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The mystery of gene mutation: How does RET gene mutation cause medullary thyroid cancer?
Medullary thyroid carcinoma (MTC) is a type of thyroid cancer that arises from accessory follicular cells (C cells), which are responsible for producing calcitonin. According to statistics, medullary thyroid cancer is the third most common type of thyroid cancer, accounting for approximately 3% of all thyroid cancer cases. This cancer was first described in 1959, and approximately 25% of medullary thyroid cancer cases are hereditary, usually due to mutations in the RET proto-oncogene. When medullary thyroid cancer occurs in isolation, it is called sporadic medullary thyroid cancer; however, it can also occur in patients with multiple endocrine tumor types 2A and 2B. When medullary thyroid cancer is caused by an inherited genetic disorder and is not accompanied by other endocrine tumors, it is called familial medullary thyroid cancer.
The main clinical symptom of medullary thyroid cancer is diarrhea, and occasionally patients may experience flushing. These symptoms are particularly common with liver metastases and may be the first manifestation of the disease.
Symptoms and signs
The main symptoms of medullary thyroid cancer are diarrhea and flushing. These symptoms occur because of elevated levels of the calcitonin gene product (calcitonin or calcitonin gene-related peptide). The source of this flushing and diarrhea is different than the diarrhea and flushing in carcinoid syndrome, which is caused by increased circulating serotonin.
In addition, medullary thyroid cancer may cause thyroid nodules and swollen lymph nodes in the neck. Sites of metastasis from medullary thyroid cancer include the lymph nodes in the neck, central lymph nodes in the chest (mediastinum), liver, lungs, and bones. Although metastases to the skin or brain may occur, they are rare.
Genetics and Heredity
The RET proto-oncogene is located on chromosome 10. Mutations in this gene lead to the expression of mutant receptor tyrosine kinase proteins, which are essential for cell proliferation and development. Germline mutations in RET are responsible for nearly all cases of familial medullary thyroid cancer. In the case of hereditary medullary thyroid cancer, this is inherited in an autosomal dominant manner, meaning that each child of an affected parent has a 50% chance of inheriting the mutated RET oncogene.
Markers and Diagnostics
Although elevated serum calcitonin levels are not harmful in themselves, they can be very useful in detecting tumors. A second marker, carcinoembryonic antigen (CEA), is also produced by medullary thyroid cancer and released into the blood, making it another serum tumor marker. In general, CEA measurements are less sensitive than calcitonin for detecting tumors, but because of their relatively smaller variability, they are more useful in indicating tumor mass.
Treatment options
Surgery and radiation therapy are the main treatments for medullary thyroid cancer. Before thyroidectomy, serum metoprine levels should be checked to assess for the presence of a pheochromocytoma. This is because approximately 25% of patients diagnosed with medullary thyroid cancer may have an associated MEN2A syndrome.
Prognosis
Depending on different sources, the overall 5-year survival rate for medullary thyroid cancer is 80% to 86%, and the 10-year survival rate is 75%. Depending on the cancer stage, the 5-year survival rate can reach 100% in Stage I, 98% in Stage II, 81% in Stage III, and only 28% in Stage IV. This suggests that the prognosis of medullary thyroid cancer after metastasis is worse than that of thyroid cellular carcinoma and papillary carcinoma.
What are the pathogenesis and mutations of medullary thyroid cancer?
