Two Sequences Variations of the E768D Mutation Found in Familial Medullary Thyroid Carcinomas

Medullary thyroid cancer or MTC is present in sporadic form (75% of cases) and in familial form (25% of cases), in this latter situation, the MTC is a part of Multiple Endocrine Neoplasia type 2 (MEN 2). The MEN2 is divided into MEN2A, MEN2B and FMTC or isolated familial MTC. The MEN2 are rare hereditary disease, transmitted as an autosomal dominant mode, linked to mutations of the RET gene. The discovery of a mutation in the RET proto-oncogene by molecular biology techniques in a index case of MTC confirms the diagnosis of familial and allows the genetic testing of healthy clinically related index case: those who carry the genetic mutation, will be offered prophylactic thyroidectomy before any biological or clinical manifestation. The genetic analysis of the RET gene was performed by PCR / sequencing. The E768D mutation was found in the exon 13 of the RET gene in 2 differences sequences forms (GAG/GAC et GAG/GAT). This mutation, already described, found in the FMTC.

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RET gene mutations and polymorphisms in medullary thyroid carcinomas in Indian patients

Journal of Biosciences ◽

10.1007/s12038-011-9095-0 ◽

2011 ◽

Vol 36 (4) ◽

pp. 603-611 ◽

Cited By ~ 12

Author(s):

B P Sharma ◽

D Saranath

Keyword(s):

Gene Mutations ◽

Medullary Thyroid ◽

Thyroid Carcinomas ◽

Ret Gene ◽

Indian Patients ◽

Medullary Thyroid Carcinomas

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Amplification and Overexpression of Mutant RET in Multiple Endocrine Neoplasia Type 2-Associated Medullary Thyroid Carcinoma

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2002-021254 ◽

2003 ◽

Vol 88 (1) ◽

pp. 459-463 ◽

Cited By ~ 37

Author(s):

Steve C. Huang ◽

Joshua Torres-Cruz ◽

Svetlana D. Pack ◽

Christian A. Koch ◽

Alexander O. Vortmeyer ◽

...

Keyword(s):

Cell Line ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Wild Type ◽

Medullary Thyroid ◽

Second Hit ◽

Men 2 ◽

Endocrine Neoplasia ◽

Associated Tumors

We have previously identified two second hit mechanisms involved in the development of multiple endocrine neoplasia type 2 (MEN 2)-associated tumors: trisomy 10 with duplication of the mutant RET allele and loss of the wild-type RET allele. However, some of the MEN 2-associated tumors investigated did not demonstrate either mechanism. Here, we studied the TT cell line derived from MEN 2-associated medullary thyroid carcinoma with a RET germline mutation in codon 634, for alternative mechanisms of tumorigenesis. Although we observed a 2:1 ratio between mutant and wild-type RET at the genomic DNA level in this cell line, fluorescence in situ hybridization analysis revealed neither trisomy 10 nor loss of the normal chromosome 10. Instead, a tandem duplication event was responsible for amplification of mutant RET. In further studies we could for the first time demonstrate that the genomic chromosome 10 abnormalities in this cell line cause an increased production of mutant RET mRNA. These findings provide evidence for a third second hit mechanism resulting in overrepresentation and overexpression of mutant RET in MEN 2-associated tumors.

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Unusual case of medullary thyroid cancer

Polski Przegląd Otorynolaryngologiczny ◽

10.5604/01.3001.0014.8911 ◽

2021 ◽

Vol 10 (1) ◽

pp. 1-11

Author(s):

Michał Leszczyński ◽

Daniel Majszyk

Keyword(s):

Thyroid Gland ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Cervical Lymphadenopathy ◽

Cervical Lymph Nodes ◽

Medullary Thyroid ◽

Thyroid Carcinomas ◽

Familial Form ◽

Additional Testing ◽

Medullary Thyroid Carcinomas

Medullary thyroid carcinomas make up 9,4% of all cancers of the thyroid gland [1]. We can divide them into sporadic and familial form. Sporadic forms are most common. The rest of medullary thyroid carcinomas are familial forms which in most cases are associated with MEN2a and MEN2b syndromes. If neoplasm is associated with MEN2a or MEN2b syndromes, other tumors can occur: pheochromocytoma or adenomas of parathyroids glands. Medullary thyroid carcinoma typically occurs as a solid tumor in the thyroid region of the neck. It can produce also: pain in thyroid region, dysphagia, hoarseness, cervical lymphadenopathy. These symptoms are caused by infiltration of adjacent tissues by neoplasm and by metastases to cervical lymph nodes. It is very rare that there is no tumor in the thyroid region, when a patient complains about signs associated with infiltration of the tumor, but in some cases lymphadenopathy can be the first sign of medullary thyroid carcinoma [2]. Rarer than that there is no tumor in thyroid gland visualized in CT scans when there are signs of cervical lymphadenopathy. In this case report we present the patient with metastases of the medullary thyroid carcinoma to the neck and no other findings in physical examination and additional testing.

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Multiple endocrine neoplasia type 2

Oxford Textbook of Endocrinology and Diabetes ◽

10.1093/med/9780199235292.003.0682 ◽

2011 ◽

pp. 951-953

Author(s):

Niamh M. Martin ◽

Karim Meeran ◽

Stephen R. Bloom

Keyword(s):

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Multiple Endocrine Neoplasia ◽

Multiple Endocrine Neoplasia Type ◽

Medullary Thyroid ◽

Men 2 ◽

Endocrine Neoplasia ◽

Endocrine Neoplasia Type ◽

Men 2A

Multiple endocrine neoplasia type 2 (MEN 2) is a rare cancer susceptibility syndrome which has at least three distinct variants: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). The syndrome was first described by John Sipple in 1961 (1). The features of MEN 2A and its clinical variants are outlined in Box 6.12.1. Medullary thyroid carcinoma (MTC) is seen in all variants of MEN 2A and is frequently the earliest neoplastic manifestation, reflecting its earlier and overall higher penetrance. MEN 2 is due to the autosomal dominant inheritance of a germline missense mutation in the ‘hot-spot’ regions of the rearranged during transfection (RET) (OMIM 164761) proto-oncogene (2, 3). MEN 2 has an estimated prevalence of 1:30 000, with MEN 2A accounting for more than 75% of cases. The introduction of RET screening in family members of affected individuals has significantly altered the clinical outcome of MEN 2, by allowing prophylactic surgery for MTC, and screening enabling early intervention for phaeochromocytoma (4, 5). Prior to the availability of genetic screening, more that half of MEN 2 affected individuals died before or during the fifth decade from metastatic MTC or cardiovascular complications from an underlying phaeochromocytoma.

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Identification of mutation in the RET gene in a patient with medullary thyroid cancer

Vietnam Journal of Biotechnology ◽

10.15625/1811-4989/14/3/9851 ◽

2016 ◽

Vol 14 (3) ◽

pp. 405-410

Author(s):

Nguyễn Hải Hà ◽

Trần Thị Hải Yến ◽

Vũ Phương Nhung ◽

Ma Thị Huyền Thương ◽

Nguyễn Đăng Tôn ◽

...

Keyword(s):

Medullary Thyroid Cancer ◽

Kinase Domain ◽

Tyrosine Kinase Domain ◽

Medullary Thyroid ◽

Ret Gene ◽

Activating Mutations ◽

Thyroid Malignancies ◽

Sanger Method ◽

Normal Health

Medullary thyroid carcinoma (MTC) is a type of tumors drived from thyroid parafollicular cells (C-cells), comprises 5–10% of all thyroid malignancies. About 25% of MTC cases occur as an autosomal dominant heredited disorder which is mostly caused by activating mutations of RET pro-oncogen and they occur as components of the multiple endocrine neoplasia type 2 syndromes (MEN 2A and 2B) or familial MTC. The guidelines for genetic testing in MTC of the European Thyroid Association recommend that exons 5, 8, 10, 11, 13, 14, 15 and 16 should always be screened starting in patients. This study aims to identify the genetic causes of a male patient diagnosed with MEN2 and pheochromocytoma. Genomic DNA was extracted from peripheral blood of patient. Eight recommened exons (5, 8, 10, 11, 13, 14, 15 and 16) of the RET gene were amplified by PCR and sequenced by Sanger method on the ABI 3500 genetic annalyzer. The results showed a heterozygous C to T transition at nucleotide 2753 in exon 16 of the RET gene. The c.2753 C>T transition resulted in a missense mutation of methionine to threonine (p.M918T) in the RET protein. This mutation was located in the intracellular tyrosine kinase domain of protein and has been reported in 95% of MEN2B cases, therefore, it would be the causative mutant of our patient. Our patient harboring a pM918T germline mutation and there is a 50% probability that he will pass this mutation to a child. Thus, his six-year-old boy with normal health status was advised to have the genetic test for this mutation. The results showed that he had not inherited the mutation c.2753T> C from his father.

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