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Expand Collapse Thyroid Tumor  - General Description This year about 56,000 people in the U.S. (77% of them women) will be told by a doctor that they have thyroid cancer. About half of these new patients will be at least 50 years old. However, more than 500,000 patients with thyroid cancer remain alive today.

The thyroid is a butterfly-shaped gland found at the base of the throat, near the windpipe (trachea). The 2 wings (lobes) of the thyroid are connected by a thin piece of tissue called the isthmus. The thyroid uses iodine from food and iodized salts to make hormones that control the heart rate, body temperature, the speed with which food is changed into energy (metabolism) and the level of calcium in the blood. Based on their appearance under the microscope, the 4 main types of thyroid cancer are papillary, follicular, medullary and anaplastic. For treatment purposes, thyroid cancers are often classified as differentiated (papillary or follicular) or poorly differentiated (medullary or anaplastic). If a cancer cell is well-differentiated, it has most of the characteristics of a normal cell. On the other hand, poorly differentiated cancer cells don't look like normal cells.

Follicular thyroid cancer is a slow-growing cancer that forms in follicular cells, which are epithelial cells that take up iodine and make certain thyroid hormones. Papillary thyroid cancer, which appears as finger-like shapes under the microscope, also begins in follicular cells and is slow-growing. It is the most common type of thyroid cancer, usually appearing before the age of 45 years. It is more common in women than in men. Medullary thyroid cancer accounts for about 4% of all thyroid cancers. It begins in C cells, which make calcitonin, a hormone that helps keep calcium at the right level in the blood. Anaplastic thyroid cancer is a rare, aggressive form of cancer whose cells don't look at all like normal thyroid cells.

Thyroid cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the cancer cells cause secondary tumors to grow. The main places to which thyroid cancer spreads are the lungs, liver, and bones.

To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist looks at it through a microscope to see if cancer cells are present. Several kinds of imaging can also be performed to determine if the cancer has spread. These include chest x-rays, ultrasound and CT scans.

The FDA has approved the targeted therapy vandetanib (Capreisa) for treatment of medullary thyroid cancer that is locally advanced and can't be removed by surgery or that has metastasized. No targeted therapies are yet available for treatment of anaplastic thyroid cancer. Therefore, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2012
Thyroid cancer represents approximately 3% of new malignancies occurring annually in the United States, with an estimated 56,460 cancer diagnoses and 1,780 cancer deaths per year. Of these cancer diagnoses, 2% to 3% are medullary thyroid cancer (MTC).

MTC arises from the calcitonin-secreting parafollicular cells of the thyroid gland. MTC occurs in sporadic and familial forms and may be preceded by C-cell hyperplasia (CCH), although CCH is a relatively common abnormality in middle-aged adults.

Average survival for MTC is lower than that for more common thyroid cancers (e.g., 83% 5-year survival for MTC compared with 90-94% 5-year survival for papillary and follicular thyroid cancer). Survival is correlated with stage at diagnosis. Decreased survival in MTC can be accounted for, in part, by a high proportion of late-stage diagnoses.

In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, familial versus sporadic form and diagnosis by biochemical screening (i.e., screening for calcitonin elevation).

A Surveillance, Epidemiology, and End Results (SEER) population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95% for disease confined to the thyroid gland to 40% for those with distant metastases.

While the majority of MTC cases are sporadic, approximately 20-25% are hereditary because of mutations in the RET proto-oncogene. Mutations in the RET gene cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominant disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant endocrinopathy that is genetically and clinically distinct from MEN 2. However, the similar nomenclature for MEN 1 and MEN 2 may cause confusion. Of note, there is no increased risk of thyroid cancer for MEN 1.

