title: A newly identified RET proto-oncogene polymorphism is found in a high number of endocrine tumor patients.
abstract: Multiple RET proto-oncogene transcripts, due to genomic variations and alternate splicing, have been described. To investigate endocrine tumor tissue characteristic RET proto-oncogene expression, we performed quantitative RT-PCR, Northern blot and Southern blot analyses of benign and malignant endocrine-derived tissues. We newly describe RET proto-oncogene expression in carcinoid-, gastrinoma- and insulinoma-derived tissue samples. In addition, the presence of a 3'-terminally truncated RET proto-oncogene mRNA variant in benign and malignant thyroid neoplasias, as well as in a pheochromocytoma, an ovarian carcinoma and a medullary thyroid carcinoma, is demonstrated. Southern blot analysis revealed no evidence of gross RET proto-oncogene rearrangements or deletions. As the underlying cause for a bi-allelic TaqI restriction fragment length polymorphism (RFLP), a C (allele 1)/T (allele 2) transition within intron 19, was characterized. This polymorphism is close to a recently described polyadenylation site and lies within a binding site for the nucleic acid binding protein Pbx-1. Screening of healthy subjects and of patients suffering from various endocrine malignancies revealed exclusively allele 1 homozygous and allele 1/allele 2 heterozygous genotypes. Heterozygous genotypes were found in a significantly higher percentage in samples derived from endocrine tumor patients when compared with those from healthy control subjects. Homozygosity for allele 2 was found exclusively in somatic DNA derived from endocrine tumors with high malignant potential. Analysis of DNA derived from varying regions within individual anaplastic thyroid carcinomas revealed an allele 1/allele 2 switch of the RFLP banding pattern, indicating loss of heterozygosity at the RET proto-oncogene locus. In conclusion, our data demonstrate presence of a 5'-terminal RET proto-oncogene transcript in endocrine tissues and reveal a bi-allelic RET proto-oncogene polymorphism. A heterozygous genotype for this polymorphism is found in a considerable number of endocrine tumor patients.
authors.affiliation: Department of Internal Medicine III, General Hospital Vienna, Vienna Medical University, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Gartner
authors.forename: Ivelina
authors.initials: I
authors.lastname: Mineva
authors.forename: Teodora
authors.initials: T
authors.lastname: Daneva
authors.forename: Sabina
authors.initials: S
authors.lastname: Baumgartner-Parzer
authors.forename: Bruno
authors.initials: B
authors.lastname: Niederle
authors.forename: Heinrich
authors.initials: H
authors.lastname: Vierhapper
authors.forename: Michael
authors.initials: M
authors.lastname: Weissel
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wagner
mesh_terms: D020413:3' Untranslated Regions / Q000096:biosynthesis / Q000235:genetics*; D000483:Alleles; D004701:Endocrine Gland Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases