Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors.
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PMID:Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. 1948 99

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.
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PMID:Medullary thyroid carcinoma and biomarkers: past, present and future. 1952 31

RET oncogene mutations are found in familial medullary thyroid carcinomas (MTC) and in one-third of sporadic cases. Oncogenic mechanisms involved in non-RET mutated sporadic MTC remain unclear. To study alterations associated with the development of both inherited and sporadic MTC, pangenomic DNA microarrays were used to analyze the transcriptome of 13 MTCs (four familial and nine sporadic). By using an ANOVA test, a list of 173 gene sequences with at least a twofold change expression was obtained. A subset of differentially expressed genes was controlled by real-time quantitative PCR and immunohistochemistry on a larger collection of MTCs. The expression pattern of those genes allowed us to distinguish two groups of sporadic tumors. The first group displays an expression profile similar to that expressed by inherited RET634 tumors. The second presents an expression profile close to that displayed by inherited RET918 tumors and includes tumors from patients with distant metastases. It is characterized by the overexpression of genes involved in proliferation and invasion (PTN, ESM1, and CEACAM6) or matrix remodeling (COL1A1, COL1A2, and FAP). Interestingly, RET918 tumors showed overexpression of the PTN gene, encoding pleiotrophin, a protein associated with metastasis. Using a MTC cell line, silencing of RET induced the inhibition of PTN gene expression. Overall, our results suggest that familial MTC and sporadic MTC could activate similar oncogenic pathways.
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PMID:Aggressive inherited and sporadic medullary thyroid carcinomas display similar oncogenic pathways. 1967 75

Therapeutic options for patients with metastatic medullary thyroid carcinoma (MTC) are limited due to lack of effective treatments. Thus, there is a need to thoroughly characterize the pathways of molecular pathogenesis and to identify potential targets for therapy in MTC. Since epidermal growth factor receptor (EGFR) seems to play a crucial role for RET activation, a key feature of MTCs, and several promising EGFR/vascular endothelial growth factor receptor 2 (VEGFR2)-targeted drugs have been developed, the present study was designed to investigate whether these proteins are altered in MTCs. We used a well-characterized series of 153 MTCs to evaluate EGFR activation by sequencing and FISH analysis, and to perform EGFR and VEGFR2 immunohistochemistry. EGFR tyrosine kinase domain mutations were not a feature of MTCs; however, EGFR polysomy and a strong EGFR expression were detected in 15 and 13% of the tumors respectively. Interestingly, EGFR was significantly overexpressed in metastases compared with primary tumors (35 vs 9%, P=0.002). We also studied whether specific RET mutations were associated with EGFR status, and found a decrease in EGFR polysomies (P=0.006) and a tendency towards lower EGFR expression for the most aggressive RET mutations (918, 883). Concerning VEGFR2, metastasis showed a higher expression than primary tumors (P=2.8 x 10(-8)). In this first study investigating the relationship between EGFR, RET, and VEGFR2 in a large MTC series, we found an activation of EGFR and VEGFR2 in metastasis, using both independent and matched primary/metastasis samples. This suggests that some MTC patients may benefit from existing anti-EGFR/VEFGR2 therapies, although additional preclinical and clinical evidence is needed.
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PMID:Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis. 1977 90

Medullary thyroid cancer (MTC) accounts for 5% to 10% of all thyroid cancers. The high frequency of familial cases mandates screening and genetic testing. The aggressiveness and age of onset of familial MTC differs depending on the specific genetic mutation, and this should determine the timing and extent of surgery. Sporadic MTC can present at any age, and it is usually associated with a palpable mass and the presence of nodal metastases. Surgery is standard treatment for any patient presenting with resectable MTC. Further studies are needed to investigate the role of radiation therapy in the palliation and local control of postresection and advanced-stage MTC. New systemic therapies for metastatic disease are being investigated. Targeted molecular therapies, based on knowledge of the pathways affected by RET mutations, are being tested in multiple clinical trials.
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PMID:Sporadic and familial medullary thyroid carcinoma: state of the art. 1983 92

Differentiated thyroid carcinoma is the most frequent neoplasm of the endocrine system. Although thyroid cancer usually has an excellent prognosis, no therapeutic options are available for patients that develop metastases and are or became resistant to radioiodine therapy. The deeper knowledge of molecular aberrations that characterize tumor growth has provided novel targets in cancer therapy. Several proteins have been implicated as having a crucial role in the carcinogenesis of differentiated thyroid cancer, such as those involved in RET/PTC-RAS-RAF-MAPK pathway. Moreover, vascular aberrations and angiogenesis equilibrium have also been related to tumor growth. The development of new, targeted therapies and their encouraging initial results have opened a hopeful opportunity of treatment for these orphan therapy tumor patients.
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PMID:Targeted therapies in thyroid cancer. 1990

