Genetic analysis of RET, GFR alpha 1 and GDNF genes in Spanish families with multiple endocrine neoplasia type 2A

• Published in: International journal of cancer Vol. 99; no. 2; pp. 299 - 304
• Main Authors: Gil, Laura, Azañedo, Marta, Pollán, Marina, Cristobal, Eva, Arribas, Begoña, García-Albert, Luis, García-Sáiz, Alfredo, Maestro, María Luisa, Torres, Antonio, Menárguez, Javier, Rojas, José M
• Format: Journal Article
• Language: English
• Published: United States 10.05.2002
• Subjects: Alleles; DNA Mutational Analysis; Drosophila Proteins; Female; Gene Frequency; Glial Cell Line-Derived Neurotrophic Factor; Glial Cell Line-Derived Neurotrophic Factor Receptors; Humans; Male; Multiple Endocrine Neoplasia Type 2a - genetics; Mutation; Nerve Growth Factors; Nerve Tissue Proteins - genetics; Pedigree; Polymorphism, Genetic; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-ret; Receptor Protein-Tyrosine Kinases - genetics; Spain; Spain
• ISSN: 0020-7136
• DOI: 10.1002/ijc.10298

Multiple endocrine neoplasia type 2A (MEN 2A) is associated with specific germline missense mutations in the RET proto-oncogene. This locus encodes a receptor tyrosine kinase whose activation requires the formation of a multimeric receptor complex including GDNF as a ligand and GFR alpha 1 as a coreceptor. In order to explore the role of RET, GFR alpha 1 and GDNF genes in the variation of phenotypes observed in MEN2A families, we analysed germline mutations of these genes in 4 unrelated Spanish MEN2A families (23 cases studied). We found 2 novel variants corresponding to a single change in position + 47 (intron 12) of RET and position +22 (intron 7) of GFR alpha 1. Furthermore, we observed strong co-segregation between 2 polymorphisms of RET [G691S (exon 11) and S904S (TCC-TCG, exon 15) (100%, Fisher's exact test, p< 0.001)]. More interestingly, we found that these polymorphisms occurred at a significantly high frequency in patients with age at onset < 20 years old (Kruskal-Wallis's and Fisher's exact test, p = 0.007). These findings suggest that the G691S and S904S variants of RET may somehow play a role on the age of onset of MEN 2A.