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Evaluation of the Genotype-Phenotype Relationship

Linwah Yip, MD; Gilbert J. Cote, PhD; Suzanne E. Shapiro, MS; Gregory D. Ayers, MS; Cynthia E. Herzog, MD; Rena V. Sellin, MD; Steven I. Sherman, MD; Robert F. Gagel, MD; Jeffrey E. Lee, MD; Douglas B. Evans, MD

Arch Surg. 2003;138:409-416.

Hypothesis  Multiple endocrine neoplasia type 2 (MEN 2) is caused by RET proto-oncogene mutations and has a strong penetrance for medullary thyroid carcinoma (MTC). Subtypes are defined by the presence or absence of pheochromocytomas, hyperparathyroidism, and characteristic clinical stigmas. We hypothesize that specific RET mutations correlate with the MEN 2 phenotype and aggressiveness of MTC.

Design  Review of endocrine surgery database from 1951 through 2002.

Setting  Tertiary referral center.

Patients  Eighty-six patients from 47 kindreds were identified with MEN 2A, MEN 2B, or familial MTC. Patients were classified into 3 RET mutation risk groups: level 1, low risk for MTC (codons 609, 768, 790, 791, 804, and 891); level 2, intermediate risk (codons 611, 618, 620, and 634); and level 3, highest risk (codons 883 and 918).

Main Outcome Measures  Stage of MTC at diagnosis and at last follow-up and frequency of pheochromocytomas and hyperparathyroidism.

Results  RET analysis was complete for 71 patients from 39 kindreds. Multivariate analysis identified an increased likelihood of stage III or IV MTC at diagnosis with increasing age (odds ratio, 1.12 per year of age at thyroidectomy; 95% confidence interval, 1.07-1.17; P<.001) and increasing risk group (odds ratio, 14.23 per incremental increase in MTC risk group from 1 to 3; 95% confidence interval, 3.05-66.55; P<.001). Pheochromocytomas were found in 21 patients from 12 kindreds; 20 of 21 patients had codon 634 or 918 mutations. Hyperparathyroidism was found in 10 patients from 7 kindreds; 7 of 10 patients had codon 634 mutations.

Conclusion  Specific RET mutations predict the phenotypic expression of disease and the MTC aggressiveness in patients with MEN 2, guiding the timing of thyroidectomy and screening for pheochromocytoma.

From the Departments of Surgical Oncology (Drs Yip, Lee, and Evans and Ms Shapiro), Endocrine Neoplasia and Hormonal Disorders (Drs Cote, Sellin, Sherman, and Gagel), Biostatistics (Mr Ayers), and Pediatrics (Dr Herzog), The University of Texas M. D. Anderson Cancer Center, Houston.

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