Abstract
Background: 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 REarranged during Transfection (RET) mutation may be caused by additional RET germline variants or somatic variants.Methods: This study was a retrospective case comparison study of all MEN 2A index patients (n = 2) with the RET L790F germline mutation in Denmark. Whole blood and MTC tissue were analyzed for RET germline variants and other somatic variants (>500), respectively.Results: Patient 1 presented with MTC (T1aN1bM0) at age 14 years, while patient 2 presented with MTC (T1bN0M0) at age 70 years. No germline RET germline variants nor other variants were found to explain this MTC variability.Conclusions: We could not confirm the previously reported finding of a somatic RET variant as likely responsible for the early onset and aggressiveness of MTC in a RET germline mutation carrier. Also, we found no RET germline variants that could explain the MTC variability among our index patients. We did, however, identify a somatic FLT3 R387Q variant with an unknown potential as genetic modifier. Further large-scale studies are needed to investigate genetic modifiers in RET L790F carriers.
Highlights
Multiple endocrine neoplasia (MEN) 2 is an autosomal dominant inherited cancer syndrome subdivided into multiple endocrine neoplasia type 2A (MEN 2A) and MEN 2B [1, 2]
The father was tested negative for REarranged during Transfection (RET) mutations, while the mother was positive for the L790F mutation
This study found no RET germline variants or other somatic variants that could convincingly explain the substantial variability in medullary thyroid carcinoma (MTC) phenotype seen in our two L790F index patients
Summary
Multiple endocrine neoplasia (MEN) 2 is an autosomal dominant inherited cancer syndrome subdivided into MEN 2A and MEN 2B [1, 2]. MEN 2A and 2B are caused by germline mutations of the REarranged during Transfection (RET) proto-oncogene [7,8,9,10,11]. Some authors have suggested that certain RET germline variants (IVS1-126G>T, IVS8+82A>G; 85-86 insC, G691S, L769L, S836S, S904S) in combination with a RET germline mutation may modify the age of onset and aggressiveness of MTC in MEN 2 patients [22,23,24,25,26]. 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 REarranged during Transfection (RET) mutation may be caused by additional RET germline variants or somatic variants
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