Historically, MEN 2 has been classified into three subtypes based on the presence or absence of certain endocrine tumors in the individual or family:

- MEN 2A
- Familial medullary thyroid carcinoma (FMTC)
- MEN 2B

All three subtypes impart a high risk of developing MTC. MEN 2A has an increased risk of pheochromocytoma and parathyroid adenoma and/or hyperplasia. MEN 2B has an increased risk of pheochromocytoma and includes additional clinical features such as mucosal neuromas of the lips and tongue, distinctive faces with enlarged lips, ganglioneuromatosis of the gastrointestinal tract and an asthenic Marfanoid body habitus. FMTC has been defined as the presence of at least four individuals with MTC without any other signs or symptoms of pheochromocytoma or hyperparathyroidism in the proband or other family members.

Some families previously classified as FMTC will go on to develop one or more of the MEN 2A-related tumors, suggesting that FMTC is simply a milder variant of MEN 2A. Offspring of affected individuals have a 50% chance of inheriting the gene mutation.

The age of onset of MTC varies in different subtypes of MEN 2. MTC typically occurs in early childhood for MEN 2B, predominantly early adulthood for MEN 2A and middle age for FMTC.

DNA-based germline testing of the RET gene (chromosomal region 10q11.2) identifies disease-causing mutations in more than 95% of individuals with MEN 2A and MEN 2B and in about 88% of individuals with FMTC.

Source: National Cancer Institute, 2012
This year about 56,000 people in the U.S. (77% of them women) will be told by a doctor that they have thyroid cancer. About half of these new patients will be at least 50 years old. However, more than 500,000 patients with thyroid cancer remain alive today.

The thyroid is a butterfly-shaped gland found at the base of the throat, near the windpipe (trachea). The 2 wings (lobes) of the thyroid are connected by a thin piece of tissue called the isthmus. The thyroid uses iodine from food and iodized salts to make hormones that control the heart rate, body temperature, the speed with which food is changed into energy (metabolism) and the level of calcium in the blood. Based on their appearance under the microscope, the 4 main types of thyroid cancer are papillary, follicular, medullary and anaplastic. For treatment purposes, thyroid cancers are often classified as differentiated (papillary or follicular) or poorly differentiated (medullary or anaplastic). If a cancer cell is well-differentiated, it has most of the characteristics of a normal cell. On the other hand, poorly differentiated cancer cells don't look like normal cells.

Follicular thyroid cancer is a slow-growing cancer that forms in follicular cells, which are epithelial cells that take up iodine and make certain thyroid hormones. Papillary thyroid cancer, which appears as finger-like shapes under the microscope, also begins in follicular cells and is slow-growing. It is the most common type of thyroid cancer, usually appearing before the age of 45 years. It is more common in women than in men. Medullary thyroid cancer accounts for about 4% of all thyroid cancers. It begins in C cells, which make calcitonin, a hormone that helps keep calcium at the right level in the blood. Anaplastic thyroid cancer is a rare, aggressive form of cancer whose cells don't look at all like normal thyroid cells.

Thyroid cancer (and other tumors) can spread (metastasize) from the place where it started (the primary tumor) in 3 ways. First, it can invade the normal tissue surrounding it. Second, cancer cells can enter the lymph system and travel through lymph vessels to distant parts of the body. Third, the cancer cells can get into the bloodstream and go to other places in the body. In these distant places, the cancer cells cause secondary tumors to grow. The main places to which thyroid cancer spreads are the lungs, liver, and bones.

To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a node near the primary tumor and a pathologist looks at it through a microscope to see if cancer cells are present. Several kinds of imaging can also be performed to determine if the cancer has spread. These include chest x-rays, ultrasound and CT scans.

The FDA has approved the targeted therapy vandetanib (Capreisa) for treatment of medullary thyroid cancer that is locally advanced and can't be removed by surgery or that has metastasized. No targeted therapies are yet available for treatment of anaplastic thyroid cancer. Therefore, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2012
Thyroid cancer represents approximately 3% of new malignancies occurring annually in the United States, with an estimated 56,460 cancer diagnoses and 1,780 cancer deaths per year. Of these cancer diagnoses, 2% to 3% are medullary thyroid cancer (MTC).

MTC arises from the calcitonin-secreting parafollicular cells of the thyroid gland. MTC occurs in sporadic and familial forms and may be preceded by C-cell hyperplasia (CCH), although CCH is a relatively common abnormality in middle-aged adults.

