JAMA · 1996 · 1K citations · 30 references
MedicineEndocrinologyGeneticsHuman GeneticsMedical GeneticsNeoplasiaEndocrine Tumor GeneticsGenetic DisordersMultiple Endocrine NeoplasiaOncogene MutationsThyroid CancerThyroid DisordersGenetic Predisposition To Medullary Thyroid CarcinomaGenotype-phenotype AssociationsGermline Mutation AnalysisMultiple Endocrine Neoplasia Type 2BMutationRet Gene MutationsRet MutationsRet Proto-oncogene Mutations
MEN 2 is an autosomal dominant disorder comprising three subtypes—MEN 2A, MEN 2B, and FMTC—each defined by distinct tumor patterns, and specific RET codon mutations have been linked to particular phenotypes. The study aimed to determine how specific RET mutations correlate with disease features in MEN 2 to inform clinical decision making. The authors conducted a multicenter survey of 477 MEN 2 families from 18 tertiary referral centers, assessing the association between RET mutation position/type and the presence of MTC, pheochromocytoma, hyperparathyroidism, and other features. The analysis found that MEN 2‑specific codon mutations occur in families with Hirschsprung disease, underscoring the need for monitoring, and confirmed that genotype‑phenotype correlations exist that could guide screening, surveillance, and prophylaxis.
Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making.Correlative survey study of 477 MEN 2 families.Eighteen tertiary referral centers worldwide.A total of 477 independent MEN 2 families.Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family.There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B--specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors.This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.
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Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A
Lois M. Mulligan, John B. Kwok, Catherine S. Healey et al. · Nature · 1993 · 2K citations
Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC
Helen Donis-Keller, Shenshen Dou, David Chi et al. · Human Molecular Genetics · 1993 · 1.3K citations
Katrin M. Carlson, Shuo‐Xing Dou, N J Scavarda et al. · Proceedings of the National Academy of Sciences · 1994 · 598 citations · Full text