Concordant Inactivated X-Chromosome Results from Early Monoclonal Expansions of Neural Crest Precursors in MEN-2A
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Background: The histologic definition of precursor lesions in MEN is controversial for both C-Cell Hyperplasia (CCH) and Adrenal Medullary Hyperplasia (AMH). They are multifocal and the clonality pattern of each focus remains unknown.
Methods: We found 10 females with bilateral CCH and another 11 with AMH in a MEN-2A kindred known to carry RET point mutation in codon 634. DNA was extracted from microdissected samples of CCH from each thyroid lobe and from 34 AMH nodules (2 nodules in 3 patients, 3 nodules in 4, and 4 nodules in 4). The samples were then used to study the methylation pattern of X-chromosome inactivation (HUMARA test using Hha-I digested and undigested samples). Appropriate and multiple tissue controls were run in every case. The inactivation pattern of X-chromosome of each sample was compared for any given patient, including only informative cases (2 alleles in both undigested and digested control samples) in the final analysis.
Results: Nine CCH patients were informative, 8 of them revealing monoclonal pattern with the same androgen receptor allele preferentially methylated in both lobes. Twenty-seven of 30 AMH nodules from 9 informative patients also revealed monoclonal unbalanced methylation of androgen receptor alleles and the same X-chromosome inactivated in nodules from a given patient. The remaining 2 CCH foci (1 patient) and 3 AMH nodules (2 patients) revealed balanced methylation of androgen receptor alleles. Under the hypothesis of independent allele methylation
in different lesions from the same patient, the combined probability of randomly finding the observed monoclonal results was less than 0.0001 for CCH and less than 0.000000001 for AMH.
Conclusions: MEN-2A-related CCH and nodular AMH are mainly monoclonal, and show the same X-chromosome inactivated in both thyroid lobes and in adrenal nodules from a given patient. This suggests a multifocal origin for both conditions related to early clonal expansions of neural crest precursors and may represent a paradigm for other germline mutations during embryogenesis.
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