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Exp Mol Pathol. 2015 Dec;99(3):416-25. doi: 10.1016/j.yexmp.2015.08.017. Epub 2015 Aug 29.

The development of rapid and accurate screening test for RET hotspot somatic and germline mutations in MEN2 syndromes.

Author information

1
Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, 1000 Ljubljana, Slovenia. Electronic address: andrej.zupan@mf.uni-lj.si.
2
Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, 1000 Ljubljana, Slovenia. Electronic address: damjan.glavac@mf.uni-lj.si.

Abstract

Medullary thyroid carcinoma (MTC) is a rare endocrine malignancy with distinctive features separating it from other thyroid cancers. Cancer may be sporadic or occur as a consequence of the hereditary syndrome called multiple endocrine neoplasia type 2 (MEN2) with three distinct phenotypes in MEN2A, MEN2B and FMTC. Each variant of MEN2 results from different RET gene mutations, with a good genotype-phenotype correlation. The goal of the study was to develop a fast and accurate screening method for a reliable detection of hot-spot RET germline and sporadic tumor mutations. From a cohort of 191 patients with MTC and their relatives, 38 tested positive and 31 tested negative for a germline or somatic tumor RET mutation were selected. A positive HRM mutation pattern was detected in all mutation-positive patients and altogether the method was able to clearly differentiate between twenty different genotypes. A novel germline variant p.Ala639Thr was detected in MTC patient, which was determined to be likely benign. Analytical specificity was determined to be 98.6% and a sensitivity threshold was determined to be 30%. The fast and accurate HRM method reduces the turnaround time providing fast and important information, especially when targeted anti-tyrosine kinase therapy on tumor samples is considered. Overall, we developed a high-throughput, accurate and cost-effective approach for the detection of RET germline and sporadic tumor mutations.

KEYWORDS:

High resolution melt analysis; MEN2A; MEN2B; Multiple endocrine neoplasia; RET proto-oncogene

PMID:
26321248
DOI:
10.1016/j.yexmp.2015.08.017
[Indexed for MEDLINE]

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