A RET double mutation in the germline of a kindred with FMTC

Abstract

Activating germline mutations of the RET proto-oncogene are found in more than 90% of families with multiple endocrine neoplasia type 2a (MEN 2a) and familial medullary thyroid carcinoma (FMTC). The majority of patients with these hereditary tumors carry germline mutations that result in the substitution of one of five cysteine residues in exon 10 and 11. Different mutations in exons 13, 14 and 15 affecting non-cysteine residues have also been described but are considered to be rare. We now for the first time report a double mutation of the RET proto-oncogene occurring in the germline of a kindred with FMTC. Both mutations occur within the tyrosine kinase domain in exon 14 and lead to the substitution of valine 804 by methionine and arginine 844 by leucine. Since the double mutated allele cosegregated with the disease and was not identified in 200 unrelated normal probands, we conclude that they represent mutations that predispose the individual to the development of FMTC with a mild phenotype.

RET Is Constitutively Activated by Novel Tandem Mutations that Alter the Active Site Resulting in Multiple Endocrine Neoplasia Type 2B

“…(34) and (d) RET V804M/R844L (35) in FMTC. We then extended the physicochemical conservation metric used in the previous study (MAPP, see Materials and Methods) to accommodate multiple substitutions in cis.…”

Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors

“…In addition, V804 mutations can be found in combination with other RET point-mutations on different (Lombardo et al, 2002) or the same RET allele. In particular, Bartsch et al (2000) described an FMTC kindred carrying a double RET mutation (V804M and R844L), Kasprzak et al (2001) reported an FMTC family carrying the double V804M and V778I mutation, Menko et al (2002) described a MEN2B-like family carrying a double V804M and S904C mutation and Iwashita et al (2000) described another MEN2B family carrying a double V804M-Y806C mutation. Intriguingly, this RET V804M-Y806C mutant exerted an eight-to 13-fold higher transforming activity than that of single RET mutants.…”

The RET proto-oncogene in human cancers

“…As shown in Figure 2, all germline mutations identi®ed in the aected members of MEN 2 families are clustered in speci®c regions of RET: the cysteine-rich domain in exons 10 and 11, or the tyrosine kinase domains in exons 13 ± 16. In addition to the mutations listed in Figure 2, which account for mutations identi®ed in more than 95% of MEN 2 families, double mutations have been found in rare MEN 2 families, such as V804M/R844L in FMTC, V804M/Y806C in MEN 2B, and C634R/A640G in MEN 2A (Tessitore et al, 1999;Bartsch et al, 2000;Iwashita et al, 2000).…”