Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10.
Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.
Endocrine Practice and Molecular Laboratory, Heidelberg, Germany.
Karin
K
Frank-Raue
Lisa A
LA
Rybicki
Zoran
Z
Erlic
Heiko
H
Schweizer
Aurelia
A
Winter
Ioana
I
Milos
Sergio P A
SP
Toledo
Rodrigo A
RA
Toledo
Marcos R
MR
Tavares
Maria
M
Alevizaki
Caterina
C
Mian
Heide
H
Siggelkow
Michael
M
Hüfner
Nelson
N
Wohllk
Giuseppe
G
Opocher
Sárka
S
Dvořáková
Bela
B
Bendlova
Małgorzata
M
Czetwertynska
Elżbieta
E
Skasko
Marta
M
Barontini
Gabriela
G
Sanso
Christian
C
Vorländer
Ana Luiza
AL
Maia
Attila
A
Patocs
Thera P
TP
Links
Jan Willem
JW
de Groot
Michiel N
MN
Kerstens
Gerlof D
GD
Valk
Konstanze
K
Miehle
Thomas J
TJ
Musholt
Josefina
J
Biarnes
Svetozar
S
Damjanovic
Mihaela
M
Muresan
Christian
C
Wüster
Martin
M
Fassnacht
Mariola
M
Peczkowska
Christine
C
Fauth
Henriette
H
Golcher
Martin A
MA
Walter
Josef
J
Pichl
Friedhelm
F
Raue
Charis
C
Eng
Hartmut P H
HP
Neumann
D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018278:Carcinoma, Neuroendocrine; D002648:Child; D002675:Child, Preschool; D003062:Codon / Q000235:genetics; D005091:Exons; 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; D009367:Neoplasm Staging; D019683:Penetrance; D010673:Pheochromocytoma / Q000235:genetics / Q000473:pathology; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology; D055815:Young Adult
D003062:Codon; D051096:Proto-Oncogene Proteins c-ret