Extensive mutation scanning of RET in sporadic medullary thyroid carcinoma and of RET and VHL in sporadic pheochromocytoma reveals involvement of these genes in only a minority of cases
RM Hofstra, T Stelwagen, RP Stulp, D de Jong, M Hulsbeek, EJ Kamsteeg, A van den Berg, RM Landsvater, A Vermey, WM Molenaar, CJ Lips and CH Buys
Department of Medical Genetics, University of Groningen, The Netherlands.
Sporadic medullary thyroid carcinoma (MTC) and pheochromocytoma (PC) have
been reported to be associated with some specific RET gene mutations. To
assess the role of RET in the development of MTC and PC, we screened 14
sporadic MTC, two MTC-derived cell lines, and 5 sporatic PC cases of RET
mutations by a systematic analysis of the whole coding sequence, including
all intron-exon junctions. In only 6 of the 14 sporadic MTC we were able to
detect a RET mutation. Apart from the MET918-->Thr mutation in 5 of the
MTC cases, we found a 3-bp deletion in exon 11, only present in the tumor,
in another case. Analysis of 2 cell lines revealed the Met918-->Thr
mutation in 1 and a Cys634-->Trp mutation in the other cell line. A
possible somatic nature of these mutations could not be confirmed because
in neither case was constitutive DNA available. We conclude that a large
proportion of sporadic MTC must be due to mutations in an unidentified
gene(s) other than RET. In none of the sporadic PC cases was a RET mutation
found. As PC is a frequent complication in families suffering from von
Hippel Lindau disease, for which mutations of the VHL gene are responsible,
we also screened the 5 sporadic PC cases for VHL mutations. This revealed a
Gly164-->Ser mutation in a single specimen. Thus, in PC, a large
majority of tumors are due to mutations in an unidentified gene(s) other
than RET and VHL.
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