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J Clin Endocrinol Metab. 2014 Jun;99(6):E1104-12. doi: 10.1210/jc.2013-2993. Epub 2014 Mar 6.

Genome-wide copy number analysis in a family with p.G533C RET mutation and medullary thyroid carcinoma identified regions potentially associated with a higher predisposition to lymph node metastasis.

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Genetic Bases of Thyroid Tumors Laboratory (A.N.A., L.M., J.M.C.), Division of Genetics, Department of Morphology and Genetics, Universidade Federal de São Paulo, and Laboratory of Molecular and Translational Endocrinology (M.I.C.F., R.M.B.M.), Division of Endocrinology, Department of Medicine, Universidade Federal de São Paulo, São Paulo SP 04039-032, Brazil; Center for Applied Genomics (H.H., J.L., R.P.), The Children's Hospital of Philadelphia, Research Institute; and Department of Pediatrics (H.H.), The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.



Our group described a p.G533C RET gene mutation in a large family with multiple endocrine neoplasia type 2 syndrome. Clinical heterogeneity, primarily associated with the presence of lymph node metastases, was observed among the p.G533C carriers.


The aim of this study was to use single-nucleotide polymorphism-array technology to identify copy number variations (CNVs), which are present in the constitutional DNA and associated with the established clinical and pathological features of aggressive medullary thyroid carcinoma (MTC), primarily the presence of lymph node metastasis.


Fifteen p.G533C carriers with MTC were chosen for the initial screening. The subjects were divided into two groups according the presence (n = 8) or absence (n = 7) of lymph node metastasis. Peripheral blood DNA was independently hybridized using a genome-wide single-nucleotide polymorphism Array 6.0 platform. The results were analyzed using both Genotyping Console and PennCNV software. To identify the possible candidate regions associated with the presence of lymph node metastasis, cases (metastatic MTC) were compared with controls (nonmetastatic MTC). The identified CNVs were validated by quantitative PCR in an extended cohort (n = 32).


Using two different algorithms, we identified nine CNV regions that may contribute to susceptibility to lymph node metastasis. The validation step confirmed that a CNV loss impacting the FMN2 gene was potentially associated with a greater predisposition to lymph node metastasis in this family (P = .0179). Finally, we sought to investigate whether the development of lymph node metastasis might not depend on a single CNV but rather a combination of various CNVs. These analyses defined a CNV pattern related to a more aggressive phenotype in this family, with CNV deletions being enriched in the metastatic group (P = .0057).


Although hereditable specific RET mutations are important to determine cancer risk, germline CNVs in disease-affected individuals may predispose them to MTC aggressiveness.

[Indexed for MEDLINE]

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