In silico analysis of RET variants in medullary thyroid cancer: from the computer to the bedside.
OBJECTIVE
The American Thyroid Association (ATA) medullary thyroid cancer (MTC) guidelines group RET variants, in the setting of familial medullary thyroid cancer and multiple endocrine neoplasia type 2, into 4 classes of severity based on epidemiological data. The aim of this study was to determine if genotype correlates with phenotype in RET missense mutations.


METHODS
In silico mutational tolerance prediction.


METHODS
Academic research hospital.


METHODS
We analyzed all RET variants currently listed in the ATA guidelines for the management of MTC using 2 computer-based (in silico) mutation tolerance prediction approaches: PolyPhen-2 HumVar and PolyPhen-2 HumDiv. Our analysis also included 27 different RET single-nucleotide polymorphisms resulting in missense variants.


RESULTS
There was a statistically significant difference in the overall HumDiv score between ATA groups A and B (P = .025) and a statistically significant different HumVar score between benign polymorphisms and ATA group A (P = .023). Overall, RET variants associated with a less aggressive clinical phenotype generally had a lower Hum Div/Var score.


CONCLUSIONS
Polyphen-2 Hum Div/Var may provide additional clinical data to help distinguish benign from MEN2/familial medullary thyroid carcinoma-causing RET variants as well as less aggressive phenotypes (ATA A) from more aggressive ones (ATA B-C). In silico genetic analyses, with proper validation, may predict the phenotypic severity of RET variants, providing clinicians with a tool to aid clinical decision making in cases in which the RET variant is currently unknown or little epidemiological data are available.
Weill Cornell Medical College, New York, New York, USA.
Thomas E
TE
Heineman
Department of Otolaryngology-Head and Neck Surgery, Weill Cornell Medical College/New York Presbyterian, New York, New York, USA.
Rohan
R
Joshi
Department of Otolaryngology-Head and Neck Surgery, Weill Cornell Medical College/New York Presbyterian, New York, New York, USA.
Marc A
MA
Cohen
Department of Otolaryngology-Head and Neck Surgery, Weill Cornell Medical College/New York Presbyterian, New York, New York, USA.
William I
WI
Kuhel
Department of Otolaryngology-Head and Neck Surgery, Weill Cornell Medical College/New York Presbyterian, New York, New York, USA dik2002@med.cornell.edu.
David I
DI
Kutler
D018276:Carcinoma, Medullary / Q000151:congenital / Q000235:genetics; D018278:Carcinoma, Neuroendocrine; D004252:DNA Mutational Analysis / Q000379:methods*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D020125:Mutation, Missense; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012984:Software; D013964:Thyroid Neoplasms / Q000235:genetics*
D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
    RET gene; in silico analysis; medullary thyroid cancer; multiple endocrine neoplasia; thyroidectomy