Abstract
Background The aim of this study was to identify germline mutation of the RET (rearranged during transfection) gene in patients with medullary thyroid carcinoma (MTC) and their first-degree relatives to find presymptomatic carriers for possible prophylactic thyroidectomy. Methods/Patients. We examined all six hot spot exons (exons 10, 11, 13, and 14–16) of the RET gene by PCR and bidirectional Sanger sequencing in 45 Iranian patients with MTC (either sporadic or familial form) from 7 unrelated kindred and 38 apparently sporadic cases. First-degree relatives of RET positive cases were also genotyped for index mutation. Moreover, presymptomatic carriers were referred to the endocrinologist for further clinical management and prophylactic thyroidectomy if needed. Results Overall, the genetic status of all of the participants was determined by RET mutation screening, including 61 affected individuals, 22 presymptomatic carriers, and 29 genetically healthy subjects. In 37.5% (17 of 45) of the MTC referral index patients, 8 distinct RET germline mutations were found, including p.C634R (35.3%), p.M918T (17.6%), p.C634Y (11.8%), p.C634F (5.9%), p.C611Y (5.9%), p.C618R (5.9%), p.C630R (5.9%), p.L790F (5.9%), and one uncertain variant p.V648I (5.9%). Also, we found a novel variant p.H648R in one of our apparently sporadic patients. Conclusion RET mutation detection is a promising/golden screening test and provides an accurate presymptomatic diagnostic test for at-risk carriers (the siblings and offspring of the patients) to consider prophylactic thyroidectomy. Thus, according to the ATA recommendations, the screening of the RET proto-oncogene is indicated for patients with MTC.
Highlights
Calcitonin-secreting parafollicular C cells of the thyroid gland are the origin of 5–10% of thyroid cancers, so called medullary thyroid carcinoma (MTC)
Hereditary forms are transmitted as autosomal dominant pattern of inheritance and are seen either as isolated familial MTC (FMTC) with a prevalence of 10% or as a syndromic form of cancer, known as multiple endocrine neoplasia type 2 (MEN2A and MEN2B, which have a prevalence of 85% and 5%, respectively) [2, 3]
Activation of the RET gene by rearrangement appears to be only seen in patients suffering from papillary thyroid carcinoma (PTC) [4] or thyroid adenoma [5], and germline missense mutations of the RET gene have been shown to be the cause of the hereditary form of MTC (MEN2) [6]
Summary
Calcitonin-secreting parafollicular C cells of the thyroid gland are the origin of 5–10% of thyroid cancers, so called medullary thyroid carcinoma (MTC). MTC has a worse prognosis than the most common form of thyroid cancer, papillary thyroid carcinoma (PTC), which accounts for 60–80% of thyroid carcinomas and originates from follicular cells [1]. Hereditary forms are transmitted as autosomal dominant pattern of inheritance and are seen either as isolated familial MTC (FMTC) with a prevalence of 10% or as a syndromic form of cancer, known as multiple endocrine neoplasia type 2 (MEN2A and MEN2B, which have a prevalence of 85% and 5%, respectively) [2, 3]. Activation of the RET gene by rearrangement (inversion or translocation) appears to be only seen in patients suffering from PTC [4] or thyroid adenoma [5], and germline missense mutations of the RET gene have been shown to be the cause of the hereditary form of MTC (MEN2) [6]. Gain of function mutations in exons 10, 11, 13, 14, and of the RET gene have mostly been reported MEN2A (e.g., codons 609, 611, 618, 620, and 634) but about 95% of the patients with MEN2B have a mutation in exon (codon 918). erefore, to obtain a reliable screening genetic test for MTC patients, exons 10, 11, 13, 14, 15, and 16 should be considered as the hot spots for RET gene mutations
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