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Germline RET 634 Mutation Positive MEN 2A-related C-Cell Hyperplasias Have Genetic Features Consistent with Intraepithelial Neoplasia

Departments of Pathology, Tufts University–New England Medical Center (S.J.D.-C., R.T., H.J.W.), Boston, Massachusetts 02111; Barts and The London Queen Mary’s School of Medicine and Dentistry (S.J.D.-C.), E1 1BB London, United Kingdom; University Hospital of Seville (M.d.M.), 41009-Seville, Spain; and University Hospital of Malaga (A.B.), 29010-Malaga, Spain

Address all correspondence and requests for reprints to: Salvador J. Diaz-Cano, M.D., Ph.D., Department of Histopathology and Morbid Anatomy, The Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom. E-mail: s.j.diaz-cano{at}mds.qmw.ac.uk

Abstract

C-cell hyperplasias are normally multifocal in multiple endocrine neoplasia type 2A. We compared clonality, microsatellite pattern of tumor suppressor genes, and cellular kinetics of C-cell hyperplasia foci in each thyroid lobe.

We selected 11 females from multiple endocrine neoplasia type 2A kindred treated with thyroidectomy due to hypercalcitoninemia. C-cell hyperplasia foci were microdissected for DNA extraction to analyze the methylation pattern of androgen receptor alleles and microsatellite regions (TP53, RB1, WT1, and NF1). Consecutive sections were selected for MIB-1, pRB1, p53, Mdm-2, and p21^WAF1 immunostaining, DNA content analysis, and in situ end labeling. Appropriate tissue controls were run.

Only two patients had medullary thyroid carcinoma foci. Nine informative C-cell hyperplasia patients showed germline point mutation in RET, eight of them with the same androgen receptor allele preferentially methylated in both lobes. C-cell hyperplasia foci showed heterogeneous DNA deletions revealed by loss of heterozygosity of TP53 (12 of 20), RB1 (6 of 14), and WT1 (4 of 20) and hypodiploid G₀/G₁ cells (14 of 20), low cellular turnover (MIB-1 index 4.5%, in situ end labeling index 0.03%), and significantly high nuclear area to DNA index ratio.

MEN 2A (germline point mutation in RET codon 634) C-cell hyperplasias are monoclonal and genetically heterogeneous and show down-regulated apoptosis, findings consistent with an intraepithelial neoplasia. Concordant X-chromosome inactivation and interstitial gene deletions suggest clone expansions of precursors occurring at a point in embryonic development before divergence of each thyroid lobe and may represent a paradigm for other germline mutations.

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