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Mutation of the RET Proto-Oncogene Is Correlated with RET Immunostaining in Subpopulations of Cells in Sporadic Medullary Thyroid Carcinoma¹

Cancer Research Campaign Human Cancer Genetics Research Group (C.E., C.S.H., C.H., B.A.J.P.) and Department of Histopathology (G.A.T., E.D.W.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Department of Adult Oncology, Charles A. Dana Human Cancer Genetics Unit (C.E.), and Department of Biostatistical Science (D.S.N.), Dana-Farber Cancer Institute, Harvard Medical School (C.E.) and Harvard School of Public Health (D.S.N.), Boston, Massachusetts 02115-6084; Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, 690 Medical Research Facility, Columbus, Ohio 43210 (C.E.); Departments of Pathology and Paediatrics, Queen’s University, Kingston, ON K7L 3N6, Canada (L.M.M.); Universitäts-Krankenhaus, Chirurgische Klinik, Universität Hamburg, 2000 Hamburg 20, Germany (A.F.); and Medizinische Klinik und Poliklinik, Abteilung Innere Medizin I, Ruprecht-Karls-Universität Heidelberg, 69118 Heidelberg, Germany (F.R.)

Address all correspondence and requests for reprints to: Charis Eng, Human Cancer Genetics Program, Ohio State University Comprehensive Cancer Center, 690C Medical Research Facility, 420 West 12th Avenue, Columbus, Ohio 43210. E-mail: eng-1{at}medctr.osu.edu

Mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, are associated with the pathogenesis of medullary thyroid carcinoma (MTC). Somatic mutations in RET, predominantly at codon 918, and very rarely at codon 883, have been found in a proportion of sporadic MTC. We have previously shown that approximately 80% of sporadic MTCs had at least one subpopulation with a somatic RET mutation. Uneven distribution of somatic mutation within a single tumor or among metastases from a single individual was notable. In the present study, we sought to correlate RET expression, as demonstrated by RET immunohistochemistry, with mutation status in sporadic MTC for each tumor. Seventy evaluable subpopulations, belonging to 28 unrelated sporadic cases, comprising primary MTC and metastases, were immunostained with two different polyclonal antibodies raised against the C-terminus of RET. The regional presence of codon 918 or 883 seemed to coincide with increased RET immunopositivity in at least 62 of 70 (89%, P < 0.000001) tumor subpopulations. The reasons for this concordance are not entirely clear but could be related to either RNA or protein stability. Preliminary studies have suggested that the presence of somatic codon 918 mutation in MTC has a prognostic significance. If these preliminary results prove true, then given our data, we can further explore the feasibility of RET immunocytochemistry as a rapid assessment for the presence of somatic codon 918 for molecular diagnostic and prognostic purposes.

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