The relationship between specific ret proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET mutation consortium analysis

Charis Eng, David Clayton, Isabelle Schuffenecker, Gilbert Lenoir, Gilbert Cote, Robert F. Gagel, Hans Kristian Ploos Van Amstel, Cornelis J M Lips, Isamu Nishisho, Shin Ichiro Takai, Debbie J. Marsh, Bruce G. Robinson, Karin Frank-Raue, Friedhelm Raue, Feiyu Xue, Walter W. Noll, Cristina Romei, Furio Pacini, Monika Fink, Bruno NiederleJan Zedenius, Magnus Nordenskjöld, Paul Komminoth, Geoffrey N. Hendy, Hossein Gharib, Stephen N Thibodeau, André Lacroix, Andrea Frilling, Bruce A J Ponder, Lois M. Mulligan

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Abstract

Objective. - 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. Design. - Correlative survey study of 477 MEN 2 families. Setting. - Eighteen tertiary referral centers worldwide. Patients. - A total of 477 independent MEN 2 families. Main Outcome Measures. - 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. Results. - 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. Conclusions. - 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.

Original languageEnglish (US)
Pages (from-to)1575-1579
Number of pages5
JournalJournal of the American Medical Association
Volume276
Issue number19
DOIs
StatePublished - Nov 20 1996

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Multiple Endocrine Neoplasia Type 2a
Proto-Oncogenes
Phenotype
Mutation
Codon
Pheochromocytoma
Hyperparathyroidism
Multiple Endocrine Neoplasia Type 2b
Hirschsprung Disease
Christianity
Germ-Line Mutation
Genetic Association Studies
Tertiary Care Centers
Outcome Assessment (Health Care)
Medullary Thyroid cancer

ASJC Scopus subject areas

  • Medicine(all)

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The relationship between specific ret proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2 : International RET mutation consortium analysis. / Eng, Charis; Clayton, David; Schuffenecker, Isabelle; Lenoir, Gilbert; Cote, Gilbert; Gagel, Robert F.; Ploos Van Amstel, Hans Kristian; Lips, Cornelis J M; Nishisho, Isamu; Takai, Shin Ichiro; Marsh, Debbie J.; Robinson, Bruce G.; Frank-Raue, Karin; Raue, Friedhelm; Xue, Feiyu; Noll, Walter W.; Romei, Cristina; Pacini, Furio; Fink, Monika; Niederle, Bruno; Zedenius, Jan; Nordenskjöld, Magnus; Komminoth, Paul; Hendy, Geoffrey N.; Gharib, Hossein; Thibodeau, Stephen N; Lacroix, André; Frilling, Andrea; Ponder, Bruce A J; Mulligan, Lois M.

In: Journal of the American Medical Association, Vol. 276, No. 19, 20.11.1996, p. 1575-1579.

Research output: Contribution to journalArticle

Eng, C, Clayton, D, Schuffenecker, I, Lenoir, G, Cote, G, Gagel, RF, Ploos Van Amstel, HK, Lips, CJM, Nishisho, I, Takai, SI, Marsh, DJ, Robinson, BG, Frank-Raue, K, Raue, F, Xue, F, Noll, WW, Romei, C, Pacini, F, Fink, M, Niederle, B, Zedenius, J, Nordenskjöld, M, Komminoth, P, Hendy, GN, Gharib, H, Thibodeau, SN, Lacroix, A, Frilling, A, Ponder, BAJ & Mulligan, LM 1996, 'The relationship between specific ret proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET mutation consortium analysis', Journal of the American Medical Association, vol. 276, no. 19, pp. 1575-1579. https://doi.org/10.1001/jama.276.19.1575
Eng, Charis ; Clayton, David ; Schuffenecker, Isabelle ; Lenoir, Gilbert ; Cote, Gilbert ; Gagel, Robert F. ; Ploos Van Amstel, Hans Kristian ; Lips, Cornelis J M ; Nishisho, Isamu ; Takai, Shin Ichiro ; Marsh, Debbie J. ; Robinson, Bruce G. ; Frank-Raue, Karin ; Raue, Friedhelm ; Xue, Feiyu ; Noll, Walter W. ; Romei, Cristina ; Pacini, Furio ; Fink, Monika ; Niederle, Bruno ; Zedenius, Jan ; Nordenskjöld, Magnus ; Komminoth, Paul ; Hendy, Geoffrey N. ; Gharib, Hossein ; Thibodeau, Stephen N ; Lacroix, André ; Frilling, Andrea ; Ponder, Bruce A J ; Mulligan, Lois M. / The relationship between specific ret proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2 : International RET mutation consortium analysis. In: Journal of the American Medical Association. 1996 ; Vol. 276, No. 19. pp. 1575-1579.
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abstract = "Objective. - 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. Design. - Correlative survey study of 477 MEN 2 families. Setting. - Eighteen tertiary referral centers worldwide. Patients. - A total of 477 independent MEN 2 families. Main Outcome Measures. - 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. Results. - 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. Conclusions. - 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.",
author = "Charis Eng and David Clayton and Isabelle Schuffenecker and Gilbert Lenoir and Gilbert Cote and Gagel, {Robert F.} and {Ploos Van Amstel}, {Hans Kristian} and Lips, {Cornelis J M} and Isamu Nishisho and Takai, {Shin Ichiro} and Marsh, {Debbie J.} and Robinson, {Bruce G.} and Karin Frank-Raue and Friedhelm Raue and Feiyu Xue and Noll, {Walter W.} and Cristina Romei and Furio Pacini and Monika Fink and Bruno Niederle and Jan Zedenius and Magnus Nordenskj{\"o}ld and Paul Komminoth and Hendy, {Geoffrey N.} and Hossein Gharib and Thibodeau, {Stephen N} and Andr{\'e} Lacroix and Andrea Frilling and Ponder, {Bruce A J} and Mulligan, {Lois M.}",
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T1 - The relationship between specific ret proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2

T2 - International RET mutation consortium analysis

AU - Eng, Charis

AU - Clayton, David

AU - Schuffenecker, Isabelle

AU - Lenoir, Gilbert

AU - Cote, Gilbert

AU - Gagel, Robert F.

AU - Ploos Van Amstel, Hans Kristian

AU - Lips, Cornelis J M

AU - Nishisho, Isamu

AU - Takai, Shin Ichiro

AU - Marsh, Debbie J.

AU - Robinson, Bruce G.

AU - Frank-Raue, Karin

AU - Raue, Friedhelm

AU - Xue, Feiyu

AU - Noll, Walter W.

AU - Romei, Cristina

AU - Pacini, Furio

AU - Fink, Monika

AU - Niederle, Bruno

AU - Zedenius, Jan

AU - Nordenskjöld, Magnus

AU - Komminoth, Paul

AU - Hendy, Geoffrey N.

AU - Gharib, Hossein

AU - Thibodeau, Stephen N

AU - Lacroix, André

AU - Frilling, Andrea

AU - Ponder, Bruce A J

AU - Mulligan, Lois M.

PY - 1996/11/20

Y1 - 1996/11/20

N2 - Objective. - 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. Design. - Correlative survey study of 477 MEN 2 families. Setting. - Eighteen tertiary referral centers worldwide. Patients. - A total of 477 independent MEN 2 families. Main Outcome Measures. - 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. Results. - 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. Conclusions. - 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.

AB - Objective. - 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. Design. - Correlative survey study of 477 MEN 2 families. Setting. - Eighteen tertiary referral centers worldwide. Patients. - A total of 477 independent MEN 2 families. Main Outcome Measures. - 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. Results. - 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. Conclusions. - 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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