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Clinical Significance NeoTYPE™ Thyroid Profile AKT1 AKT1 mutations have been detected in patients with thyroid carcinomas. AKT1 mutations can lead to the progression of thyroid cancers due to the constitutive activation of the cell signaling pathways. AKT inhibitors are currently being explored as a mechanism to induce apoptosis in thyroid cancer cells. Testing for AKT1 mutations can be useful for determining sensitivity to various drugs such as PI3K/AKT inhibitors. ALK ALK mutations are gain-of-function mutations that have been detected in thyroid cancers such as anaplastic thyroid carcinomas. Mutations in ALK are oncogenic and can lead to the further progression of thyroid cancers into more aggressive forms of the the disease. Testing for ALK mutations can be useful for identifying patients who may be sensitive to ALK inhibitors. BRAF BRAF mutations are common in thyroid cancers and are detected in 40-45% of papillary thyroid cancers, 20-40% of poorly differentiated carcinomas, 30-40% of anaplastic thyroid cancers and in some instances of follicular thyroid cancers. BRAF mutations are pathogenic and testing for these mutations are critical in determining drug sensitivity to BRAF inhibitors. Several kinase inhibitor drugs targeting patients with thyroid cancers are currently in various phases of clinical trials. CTNNB1 CTNNB1 mutations have been detected in thyroid cancers such as papillary thyroid cancers and anaplastic thyroid cancers. These mutations play a role in the pathogenesis of thyroid cancers by affecting the Wnt signaling pathways. Wnt inhibitors are currently being developed for patients with thyroid carcinomas. Testing for CTNNB1 mutations in thyroid cancer patients can aid in determining their sensitivity to Wnt inhibitors and other targeted therapies that are currently in clinical trials. ERBB2 ERBB2 mutations are present in thyroid cancers. These mutations lead to the constitutive activation of the tyrosine kinase signaling pathways, which promotes cancer growth. This gene is part of a targetable pathway and testing for ERBB2 mutations can be useful in determining a thyroid cancer patients sensitivity to tyrosine kinase inhibitors. ERBB4 Oncogenic ERBB4 mutations have been detected in patients with thyroid cancer. ERBB4 is part of a targetable pathway and testing for ERBB4 mutations can be useful in determining a thyroid cancer patients sensitivity to tyrosine kinase inhibitors. HRAS HRAS mutations have been detected in 4% of thyroid cancers. The MEK inhibitor selumetinib in combination with radioactive iodine has been shown to be effective in treating thyroid cancer patients with RAS mutations during clinical trials. Testing for HRAS mutations may be useful in identifying thyroid cancer patients who are sensitive to MEK inhibitors as well as other tyrosine kinase inhibitors. KRAS KRAS mutations have been detected in 3% of thyroid cancers. The MEK inhibitor selumetinib in combination with radioactive iodine has been shown to be effective in treating thyroid cancer patients with RAS mutations during clinical trials. Testing for KRAS mutations may be useful in identifying thyroid cancer patients who are sensitive to MEK inhibitors as well as other tyrosine kinase inhibitors. MET Activating MET mutations have been found in a variety of thyroid cancers. MET mutations are pathogenic and leads to increased cancer cell proliferation. MET inhibitors are currently in clinical trials for the treatment of thyroid cancers in patients with overexpression of MET. Early studies have shown that MET inhibitors can inhibit the growth of thyroid cancer cells. Testing for MET mutations can be useful in determining a patients sensitivity to various tyrosine kinase inhibitors. Page 1 of 2 NRAS NRAS mutations have been detected in 6% of thyroid cancers. Numerous clinical trials targeting RAS mutations in thyroid cancers are currently in development. The MEK inhibitor selumetinib in combination with radioactive iodine has been shown to be effective in treating thyroid cancer patients with RAS mutations during clinical trials. Testing for NRAS mutations may be useful in identifying thyroid cancer patients who are sensitive to MEK inhibitors as well as other tyrosine kinase inhibitors. PIK3CA PIK3CA mutations have been identified in patient with thyroid cancers such as anaplastic thyroid cancers. PIK3CA mutations are gain of function mutations that increases cancer activity. Testing for PIK3CA mutations may be useful in identifying thyroid cancer patients who may be sensitive to PI3K/AKT inhibitors or other kinase therapies. RET Somatic RET mutations are frequently detected in patients with thyroid cancer. RET inhibitors are currently in development for the treatment of thyroid cancers and have shown to improve progression free-survival in various clinical trials. Vandetanib has also been approved by the FDA to treat patients with metastatic medullary thyroid carcinomas. Testing for RET mutations is recommended by published guidelines. SMO SMO is crucial in the Hedgehog pathway and is very important in oncogenesis. SMO mutations have been detected in thyroid cancers including papillary thyroid cancers. Testing for SMO mutations can be useful as a prognostic or therapeutic indicator. For example, itraconazole targets SMO and patients with SMO mutations could potentially respond to this type of therapy. Clinical trials are currently being conducted on SMO mutated patients with solid tumor cancers. MET FISH MET gene amplification, as detected by FISH, is one mechanism of MET overexpression and is a known mechanism of EGFR-TKI resistance. Clinical trials have demonstrated activity of MET inhibitors against numerous solid tumors. MET amplification is a targetable abnormality that may be useful in determining a patient’s sensitivity to targeted therapies. RET FISH RET translocations occur in 10-20% of papillary thyroid carcinomas and have been seen in other thyroid cancers as well. RET inhibitors are currently in development for the treatment of thyroid cancers and have shown to improve progression free-survival in various clinical trials. Vandetanib has also been approved by the FDA to treat patients with metastatic medullary thyroid carcinomas. Testing for RET translocations can be useful in identifying thyroid caner patients who may be sensitive to targeted tyrosine kinase inhibitor therapies. Please see our website neogenomics.com for a complete test description and printable specimen requirements. References on file. 12701 Commonwealth Dr., Suite 9 Fort Myers, FL 33913 Phone: 886.776.5907/ Fax: 239.768.0711 neogenomics.com © 2017 NeoGenomics Laboratories, Inc. All Rights Reserved. All other trademarks are the property of their respective owners. Rev. 021017