AUTHOR=Mathiesen Jes Sloth , Nielsen Søren Grønlund , Rasmussen Åse Krogh , Kiss Katalin , Wadt Karin , Hermann Anne Pernille , Nielsen Morten Frost , Larsen Stine Rosenkilde , Brusgaard Klaus , Frederiksen Anja Lisbeth , Godballe Christian , Rossing Maria 

TITLE=Variability in Medullary Thyroid Carcinoma in RET L790F Carriers: A Case Comparison Study of Index Patients

JOURNAL=Frontiers in Endocrinology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2020.00251

DOI=10.3389/fendo.2020.00251

ISSN=1664-2392

ABSTRACT=<p><bold>Background:</bold> Previous studies have suggested that the variability in age of onset and aggressiveness of medullary thyroid carcinoma (MTC) in patients with multiple endocrine neoplasia type 2A (MEN 2A) carrying the same <italic>RE</italic>arranged during <italic>T</italic>ransfection (<italic>RET</italic>) mutation may be caused by additional <italic>RET</italic> germline variants or somatic variants.</p><p><bold>Methods:</bold> This study was a retrospective case comparison study of all MEN 2A index patients (<italic>n</italic> = 2) with the <italic>RET</italic> L790F germline mutation in Denmark. Whole blood and MTC tissue were analyzed for <italic>RET</italic> germline variants and other somatic variants (&gt;500), respectively.</p><p><bold>Results:</bold> Patient 1 presented with MTC (T1aN1bM0) at age 14 years, while patient 2 presented with MTC (T1bN0M0) at age 70 years. No germline <italic>RET</italic> germline variants nor other variants were found to explain this MTC variability.</p><p><bold>Conclusions:</bold> We could not confirm the previously reported finding of a somatic <italic>RET</italic> variant as likely responsible for the early onset and aggressiveness of MTC in a <italic>RET</italic> germline mutation carrier. Also, we found no <italic>RET</italic> germline variants that could explain the MTC variability among our index patients. We did, however, identify a somatic <italic>FLT3</italic> R387Q variant with an unknown potential as genetic modifier. Further large-scale studies are needed to investigate genetic modifiers in <italic>RET</italic> L790F carriers.</p>