A patient with MEN 2 and multiple mutations of RET in the germline

We read with interest the article by [Bartsch et al. (2000)] on a RET double mutation in the germline of a family with multiple endocrine neoplasia type 2 (MEN 2). Although mutations of the RET proto-oncogene are responsible for the development of MEN 2-associated tumors, the mechanism(s) explaining why only few of the affected cells in the target organs develop into tumors, are unknown ([Ponder, 1999]). Interestingly, recently described RET double mutations in the germline of patients with MEN 2 did not correlate with a more aggressive phenotype, although these double mutations affected functional domains of RET, in the case described by [Bartsch et al. (2000)] the cysteine-rich domain of exon 11, and in another case the tyrosine kinase domain of exon 14 ([Tessitore et al., 1999]). Importantly, in both of these cases, the double mutations of RET occurred on the same RET allele with one allele still remaining wild-type RET. Wild-type RET may exert a protective/neutralizing effect and may thereby compensate for the activating effects of the mutant RET allele. We would like to report a patient with MEN 2A, in whom we found 3 germline mutations of RET. A 40-year-old Caucasian woman presented with a neck mass that was diagnosed as metastatic medullary thyroid cancer. Biochemical screening for catecholamines revealed that the patient also had pheochromocytoma. She underwent thyroidectomy with radical neck dissection and bilateral adrenalectomy. On 3 year follow-up, she has no evidence of (recurrent) pheochromocytoma but of metastatic thyroid cancer with plasma calcitonin levels around 400 pg/ml (normal, < 14). Mutation analysis of geonomic blood DNA for RET revealed an exon 11 mutation (codon 631 GAC/TAC) in association with two new mutations of exon 14 (codon 819 AGC/ATC, codon 843 GAG/GAT) (Fig. [1]), both in functional domains of RET. In patients with MEN 2, the biological significance of more than one RET mutation needs to be further elucidated.

Fig. 1 Sequencing analysis of two new mutations/polymorphisms Ser819Ile (AGC to ATC) and Glu843Asp (GAG to GAT) in exon 14 of RET. Sequencing was performed from PCR-amplified DNA using the AmpliCycle sequencing (Perkin Elmer Roche) kit

References

• 1 Bartsch D C, Hasse C, Schug C, Barth P, Rothmund M, Hoppner W. A RET double mutation in the germline of a kindred with FMTC.  Exp Clin Endocrinol Diabetes. 108 128-132 2000; 
• 2 Ponder BA J. The phenotypes of patients with RET mutations in the multiple endocrine neoplasia type 2 syndrome.  Cancer Res. 59 1736-1742 1999; 
• 3 Tessitore A, Sinisi A A, Pasquali D, Cardone M, Vitale D, Bellastella A, Colantoni V. A novel case of multiple endocrine neoplasia type 2A associated with two de novo mutations of the RET proto-oncogene.  J. Clin endocrinol Metab. 84 3522-3527 1999;