A COMPLEX 9 BASE-PAIR DELETION IN RET EXON-11 COMMON IN SPORADIC MEDULLARY-THYROID CARCINOMA

Genetic alteration of the RET proto-oncogene is associated with multip le endocrine neoplasia type 2A and 2B (MEN 2A and MEN 2B), familial me dullary thyroid carcinoma (FMTC) and Hirschprung's disease. Oncogenica lly activated RET has also been demonstrated in sporadic medullary thy roid tumors, which in some cases show somatic missense mutations, We h ave recently described a complex 9 bp deletion in RET exon 11 in a sin gle case of sporadic MTC, In order to determine the prevalence of this mutation among sporadic MTC tumors, we have now analysed 15 cases and five normal controls by PCR-based nonradioactive single-strand confor mational polymorphism analysis (PCR-SSCP) and fragment size analysis o f exon 11, DNA was extracted from microdissected tumor tissue or norma l cells and subjected to nested PCR prior to analysis, A markedly dive rgent SSCP pattern and a PCR fragment 9 bp shorter than normal were de monstrated in 14 of the 15 MTC tumors. Sequencing revealed the deletio n of nine bases encompassing a key cysteine at codon 634, often altere d in MEN 2A, Four lymphocyte controls and normal thyroid tissue from o ne patient failed to show the deletion, Several factors in the DNA seq uence environment immediately surrounding the deletions, including an extended inverted repeat, several direct repeats and a so-called symme tric element suggest that the deletional events may be non-random.