TY - JOUR
T1 - RET C611Y Germline Variant in Multiple Endocrine Neoplasia Type 2A in Denmark 1930-2021
T2 - A Nationwide Study
AU - Danish Thyroid Cancer Group (DATHYRCA)
AU - Hansen, Anders Würgler
AU - Vestergaard, Peter
AU - Poulsen, Morten Møller
AU - Rasmussen, Åse Krogh
AU - Feldt-Rasmussen, Ulla
AU - Madsen, Mette
AU - Næraa, Rune Weis
AU - Hansen, Dorte
AU - Main, Katharina
AU - Pedersen, Henrik Baymler
AU - Londero, Stefano Christian
AU - Rolighed, Lars
AU - Hahn, Christoffer Holst
AU - Rask, Klara Bay
AU - Maare, Christian
AU - Nielsen, Heidi Hvid
AU - Gaustadnes, Mette
AU - Rossing, Maria
AU - Hermann, Pernille
AU - Mathiesen, Jes Sloth
PY - 2025/1/23
Y1 - 2025/1/23
N2 - Background: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare hereditary cancer syndrome caused by pathogenic variants in the rearranged during transfection (RET) gene and is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), primary hyperparathyroidism (PHPT), cutaneous lichen amyloidosis (CLA), and Hirschsprung's disease. Phenotypic data on the RET C611Y variant remain sparse. Consequently, we aimed to establish a clinical risk profile. Methods: We conducted a nationwide study of all cases (n = 128) born after 1 January 1930 and recognized as carrying the RET C611Y variant in Denmark before 1 April 2021. Results: The median follow-up after birth was 47 years (range, 3-92). Age-related penetrance at age 70 years for MTC was 98% (CI, 91-100), for PHEO 24% (CI, 16-37), and for PHPT 10% (CI, 5-20). None had CLA or Hirschsprung's disease. The age-related progression of MTC was significant (p < 0.001). The median age at T0N0M0 was 11 years (2-62), at T1-4N0M0 was 37 years (12-65), at TxN1M0 was 47 years (16-79), and at TxNxM1 was 50 years (28-70). At the last follow-up, 56% of thyroidectomized cases (n = 103) were biochemically cured. Overall survival at 70 years was 74% (CI, 59-84). Conclusions: RET C611Y is associated with a very high penetrance of MTC and a low penetrance of PHEO and PHPT. CLA and Hirschsprung's disease almost never occur. MTC seems moderately aggressive, but large variability can be seen. Overall survival may be comparable to that of the general population.
AB - Background: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare hereditary cancer syndrome caused by pathogenic variants in the rearranged during transfection (RET) gene and is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), primary hyperparathyroidism (PHPT), cutaneous lichen amyloidosis (CLA), and Hirschsprung's disease. Phenotypic data on the RET C611Y variant remain sparse. Consequently, we aimed to establish a clinical risk profile. Methods: We conducted a nationwide study of all cases (n = 128) born after 1 January 1930 and recognized as carrying the RET C611Y variant in Denmark before 1 April 2021. Results: The median follow-up after birth was 47 years (range, 3-92). Age-related penetrance at age 70 years for MTC was 98% (CI, 91-100), for PHEO 24% (CI, 16-37), and for PHPT 10% (CI, 5-20). None had CLA or Hirschsprung's disease. The age-related progression of MTC was significant (p < 0.001). The median age at T0N0M0 was 11 years (2-62), at T1-4N0M0 was 37 years (12-65), at TxN1M0 was 47 years (16-79), and at TxNxM1 was 50 years (28-70). At the last follow-up, 56% of thyroidectomized cases (n = 103) were biochemically cured. Overall survival at 70 years was 74% (CI, 59-84). Conclusions: RET C611Y is associated with a very high penetrance of MTC and a low penetrance of PHEO and PHPT. CLA and Hirschsprung's disease almost never occur. MTC seems moderately aggressive, but large variability can be seen. Overall survival may be comparable to that of the general population.
U2 - 10.3390/cancers17030374
DO - 10.3390/cancers17030374
M3 - Article
C2 - 39941743
SN - 2072-6694
VL - 17
JO - Cancers
JF - Cancers
IS - 3
M1 - 374
ER -