Specific Amino Acid Substitution As Well As RET Codon Location Influence Age Of Onset and Penetrance Of Pheochromocytoma In MEN2 Kindreds
Danielle B Cameron1, Jill C Rubinstein2, Glenda G Callender3, *Catherine W Dinauer3, Emily R Christison-Lagay3
1Massachusetts General Hospital, Boston, MA;2Memorial Sloan Kettering Cancer Center, New York, NY;3Yale School of Medicine, New Haven, CT
Objective: Risk categories by RET mutation in Multiple Endocrine Neoplasia Type 2A and 2B (MEN2) are well outlined for medullary thyroid cancer (MTC), but less defined for other components of the syndrome including pheochromocytoma. We sought to better define the age of onset and phenotypic penetrance of pheochromocytoma by specific mutation.
Design: Scoping Review of PubMed Indexed Papers and institution specific MEN2 kindreds.
Setting: Multi-institutional, multi-national data.
Patients: Patients within the PubMed indexed literature in whom Sanger Sequencing or Next Generation Sequencing identified a germline RET mutation and in whom data was available either regarding age of onset of pheochromocytoma or kindred incidence of pheochromocytoma.
Main Outcome Measures: Specific RET mutation by base-pair substitution or insertion-deletion, age of onset of pheochromocytoma, phenotypic penetrance of pheochromocytoma across kindred.
Results: A total of 104 patients with MEN2-associated pheochromocytoma were identified including 9 patients from Yale-New Haven Hospital. Twenty-three unique RET mutations were identified. Average age of onset ranged from 27 years (p.M918T) to 76 years (p.G533C). The most frequently occurring mutations were C634R (31% of all mutations), followed by p.C634Y (20%), pC634S (7%), and p.C634W, p.C618R, and p.C634G (6% each). Within mutations at the 634 position, p.C634R had the earliest age of onset (34yrs), while p.C634S had the latest average presentation (53yrs). Phenotypic penetrance ranged from 12% (p.C611Y) to 61% (p.C634R).
Conclusions: Specific RET mutation, not simply codon location as previously described, influences both the age of onset and phenotypic penetrance of pheochromocytoma. This information should be incorporated into future screening strategies and prognostication nomograms in patients with MEN2.
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