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.
Frank-Raue
Karin
K
Endocrine Practice and Molecular Laboratory, Heidelberg, Germany.
Rybicki
Lisa A
LA
Erlic
Zoran
Z
Schweizer
Heiko
H
Winter
Aurelia
A
Milos
Ioana
I
Toledo
Sergio P A
SP
Toledo
Rodrigo A
RA
Tavares
Marcos R
MR
Alevizaki
Maria
M
Mian
Caterina
C
Siggelkow
Heide
H
Hüfner
Michael
M
Wohllk
Nelson
N
Opocher
Giuseppe
G
Dvořáková
Sárka
S
Bendlova
Bela
B
Czetwertynska
Małgorzata
M
Skasko
Elżbieta
E
Barontini
Marta
M
Sanso
Gabriela
G
Vorländer
Christian
C
Maia
Ana Luiza
AL
Patocs
Attila
A
Links
Thera P
TP
de Groot
Jan Willem
JW
Kerstens
Michiel N
MN
Valk
Gerlof D
GD
Miehle
Konstanze
K
Musholt
Thomas J
TJ
Biarnes
Josefina
J
Damjanovic
Svetozar
S
Muresan
Mihaela
M
Wüster
Christian
C
Fassnacht
Martin
M
Peczkowska
Mariola
M
Fauth
Christine
C
Golcher
Henriette
H
Walter
Martin A
MA
Pichl
Josef
J
Raue
Friedhelm
F
Eng
Charis
C
Neumann
Hartmut P H
HP
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