A 28-year old patient presented with a sub-centimeter cytology-verified primary
papillary thyroid carcinoma (PTC) and a synchronous lateral
lymph node metastasis. Following surgery, histopathology confirmed a 9 mm oxyphilic PTC and a synchronous
metastasis of poorly differentiated
thyroid carcinoma (
PDTC). Extensive molecular examinations of both lesions revealed wildtype DICER1 sequences, but identified a somatic ETV6-NTRK3 gene fusion and a MET germline variant (c.1076G > A, p.Arg359Gln). MET is an established oncogene known to be overexpressed in
thyroid cancer, and this specific alteration was not reported as a single nucleotide polymorphism (SNP), suggestive of a mutation. Both the primary PTC and the metastatic
PDTC displayed strong MET immunoreactivity. A validation cohort of 50 PTCs from young patients were analyzed using quantitative real-time PCR, revealing significantly higher MET gene expression in
tumors than normal thyroid controls, a finding which was particularly pronounced in BRAF V600E mutated cases. No additional
tumors apart from the index case harbored the p.Arg359Gln MET mutation. Transfecting PTC cell lines MDA-T32 and MDA-T41 with a p.Arg359Gln MET plasmid construct revealed no obvious effects on cellular migratory or invasive properties, whereas overexpression of wildtype MET stimulated invasion.
CONCLUSIONS: The question of whether the observed MET mutation in any way influenced the dedifferentiation of a primary PTC into a
PDTC metastasis remains to be established. Moreover, our data corroborate earlier studies, indicating that MET is aberrantly expressed in PTC and may influence the invasive behavior of these
tumors.