Endocrine Abstracts

Introduction: Mutations in the RET gene cause multiple endocrine neoplasia type 2A (MEN2A), MEN2B, and familial medullary thyroid carcinoma (FMTC). The identification of a germline RET mutation aids clinical management, enables the identification and predictive testing of at risk family members and provides reassurance for mutation-negative family members. In the research setting, mutations in exons 5, 8, 10, 11, 13–16 of the RET gene have been identified in >98% MEN2A and FMTC cases^1,2. Approximately 95% of individuals with the MEN2B phenotype have the RET p.Met918Thr (p.M918T)¹ or p.Ala883Phe (p.A883F) mutation³. Approximately 7% patients with presumed sporadic medullary thyroid carcinoma have a germline mutation⁴. However, mutation detection rate in routine diagnostic setting is less known.

Methods: Our laboratory has been offering routine diagnostic RET testing for MEN2 and MTC for 16 years and have performed genetic screening in 720 cases (which included 269 cases of apparent sporadic MTC). We examined the cases we had tested in order to determine our mutation detection rate.

Results: We identified a RET mutation in 70 cases (10%) of our cohort: 16% of MEN2A cases, 30% of MEN2B cases, and 14% cases with FMTC. Further testing of the remaining exons of the RET gene in 21 patients did not detect any mutations. We identified a germline mutation in 9% of apparent sporadic MTC patients in our cohort.

Conclusions: Our data suggests that the mutation detection rate is lower in routine diagnostic laboratories than in a research setting, which may be due to less stringent testing criteria. Our data supports American (ATA) and European Thyroid Association (ETA) recommendation that all patients with MTC should be offered germline RET testing.

References: 1. Eng et al. JAMA 1996 276 1575–1579.

2. Hansford and Mulligan. J Med Genet 2000 37 817–827.

3. Gimm et al. J Clin Endocrinol Metab 1997 82 3902–3904.

4. Romei et al. Clin Endocrinol 2011 74 241–247.