Abstract
Activating variants in the receptor tyrosine kinase REarranged during Transfection (RET) cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominantly inherited cancer-susceptibility syndrome. The variant c.166C>A, p.Leu56Met in RET was recently reported in two patients with medullary thyroid cancer (MTC). The presence of a pheochromocytoma in one of the patients, suggested a possible pathogenic role of the variant in MEN 2A. Here, we present clinical follow up of a Danish RET Leu56Met cohort. Patients were evaluated for signs of MEN 2 according to a set of predefined criteria. None of the seven patients in our cohort exhibited evidence of MEN 2. Furthermore, we found the Leu56Met variant in our in-house diagnostic cohort with an allele frequency of 0.59%, suggesting that it is a common variant in the population. Additionally, none of the patients who harbored the allele were listed in the Danish MTC and MEN 2 registries. In conclusion, our findings do not support a pathogenic role of the Leu56Met variant in MEN 2.
Highlights
REarranged during Transfection (RET) is a receptor tyrosine kinase that plays essential roles in several intracellular pathways as well as processes such as embryonic development of the enteric nervous system
The MEN 2A subtype is characterized by medullary thyroid cancer (MTC) with pheochromocytoma, primary hyperparathyroidism (PHPT) and in some cases, cutaneous lichen amyloidosis and Hirschsprung’s disease (HSCR), while MEN2B is characterized by MTC, pheochromocytoma, gastrointestinal and/or mucosal neuromas and a marfanoid habitus [1, 5]
Evidence of multiple endocrine neoplasia type 2 (MEN 2) in RET Leu56Met carriers was evaluated by the following criteria, as previously described [10] with additional criteria to include MEN2B: (i) the patient demonstrates more than one MEN 2 manifestation, including histologically verified MTC, histologically verified pheochromocytoma, histologically verified gastrointestinal or mucosal neuromas, histologically verified HSCR, biochemically verified PHPT, and clinically or histologically verified cutaneous lichen amyloidosis, or (ii) the patient has one MEN 2 manifestation and a relative with MTC and the RET Leu56Met variant
Summary
REarranged during Transfection (RET) is a receptor tyrosine kinase that plays essential roles in several intracellular pathways as well as processes such as embryonic development of the enteric nervous system. Evidence of MEN 2 in RET Leu56Met carriers was evaluated by the following criteria, as previously described [10] with additional criteria to include MEN2B: (i) the patient demonstrates more than one MEN 2 manifestation, including histologically verified MTC, histologically verified pheochromocytoma, histologically verified gastrointestinal or mucosal neuromas, histologically verified HSCR, biochemically verified PHPT, and clinically or histologically verified cutaneous lichen amyloidosis, or (ii) the patient has one MEN 2 manifestation and a relative with MTC and the RET Leu56Met variant. Data was compiled from patients for whom RET sequencing was performed at our department until 2020, as part of a larger gene panel for hereditary endocrinological diseases, renal cancers and malignant melanoma These patients constituted our inhouse diagnostic cohort. This study was approved by the local Ethics Committee in the capital region of Denmark (H-42010-050) as well as the Danish Health Authority (3‐3013‐395/3) and the Danish Data Protection Agency (18/17801)
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