title: Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation.
abstract: RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3-72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20-72 and distant metastases in 4 subjects aged 28-69. Forty-one subjects had pheochromocytoma detected at age 18-67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26-52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.
authors.affiliation: Section of Preventive Medicine, Department of Nephrology, University of Freiburg Medical Centre, Freiburg im Breisgau, Germany.
authors.forename: Ioana N
authors.initials: IN
authors.lastname: Milos
authors.forename: Karin
authors.initials: K
authors.lastname: Frank-Raue
authors.forename: Nelson
authors.initials: N
authors.lastname: Wohllk
authors.forename: Ana Luiza
authors.initials: AL
authors.lastname: Maia
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pusiol
authors.forename: Attila
authors.initials: A
authors.lastname: Patocs
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Josefina
authors.initials: J
authors.lastname: Biarnes
authors.forename: Marta
authors.initials: M
authors.lastname: Barontini
authors.forename: Thera P
authors.initials: TP
authors.lastname: Links
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: de Groot
authors.forename: Sarka
authors.initials: S
authors.lastname: Dvorakova
authors.forename: Mariola
authors.initials: M
authors.lastname: Peczkowska
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Rybicki
authors.forename: Maren
authors.initials: M
authors.lastname: Sullivan
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Raue
authors.forename: Ioana
authors.initials: I
authors.lastname: Zosin
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000473:pathology; D002423:Cause of Death; D002648:Child; D002675:Child, Preschool; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D006961:Hyperparathyroidism / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000473:pathology; D019683:Penetrance; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012307:Risk Factors; D015996:Survival Rate; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: D051096:Proto-Oncogene Proteins c-ret