GENETIC EVOLUTION OF NEURAL CREST DERIVATIVES IN MULTIPLE ENDOCRINE NEOPLASIA 2A. DIFFERENTIAL PATTERNS FOR C-CELL AND ADRENAL MEDULLARY HYPERPLASIAS

Salvador J. Diaz-Cano, A Blanes, M De Miguel, R Tashjian, HJ Wolfe
2012 Figshare  
C-cell hyperplasias (CCH) and adrenal medullary hyperplasias (AMH) have been reported multifocal and monoclonal in multiple endocrine neoplasia2A, but the genetic evolution of those lesions remains unknown.Methods: We selected 10 females with bilateral CCH and 11 with AMH from known MEN-2A kindred (RET point mutation in codon 634). DNA was extracted from microdissected samples of 22 CCH foci (one per lobe) and from 34 AMH nodules. The samples were used for HUMARA clonality test (with Hhal
more » ... st (with Hhal digestion) and microsatellite pattern analysis of TP53, RB1, WT1, and NF1 by PCR denaturing gradient gel electrophoresis. Sample clonality and microsatellite patterns were compared !n each patient, including only informative cases in the final analysis.Results: CCH foci (I6118 from 9 informative patients) and AMH nodules (27/30 from 9 informative patients) revealed the same androgen receptor allele inactivated in each patient. The microsatellite analysis showed loss of heterozygosity (LOH) for TP53 (6110, 60%), RB1 (4/7, 57%) in CCH, all with concordant LOH pattern in each lobe. In contrast, AMH revealed heterogeneous and lower incidence of LOH for TP53 (3110, 30%), RB1 (118, 13%), WT1 (319, 33%), and NF1 (316, 50%), with discordant microsatellite pattern in 67% of cases.Conclusions: Both CCH and AMH are essentially monoclonal lesions in MEN-PA and reveal divergent genetic evolution. Early TP53 and RE1 genetic alterations (concordant in both lobes) characterize CCH and support the neoplastic nature of this lesion. AMH is heterogeneous and shows low incidence of microsatellite abnormalities.with discordant patterns involving NF1 locus; these genetic findings are not consistent with a fully established neoplasm.
doi:10.6084/m9.figshare.97902.v1 fatcat:yegdw63wfzgo7pydq3h2k4k6c4