No evidence of RET germline mutations in familial pituitary adenoma.
Pituitary adenomas are common in the general population. Although most of them are sporadic, some occur in a familial setting. In familial pituitary adenoma patients it is common that no germline defects are found after screening of aryl hydrocarbon receptor interacting protein (AIP) and other genes known to underlie the condition, suggesting the existence of yet unknown predisposition genes. Recently, the RET proto-oncogene was found to be a novel in vivo interaction partner of AIP in the pituitary gland. Here, we have screened patients from 16 AIP mutation negative (AIPmut-) pituitary adenoma families for RET germline mutations to assess whether RET could play a role in pituitary adenoma predisposition, similar to AIP. We found five novel germline RET changes: one in RET Exon 4 and the rest in noncoding regions of RET. Two changes, c.1560*G > A and -1285 G > A, were segregated in affected family members. We also analyzed the RET region with enhancer element locator (EEL) to identify RET regulatory elements, and to see whether the changes resided in these. None of the variants mapped to the regions predicted by EEL. Expression of RET was examined in ten AIPmut- and seven AIP mutation positive (AIPmut+) somatotropinomas by immunohistochemistry, with a trend showing reduced expression in the latter (P = 0.05). We conclude that the RET variants are presumably not related to pituitary adenoma predisposition, although reduced RET expression may play a role in AIP-related genesis of somatotropinomas.
Heliövaara
Elina
E
Genome-Scale Biology Research Program, Department of Medical Genetics, University of Helsinki, 00014 Helsinki, Finland.
Tuupanen
Sari
S
Ahlsten
Manuel
M
Hodgson
Shirley
S
de Menis
Ernesto
E
Kuismin
Outi
O
Izatt
Louise
L
McKinlay Gardner
R J
RJ
Gundogdu
Sadi
S
Lucassen
Anneke
A
Arola
Johanna
J
Tuomisto
Anne
A
Mäkinen
Markus
M
Karhu
Auli
A
Aaltonen
Lauri A
LA
D000236:Adenoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002874:Chromosome Mapping; D004742:Enhancer Elements, Genetic; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D017422:Sequence Analysis, DNA
D047908:Intracellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C103265:aryl hydrocarbon receptor-interacting protein; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human