Primary hyperparathyroidism (PHP; serum calcium 2.75 mmol/L, PTH 226 pg/ml) had been the first clinical manifestation of MEN-2A in a female patient (aged 55 years) with a mutation (Y791F, TAT-->TTT) in exon 13 of the RET proto-oncogene. The patient has a pentagastrin-induced rise in serum calcitonin (up to 57 pg/ml) considered normal for noncarriers but abnormal in family members of MEN-2 patients. This is the first case of MEN-2 due to this specific mutation with primary hyperparathyroidism as the first manifestation of the disease. In addition, the patient harbored, within the Menin gene, a polymorphism (D418D) reportedly associated with sporadic primary hyperparathyroidism. This case report indicates that molecular biological tests in MEN- 2 may only suggest a certain phenotype but cannot predict it with certainty. It may also suggest that genetic screening for MEN-2 may be advisable in patients with primary hyperparathyroidism and a borderline-high pentagastrin stimulation test, even in the absence of a positive family history.
"Patients with Y791F who display hyperparathyroidism and no MTC have been reported as well (Vierhapper et al. 2005). Another study identified RET Y791F in German patients with glioblastoma multiforme and gastric and pancreatic cancers who showed no clinical features of MTC or MEN2 (Rückert et al. 2011). "
[Show abstract][Hide abstract] ABSTRACT: Accurate interpretation of the RET proto-oncogene germline mutations is vital for the proper recommendation of preventive thyroidectomy in medullary thyroid carcinoma (MTC)-prone carriers. To gain information regarding the most disputed variant of RET, ATA-A Y791F, we sequenced blood DNA samples from a cohort of 2,904 cancer-free elderly individuals (1,261 via Sanger sequencing and 1,643 via whole-exome/genome sequencing). We also accessed the exome sequences of an additional 8,069 individuals from non-cancer-related laboratories and public databanks as well as genetic results from the COSMIC cancer project. The mean allelic frequency observed in the controls was 0.0031, with higher occurrences in Central European populations (0.006/0.008). The prevalence of RET Y791F in the control databases was extremely high compared with the 40 known RET pathogenic mutations (p=0.0000), while no somatic occurrence has been reported in tumours. Here, we report new, unrelated Brazilian individuals with germline RET Y791F-only: two tumour-free elderly controls; two individuals with sporadic MTC whose Y791F-carrying relatives did not show evidence of tumours; and a 74-year-old pheochromocytoma patient without MTC. Furthermore, we showed that the co-occurrence of Y791F with the strong RET C634Y mutation explains the aggressive MTC phenotypes observed in a large affected family that was initially reported as Y791F-only. Our literature review revealed that limited analyses have led to the misclassification of RET Y791F as a likely pathogenic variant and, consequently, to the occurrence of unnecessary thyroidectomies. The current study will have a substantial clinical impact, as it reveals, in a comprehensive manner, that the RET Y791F alone shows no association with MTC susceptibility.
Endocrine Related Cancer 11/2014; 22(1). DOI:10.1530/ERC-14-0491 · 4.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We aimed to investigate the occurrence and types of pathogenic mutations in the RET gene in patients with MTC of the Central Poland population and in their relatives. DNA was extracted from the peripheral blood lymphocytes of a total of 330 persons, including 235 MTC patients and 95 of their unaffected kindred's. Exons 10, 11, 13, 14, 15 and 16 of the RET gene were amplified by PCR and sequenced. Sixty-seven people were found to carry pathogenic, germline mutations in the RET gene. In exon 10, C609F, C609R and C609Y (3 families), C618G, C618F (2 families), and C620G (4 families) mutations were identified. In exon 11, C634R (8 families) and C649L mutations (1 patient) were found. Five families carried Y791F mutation in exon 13. One patient with PTC revealed the presence of a Y791F mutation. In 3 families, exon 14 of the RET gene harbored the following mutations: V804L (1 patient), E819K (1 patient) and R844Q (1 patient). In 1 family, the S891A mutation was identified in exon 15, 3 families were found to carry mutations in exon16, R912P in 1 family and M918T in 2 families. In summary, of the 235 patients affected by MTC, 46 (19.6%) carried pathogenic RET gene mutations, 1 patient with RET mutation had kidney carcinoma, and 1 had PTC. The results show the occurrence of a variety of mutations prevalent in patients with MTC in the population of Central Poland. These results may contribute to a better diagnosis of medullary thyroid carcinoma.
Cancer Investigation 01/2008; 25(8):742-9. DOI:10.1080/07357900701518735 · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hereditary medullary thyroid carcinoma (MTC) is caused by germ-line mutations in the RET proto-oncogene. Our study addresses the difference in development of MTC between rare mutations in RET codons 790, 791 and 804.
We evaluated tumour stage, calcitonin levels, biochemical cure rates and associated endocrinopathies in 153 German/Austrian patients with RET 790 (n = 47), 791 (n = 56) and 804 mutations (n = 50), divided into index- and screening groups.
Age at diagnosis in index-patients did not differ significantly among the three codon groups (medians of 57, 61 and 53 years). Tumour stage at diagnosis was significantly less advanced with codon 791 (n = 22) than 790 (n = 16) and 804 (n = 16) mutations (P = 0.001). In screening patients, age at diagnosis did not differ significantly among the three groups (medians 19, 24 and 32 years). Tumour stage at diagnosis was also significantly less advanced with codon 791 (n = 34) than 790 (n = 31) and 804 (n = 34) (P = 0.032). Preoperative basal calcitonin levels were significantly lower in codon 791 carriers compared to codon 790 carriers, and cure rates were significantly higher in both index (75%vs. 31%; P = 0.03) and screening patients (100%vs. 75%; P = 0.015). Additional endocrinopathies were observed only with codon 791 carriers (four pheochromocytomas and two hyperparathyroidism).
There is a significant difference in MTC development with less extensive C-cell disease, higher cure rate and more frequent additional endocrinopathies in carriers of RET codon 791 mutations compared with carriers of codons 790 and 804 mutations. This information should be considered when age of prophylactic thyroidectomy is discussed.
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