Genetic testing for familial cancer. Consequences of RET proto-oncogene mutation analysis in multiple endocrine neoplasia, type 2.

OBJECTIVE

To assess clinician use and acceptance of RET proto-oncogene mutation testing in multiple endocrine neoplasia, type 2 (MEN 2) family members.

DESIGN

A retrospective survey of clinicians managing 26 MEN 2 families with documented RET mutations to assess the effect of genetic screening on subsequent investigation and management of family members.

SETTING

Tertiary referral center for RET mutation testing.

MAIN OUTCOME MEASURES: The screening procedures used by clinicians and the altered incidence of C-cell hyperplasia vs medullary thyroid carcinoma in genetically as opposed to biochemically identified affected family members.

RESULTS

Among RET mutation-positive patients, thyroidectomy performed for clinical or biochemical indication disclosed medullary thyroid carcinoma in 44 (98%) of 45 patients and precursor C-cell hyperplasia in only 1 (2%) patient. When prophylactic thyroidectomy was performed based on a positive genetic result, medullary thyroid carcinoma occurred in 3 (43%) of 7 patients and C-cell hyperplasia in 4 (57%) of 7 patients (P < .001). RET mutation-negative patients were not subjected to further biochemical testing, but 4 had already undergone thyroidectomy based on abnormal results of pentagastrin stimulation tests, including 2 patients who were known to be RET mutation-negative at the time of surgery. RET mutation testing was well accepted and resulted in additional family members consenting to screening in more than 85% of families.

CONCLUSIONS

Genetic screening for RET proto-oncogene mutations in MEN 2 is a powerful diagnostic tool that enables prophylactic thyroidectomy to be performed in RET mutation-positive patients at an earlier stage of the disease process than does traditional biochemical screening.