Medullary Thyroid Carcinoma Associated with Germline RETK666NMutation.
Multiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The RETK666NDNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown.



The clinical features, genetic data, and family information of eight index MTC patients with a germline RETK666Nvariant were assessed.



Four probands presented with MTC and extensive nodal metastasis, one with biopsy-confirmed distant metastasis. Two additional probands presented with localized disease. However, nodal status was not available. Of the final two probands, one had an incidental 1.5 mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had two foci of MTC (largest dimension 2.3 cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (aged 5-90 years), 11 of whom have documented evaluation for MTC. Of these, only two were found to have elevated basal serum calcitonin upon screening, and the remaining patients had calcitonin levels within the reference range. One patient who elected to have a thyroidectomy at 70 years of age was confirmed to have MTC. The other subject, 57 years old, elected surveillance. Four prophylactic thyroidectomies were performed, with one case of C-cell hyperplasia at 20 years and three cases that revealed normal pathology at ages 21, 30, and 30 years. None of the K666N DNA variant carriers had evidence of primary hyperparathyroidism or pheochromocytoma.



From this case series, the largest such experience to date, it is concluded that the RETK666Nvariant is likely pathogenic and associated with low penetrance of MTC. However, the findings are insufficient to define its pathogenicity clearly and make firm recommendations for screening and treatment. Given the potential benefit associated with early detection of aberrant C-cell growth, and the noninvasive nature of genetic testing, "at risk" individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.
1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center , Houston, Texas.|2 Division of Endocrinology, Baylor College of Medicine , Houston, Texas.
Jian Yu
JY
Xu
3 Department of Surgical Oncology, University of Texas MD Anderson Cancer Center , Houston, Texas.
Elizabeth G
EG
Grubbs
1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center , Houston, Texas.
Steven G
SG
Waguespack
1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center , Houston, Texas.
Camilo
C
Jimenez
1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center , Houston, Texas.
Robert F
RF
Gagel
4 Departments of Surgery and Medicine, Duke Cancer Institute, and Duke Clinical Research Institute, Duke University Medical Center , Durham, North Carolina.
Julie A
JA
Sosa
1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center , Houston, Texas.
Rena V
RV
Sellin
1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center , Houston, Texas.
Ramona
R
Dadu
1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center , Houston, Texas.
Mimi I
MI
Hu
3 Department of Surgical Oncology, University of Texas MD Anderson Cancer Center , Houston, Texas.
Chardria S
CS
Trotter
5 Department of Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center , Houston, Texas.
Michelle
M
Jackson
5 Department of Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center , Houston, Texas.
Thereasa A
TA
Rich
5 Department of Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center , Houston, Texas.
Samuel M
SM
Hyde
1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center , Houston, Texas.
Steven I
SI
Sherman
1 Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center , Houston, Texas.
Gilbert J
GJ
Cote
D000328:Adult; D000368:Aged; D002116:Calcitonin / Q000097:blood; D018276:Carcinoma, Medullary / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013961:Thyroid Gland / Q000473:pathology; D013964:Thyroid Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
K666N mutation; RET proto-oncogene; medullary thyroid cancer; multiple endocrine neoplasia type 2A
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