Average survival for MTC is lower than that for more common thyroid cancers (e.g., 83% 5-year survival for MTC compared with 90-94% 5-year survival for papillary and follicular thyroid cancer). Survival is correlated with stage at diagnosis. Decreased survival in MTC can be accounted for, in part, by a high proportion of late-stage diagnoses.

In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, familial versus sporadic form and diagnosis by biochemical screening (i.e., screening for calcitonin elevation).

A Surveillance, Epidemiology, and End Results (SEER) population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95% for disease confined to the thyroid gland to 40% for those with distant metastases.

While the majority of MTC cases are sporadic, approximately 20-25% are hereditary because of mutations in the RET proto-oncogene. Mutations in the RET gene cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominant disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant endocrinopathy that is genetically and clinically distinct from MEN 2. However, the similar nomenclature for MEN 1 and MEN 2 may cause confusion. Of note, there is no increased risk of thyroid cancer for MEN 1.

Historically, MEN 2 has been classified into three subtypes based on the presence or absence of certain endocrine tumors in the individual or family:

- MEN 2A
- Familial medullary thyroid carcinoma (FMTC)
- MEN 2B

All three subtypes impart a high risk of developing MTC. MEN 2A has an increased risk of pheochromocytoma and parathyroid adenoma and/or hyperplasia. MEN 2B has an increased risk of pheochromocytoma and includes additional clinical features such as mucosal neuromas of the lips and tongue, distinctive faces with enlarged lips, ganglioneuromatosis of the gastrointestinal tract and an asthenic Marfanoid body habitus. FMTC has been defined as the presence of at least four individuals with MTC without any other signs or symptoms of pheochromocytoma or hyperparathyroidism in the proband or other family members.

Some families previously classified as FMTC will go on to develop one or more of the MEN 2A-related tumors, suggesting that FMTC is simply a milder variant of MEN 2A. Offspring of affected individuals have a 50% chance of inheriting the gene mutation.

The age of onset of MTC varies in different subtypes of MEN 2. MTC typically occurs in early childhood for MEN 2B, predominantly early adulthood for MEN 2A and middle age for FMTC.

DNA-based germline testing of the RET gene (chromosomal region 10q11.2) identifies disease-causing mutations in more than 95% of individuals with MEN 2A and MEN 2B and in about 88% of individuals with FMTC.

Source: National Cancer Institute, 2012
Expand Collapse TP53  - General Description
CLICK IMAGE FOR MORE INFORMATION
The p53 (TP53) gene produces a protein, P53 which has many complex functions within the cell. It has been called the “guardian of the genome” for reasons that have to do with these complex functions. Normal, non-cancerous cells have tightly regulated pathways that control cell growth, mediating cessation of growth or even cell death when circumstances warrant it. P53 is at the center of these pathways, acting as a “tumor suppressor” in responding to circumstances in the cell that require a cessation of growth. Perhaps for this reason, P53 is one of the most commonly mutated genes across all cancer types.

P53 itself regulates the expression of several genes that are involved in growth arrest or “cell cycle arrest”. Growth arrest is important for stopping the cell from normal growth and cell division so that if, for instance, there has been damage to the DNA from UV irradiation or some other insult causing DNA damage, the cessation of the cell cycle allows DNA repair to take place before the cell resumes growth. If the damage to the DNA is too extensive to repair, or if other factors such as oncogenic stress impact the cell, P53 then has roles in other processes that are part of the cell’s repertoire of responses. These include processes such as apoptosis (programmed cell death), senescence (irreversible cell cycle arrest), autophagy (regulated destruction of selected proteins within the cell, leading to cell death), and some important metabolic changes in the cell (see graphic above, adapted with permission).

