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Loss of Heterozygosity at the RET Protooncogene Locus in a Case of Multiple Endocrine Neoplasia Type 2A¹

Dipartimento di Biochimica e Biotecnologie Mediche and CEINGE Centro di Ingegneria Genetica (L.Q., O.F., M.P.C., V.C.), and Dipartimento di Patologia e Biologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli Federico II (A.P.), 80131 Naples; Divisione di Endocrinologia Ospedale Niguarda (U.V., A.L.), 20100 Milan; and Facoltà di Scienze Matematiche, Fisiche e Naturali, Università del Sannio (L.Q., V.C.), 82100 Benevento, Italy

Address all correspondence and requests for reprints to: Dr. Loredana Quadro, Facoltà di Scienze Matematiche, Fisiche e Naturali, Università del Sannio, 82100 Benevento, Italy. E-mail: quadro{at}dbbm unina.it; or Dr. Vittorio Colantuoni, Dipartimento di

We describe a patient affected by multiple endocrine neoplasia type 2A (MEN 2A) bearing a heterozygous germline mutation (Cys⁶³⁴Arg) in exon 11 and an additional somatic mutation of the RET protooncogene. A large intragenic deletion, spanning exon 4 to exon 16, affected the normal allele and was detected by quantitative PCR, Southern blot analysis, and screening of several polymorphic markers. This deletion causes RET loss of heterozygosity exclusively in the metastasis, thus suggesting a role for this second mutational event in tumor progression. No additional mutations were found in the other exons analyzed. We provide the first evidence that RET, a dominant oncogene, is affected by a germline mutation and by an additional somatic deletion of the wild-type allele. This unusual genetic profile may be related to the clinical course and very poor outcome.

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