (AU)

• FAPESP's process: 05/60330-8 - Molecular markers in diagnosis and prognosis of patients with tumors of the human thyroid: transition from basic to clinical research
• Grantee: Janete Maria Cerutti
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 06/60402-1 - Medular carcinoma of the thyroid: revisiting the clinical, molecular biological, biochemical and biological aspects following findings of molecular genetics
• Grantee: Rui Monteiro de Barros Maciel
• Support Opportunities: Research Projects - Thematic Grants