Human Molecular Genetics, Vol 7, 129-134, Copyright © 1998 by Oxford University Press
RA Decker, ML Peacock and P Watson
The RET proto-oncogene encodes a transmembrane receptor with tyrosine
kinase activity. Germline mutations in RET are responsible for a number of
inherited diseases. These include the dominantly inherited cancer syndromes
multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and
familial medullary thyroid carcinoma (FMTC), as well as some cases of
familial Hirschsprung disease (HSCR1). RET mutations in HSCR1 have been
shown to cause a loss of RET function, while the cancer syndromes result in
RET oncogenic activation. Occasionally MEN 2A or FMTC occurs in association
with HSCR1, albeit with low penetrance. An initial report linked HSCR1 in
MEN 2A solely to the C618R and C620R RET mutations. In this study we have
analyzed 44 families with MEN 2A. HSCR1 co-segregated with MEN 2A in seven
(16%) of the 44 families. The predisposing RET mutation in all seven
families had been previously reported in MEN 2A or FMTC and occurred in
exon 10 at codons 609, 618 or 620, resulting in C609Y, C618S, C620R or
C620W substitution. MEN 2A families with RET exon 10 Cys mutations had a
substantially greater risk of developing HSCR1 than those with the more
common RET exon 11 Cys634 or exon 14 c804 mutations (P = 0.0005). These
findings suggest that expression of HSCR1 in MEN 2A may be peculiar to RET
exon 10 Cys mutations . However, HSCR1 in MEN 2A is not exclusive to C618R
or C620R RET mutations and can occur with other exon 10 Cys amino acid
substitutions. The strong correlation between disease phenotype and
position of the MEN 2A RET mutation suggests that oncogenic activation of
RET alone is insufficient to account for co-expression of the diseases.
ARTICLES
Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation
The Charlie Hays Division of Cancer Research, The Decker Foundation, 7536 Forsyth Boulevard, St Louis, MO 63105, USA. r-decker2@nwu.edu
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