Cys611Ser mutation in RET proto-oncogene in a kindred with medullary thyroid carcinoma and Hirschsprung's disease

Abstract

Germline mutations in the RET proto-oncogene are responsible for the development of human hereditary diseases, including multiple endocrine neoplasia (MEN) type 2A and 2B, familial medullary thyroid carcinoma (FMTC), and Hirschsprung's disease (HSCR). It has been reported that some families developed both MEN 2A/FMTC and HSCR, in which a mutation in a cysteine residue at codon 609, 618, or 620 in the RET gene was present. Here we report a novel RET mutation detected in a Japanese family with medullary thyroid carcinoma and HSCR. A germline mutation in cysteine 611 of the RET gene was identified in this family, which introduced an amino-acid change from cysteine to serine. By biological and biochemical analyses of mutant RET proteins, we previously predicted the potentiality that amino-acid substitution for cysteine 611 as well as cysteines 609, 618, and 620 would promote the development of MEN 2A/FMTC and HSCR. This clinical case substantiates our suggestion for the mechanism of the development of both the diseases.

Thyroid cancer and co-occurring RET mutations in Hirschsprung disease

“…Mutations in codon 791 of the RET gene appear to be weak or nonpathogenic mutations for MEN2A and FMTC (FrankRaue et al 2008, Erlic et al 2010. Our screening identified four patients aged between 31 and 50 years with mutations of the RET gene associated with development of MTC without any clinical evidence of thyroid cancer at screening (Mulligan et al 1994a,b, Romeo et al 1998, Sijmons et al 1998, Nishikawa et al 2003. These mutations included a C609R of exon 10 and Y791F (nZ3) of exon 13.…”

“…MEN2A/FMTC has been found to co-occur with HD in few patients worldwide (Borst et al 1995, Borrego et al 1999, Eng 1999, Fernández et al 2003, Nishikawa et al 2003, De Groot et al 2005, Dvoráková et al 2005, Bütter et al 2007, Fialkowski et al 2008. The main focus of these studies has been in the genetic screening of certain RET germline mutations (Pasini et al 2002, Nishikawa et al 2003, Dvoráková et al 2005. In some studies, HD patients or their relatives with MTC were genetically screened after the diagnosis of thyroid cancer (Fernández et al 2003).…”

“…All thus far identified HD-associated thyroid cancer mutations are located in exon 10 of the RET gene (Mulligan et al 1994a,b, Romeo et al 1998, Sijmons et al 1998, Nishikawa et al 2003. Mutations in codons 609, 611, and 620 carry markedly increased risk for developing MTC (Brandi et al 2001, Frank-Raue et al 2006.…”

“…Only mutations in codons 609, 611, 618, and 620 of exon 10 are known to co-segregate with HD and MEN syndromes (Mulligan et al 1994a,b, Romeo et al 1998, Sijmons et al 1998, Nishikawa et al 2003. Mutations in codon 791 of the RET gene are suggested to be weak or nonpathogenic mutations for MEN2A and familial medullary thyroid carcinoma (FMTC) (Frank-Raue et al 2008, Erlic et al 2010.…”

“…Previous studies have focused on genetic screening of certain germline RET mutations in non-population-based cohorts of selected HD and/or MTC patients or their families (Nishikawa et al 2003, De Groot et al 2005, Bütter et al 2007, Fialkowski et al 2008. Taking into account that genetics of HD is still incompletely understood, this approach may lead to biased conclusions regarding the risk of thyroid malignancies or co-occurring RET mutations among HD patients in general.…”