A newly identified RET proto-oncogene polymorphism is found in a high number of endocrine tumor patients.
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.
Gartner
Wolfgang
W
Department of Internal Medicine III, General Hospital Vienna, Vienna Medical University, Waehringer Guertel 18-20, 1090 Vienna, Austria.
Mineva
Ivelina
I
Daneva
Teodora
T
Baumgartner-Parzer
Sabina
S
Niederle
Bruno
B
Vierhapper
Heinrich
H
Weissel
Michael
M
Wagner
Ludwig
L
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*
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