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RET mutations in exons 13 and 14 of FMTC patients
A Bolino1, I Schuffenecker, Y Luo
1Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genova, Italy.
Abstract:
RET is a receptor tyrosine kinase gene which is responsible for three different inherited cancer syndromes namely multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC) as well as for Hirschsprung disease (HSCR), a congenital disorder affecting the intestinal motility. Germ-line mutations in the RET exons 10 and 11 were demonstrated in the majority of the MEN 2A and FMTC patients. On the other hand, one codon of RET exon 16 is preferentially changed in MEN 2B patients. Recently, a germ-line mutation in the exon 13 was described in one FMTC family as well as in four sporadic MTCs. In the present study, we observed the same exon 13 mutation in two FMTC families. In addition, we identified a previously unreported substitution of RET exon 14 in two unrelated FMTC families. Both mutations segregate with the disease in these four FMTC families and involve the tyrosine kinase domain of RET. Haplotype analysis using polymorphic markers tightly linked to the RET gene indicates that in each pedigree the mutation arose as an independent event.
Insights
New RET gene mutations in exon 13 and 14 were found in familial medullary thyroid carcinoma (FMTC) families. These mutations, identified in the tyrosine kinase domain, arose independently in each family studied.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The RET proto-oncogene encodes a receptor tyrosine kinase crucial for development.
- Germline mutations in RET cause inherited cancer syndromes like Multiple Endocrine Neoplasia types 2A and 2B (MEN 2A, MEN 2B), and Familial Medullary Thyroid Carcinoma (FMTC).
- Specific RET exons (10, 11, 16) are commonly associated with these syndromes, but novel mutations are continually being discovered.
Purpose of the Study:
- To investigate novel germline mutations in the RET gene associated with Familial Medullary Thyroid Carcinoma (FMTC).
- To characterize the location and inheritance patterns of newly identified RET mutations.
- To determine if these mutations represent independent mutational events within affected families.
Main Methods:
- Germline DNA sequencing of RET exons in patients with FMTC.
- Segregation analysis within affected families to confirm disease association.
- Haplotype analysis using polymorphic markers linked to the RET gene to assess mutational origin.
Main Results:
- Identified a previously reported RET exon 13 mutation in two additional FMTC families.
- Discovered a novel RET exon 14 substitution in two unrelated FMTC families.
- Confirmed that both mutations segregate with FMTC and involve the RET tyrosine kinase domain, with evidence of independent origins.
Conclusions:
- Germline mutations in RET exon 13 and a novel mutation in exon 14 are associated with FMTC.
- These findings expand the spectrum of RET mutations implicated in FMTC.
- The independent occurrence of these mutations highlights the complex genetic landscape of inherited thyroid cancer.