Loss of heterozygosity at the RET protooncogene locus in a case of multiple endocrine neoplasia type 2A

We describe a patient affected by multiple endocrine neoplasia type 2A (MEN 2A) bearing a heterozygous germline mutation (Cys(634)Arg) 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 d etected by quantitative PCR, Southern blot analysis, and screening of sever al polymorphic markers. This deletion causes RET loss of heterozygosity exc lusively in the metastasis, thus suggesting a role for this second mutation al event in tumor progression. No additional mutations were found in the ot her exons analyzed. We provide the first evidence that RET, a dominant onco gene, is affected by a germline mutation and by an additional somatic delet ion of the wild-type allele. This unusual genetic profile may be related to the clinical course and very poor outcome.