Encapsulated thyroid tumors of follicular cell origin with high-grade features (EFHG) are unusual neoplasms. In current classification schemes, they are called atypical adenomas or follicular, papillary, or poorly differentiated carcinoma. When noninvasive, EFHG create a major therapeutic/diagnostic dilemma stemming from their rarity, low-stage, high-grade appearance, and lack of long-term follow-up studies. All cases of EFHG were defined as encapsulated tumors of follicular cell origin with at least 5 mitoses per 10 high-power fields and/or tumor necrosis. Available tissues were subjected to a thyroid carcinoma platform for mass spectrometry high-throughput genotyping, which consisted of 111 known mutations in 16 different genes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes. Twenty-five cases met the selection criteria. Tumor necrosis was present in 56.0% (n = 14). Extensive vascular invasion was identified in 24.0% (n = 6). Eight (32%) of 25 tumors were noninvasive. Twenty-two patients (88%) were free of disease (median follow up: 8.5 years). All 8 noninvasive tumor did not recur despite focal/extensive tumor necrosis in 3 cases and a median follow-up of 11.9 years. EFHG with no vascular invasion did not recur. In patients without distant metastases at presentation (n = 24), 33% (2/6) of patients with extensive angioinvasion relapsed, whereas none of 18 with absent/focal vascular invasion recurred (P = .054). Mutations were found in 10 (45%) of 22 cases tested: 8 had NRAS codon 61, 1 KRAS codon 61, and 1 had coexistent BRAF V600E and AKT1. There was a higher frequency of RAS (9/22, 41%) than BRAF mutations (1/22, 4.5%) (P = .009). Noninvasive EFHG have an indolent behavior even in the presence of extensive tumor necrosis. EFHG with absent vascular invasion have an excellent prognosis despite the frequent occurrence of tumor necrosis. NRAS mutations are the most frequent oncogenic event in EFHG.
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PMID:Encapsulated thyroid tumors of follicular cell origin with high grade features (high mitotic rate/tumor necrosis): a clinicopathologic and molecular study. 1991 80

BACKGROUND Multiple endocrine neoplasia type 2 (MEN 2) is caused by a RET mutation in chromosome 10. All MEN 2 patients develop medullary thyroid carcinoma (MTC). The age-related risk of MTC is associated with the type of RET mutation. Our aim was to identify prognostic factors associated with recurrent MTC in MEN 2 patients. METHODS In a nationwide case-control study, all patients who underwent total thyroidectomy in the Netherlands under the age of 20 years were classified into standard (1), high (2), or very high risk (3) for MTC based on RET-mutation type. Disease-free patients were compared with those with recurrent disease. RESULTS A total of 93 patients were included in the study. Sixty-six percent had MTC on histology, the youngest being 1 year old. Codon 634 was most affected. Sixteen (18%) patients had persistent or recurrent disease, one of whom died. Significantly associated determinants of outcome in univariate analysis were higher age at surgery, no age-appropriate prophylactic surgery according to risk level, elevated preoperative calcitonin levels, affected codon, and the presence of lymph node metastases at surgery. On multivariate analysis only age of surgery was the single independent factor associated with persistent disease. CONCLUSIONS Prophylactic thyroidectomy beyond the recommended age is associated with persistent/recurrent disease. In addition, codon 634 mutation is associated with a high risk of recurrence requiring early surgery for all these patients.
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PMID:Factors predicting outcome of total thyroidectomy in young patients with multiple endocrine neoplasia type 2: a nationwide long-term follow-up study. 2006 95

Differentiated thyroid cancer accounts for >90% of cases of thyroid cancer, with most patients having an excellent prognosis. Distant metastases occur in 10%-15% of patients, decreasing the overall 10-year survival rate in this group to 40%. Radioactive iodine has been the mainstay of treatment for distant metastases, with good results when lesions retain the ability to take up iodine. For patients with metastatic disease resistant to radioactive iodine, treatment options are few and survival is poor. Chemotherapy and external beam radiotherapy have been used in these patients, but with disappointing results. In recent years, our understanding of the molecular pathways involved in thyroid cancer has increased and a number of molecular targets have been identified. These targets include the proto-oncogenes BRAF and RET, known to be common mutations in thyroid cancer; vascular endothelial growth factor receptor and platelet-derived growth factor receptor, associated with angiogenesis; and the sodium-iodide symporter, with the aim of restoring its expression and hence radioactive iodine uptake. There are now multiple trials of tyrosine kinase inhibitors, angiogenesis inhibitors, and other novel agents available to patients with metastatic thyroid cancer. This review discusses both traditional and novel treatments for metastatic differentiated thyroid cancer with a particular focus on emerging treatments for patients with radioactive iodine-refractory disease.
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PMID:Standard and emerging therapies for metastatic differentiated thyroid cancer. 2014 32

Medullary thyroid carcinoma (MTC) is an uncommon malignancy of the parafollicular C cells of the thyroid, with a propensity for early lymph node spread and distant metastasis. It is hereditary in approximately 25% of cases, involving specific point mutations of the RET proto-oncogene inherited in an autosomal dominant fashion. While European professional organizations have put forth calcitonin screening guidelines for earlier detection of MTC, the American Thyroid Association, which has published recent guidelines for MTC treatment, have not had a position on routine screening in the USA. Surgical extirpation of the primary tumor and involved lymph node metastases is the mainstay of treatment and the only chance for cure. Conventional systemic chemotherapies for metastatic MTC have been disappointing; however, newer agents which affect specific RET proteins and tyrosine kinase growth factor receptors show promise in phase 1 and 2 clinical trials.
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PMID:Current management of medullary thyroid cancer. 2021 15


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