Mutation of the RET proto-oncogene is correlated with RET immunostaining in subpopulations of cells in sporadic medullary thyroid carcinoma

Mutations in the RET proto-oncogene, which encodes a receptor tyrosine kina se, are associated with the pathogenesis of medullary thyroid carcinoma (MT C). Somatic mutations in RET, predominantly at codon 918, and very rarely a t codon 883, have been found in a proportion of sporadic MTC. Fire have pre viously shown that approximately 80% of sporadic MTCs had at least one subp opulation with a somatic RET mutation. Uneven distribution of somatic mutat ion within a single tumor or among metastases from a single individual was notable. In the present study, we sought to correlate RET expression, as de monstrated by RET immunohistochemistry, with mutation status in sporadic MT C for each tumor. Seventy evaluable subpopulations, belonging to 28 unrelat ed sporadic cases, comprising primary MIC and metastases, were immunostaine d with two different polyclonal antibodies raised against the C-terminus of RET. The regional presence of codon 918 or 883 seemed to coincide with inc reased RET immunopositivity in at least 62 of 70 (89%, P < 0.000001 tumor s ubpopulations. The reasons for this concordance are not entirely clear but could be related to either RNA or protein stability. Preliminary studies ha ve suggested that the presence of somatic codon 918 mutation in MTC has a p rognostic significance. If these preliminary results prove true, then given our data, we can further explore the feasibility of RET immunocytochemistr y as a rapid assessment for the presence of somatic codon 918 for molecular diagnostic and prognostic purposes.