The evolving clinical, genetic and therapeutic landscape of multiple endocrine neoplasia type 2

    1. Lois M Mulligan1
    1. 1Division of Cancer Biology and Genetics, Cancer Research Institute, and Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada
    2. 2Department of General-, Visceral- and Transplantations Surgery, Division of Endocrine Surgery, Medical Faculty, University of Duisburg-Essen, Duisburg, Germany
    1. Correspondence should be addressed to L M Mulligan: mulligal{at}

    The association of medullary thyroid carcinoma (MTC) and pheochromocytoma (PHEO) that we now recognize as multiple endocrine neoplasia type 2 (MEN2) (Fig. 1) was first reported by John Sipple in 1961 (Sipple 1961), but over 30 years passed before the cause of this inherited cancer syndrome was identified as mutations of the rearranged during transfection (RET) receptor tyrosine kinase (Donis-Keller et al. 1993, Mulligan et al. 1993). In the ensuing 25 years, RET mutation detection has changed our approaches to MEN2 risk prediction, diagnosis, management and treatment and has greatly improved disease outcomes and quality of life for patients and families with the disease. Moreover, advances in research and technology and better understanding of the disease are pushing the barrier toward earlier, less intensive, personalized care.

    Figure 1

    Pedigree of a family with MEN2 showing autosomal dominant inheritance pattern.

    The identification of activating RET point mutations as the cause of MEN2 represented a novel paradigm for the origins of hereditary cancers, which had previously been exclusively linked to tumor suppressors. As MEN2 mutations activate or enhance RET kinase function, there were relatively few unique mutations (Fig. 2), which simplified detection and interpretation. This has led to our current abilities to predict disease course and optimize management based on the specific RET mutation observed (Wells et al. 2015).

    Figure 2

    MEN2 mutations in the RET receptor tyrosine kinase. Schematic diagram showing locations of the common RET mutations identified in MEN2 patients. The two mutations associated with MEN2B are indicated in red. Two sequence variants suggested to act as modifiers, either affecting severity of other RET mutations or as risk-associated alleles in other cancers, are indicted in blue. RET protein domains indicated are CLD, cadherin-like domains; CRD, cysteine-rich domain; KD, kinase domain; TM, transmembrane domain.

    The current outlook of MEN2 clinical management, treatment and quality of care

    In ‘Advances in the management of MEN2’, Samuel Wells …

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