P53 is itself acted upon by proteins in the cell that detect DNA damage or oncogenic stress (see graphic depicting P53 at the center of a number of cellular responses). In the case of DNA damage to the cell, P53 is acted upon by a protein called ATM and another designated CHK2 (see glossary for more information). These proteins activate P53 to regulate the changes that will cause growth arrest. Interestingly, these two genes themselves are found to be mutated and have altered function in certain cancers. The fact that both P53 and the genes that trigger P53’s response and initiation of growth arrest are mutated in some cancers highlights the importance of P53 to normal cell growth. P53 is found to be mutated in over half of cancers studied, including ovarian cancer, colon and esophageal cancer, and many other types of cancer. Because p53 plays so many complex roles in the cell, we do not depict it in a simple graphic as we have with other proteins on this web site in which genetic alterations have been found in specific tumors that lead to dysregulation of these proteins. Rather, P53 as a negative regulator of cell growth under important circumstances plays this role at the center of a complex network of pathways within the cell. Many of the proteins involved in the pathways that regulate P53 and its responses are also found to be genetically altered in some cancers.

As we have seen, the P53 protein has many functions in the cell, and because of these many roles, its location in the nucleus or cytoplasm varies, depending on the function and when it exerts its effect during the cell cycle. One important protein that regulates P53 is called HDM2/MDM2, depicted in the graphic above. The HDM2/MDM2 protein contains a p53 binding domain, and once bound to p53, it inhibits the activation of the P53 protein, and thereby prevents P53 from regulating growth arrest, even when there is damage to the DNA. Some cancers have been found to overexpress HDM2/MDM2, meaning there is an excess of the protein which binds to P53, preventing it from exerting its important role in regulating growth arrest. Cell division that occurs despite damage to the DNA can lead to cancer. Interestingly, those cancers that have been found to over-express HDM2/MDM2 typically are not found to have p53 mutations. This provides scientists with evidence that by whatever means, either through increasing the amount of the P53 inhibitor HDM2/MDM2, or, through mutations in P53 that prevent the normal activities of the protein, the normal function of P53 is important in preventing cancer. MDM2 was named after its discovery in studies on laboratory mice. The human version of the gene is designated HumanDM2, or HDM2. Genetic alterations leading to over-expression of MDM2 are observed most commonly in sarcomas, but have also been observed in endometrial cancer, colon cancer, and stomach cancer.

Source: Molecular Genetics of Cancer, Second Edition
Chapter No. 2, Section No. 12
Leif W. Ellisen, MD, PhD
The p53 (TP53) gene produces a protein, P53 which has many complex functions within the cell. It has been called the “guardian of the genome” for reasons that have to do with these complex functions. Normal, non-cancerous cells have tightly regulated pathways that control cell growth, mediating cessation of growth or even cell death when circumstances warrant it. P53 is at the center of these pathways, acting as a “tumor suppressor” in responding to circumstances in the cell that require a cessation of growth. Perhaps for this reason, P53 is one of the most commonly mutated genes across all cancer types.

P53 itself regulates the expression of several genes that are involved in growth arrest or “cell cycle arrest”. Growth arrest is important for stopping the cell from normal growth and cell division so that if, for instance, there has been damage to the DNA from UV irradiation or some other insult causing DNA damage, the cessation of the cell cycle allows DNA repair to take place before the cell resumes growth. If the damage to the DNA is too extensive to repair, or if other factors such as oncogenic stress impact the cell, P53 then has roles in other processes that are part of the cell’s repertoire of responses. These include processes such as apoptosis (programmed cell death), senescence (irreversible cell cycle arrest), autophagy (regulated destruction of selected proteins within the cell, leading to cell death), and some important metabolic changes in the cell (see graphic above, adapted with permission).

P53 is itself acted upon by proteins in the cell that detect DNA damage or oncogenic stress (see graphic depicting P53 at the center of a number of cellular responses). In the case of DNA damage to the cell, P53 is acted upon by a protein called ATM and another designated CHK2 (see glossary for more information). These proteins activate P53 to regulate the changes that will cause growth arrest. Interestingly, these two genes themselves are found to be mutated and have altered function in certain cancers. The fact that both P53 and the genes that trigger P53’s response and initiation of growth arrest are mutated in some cancers highlights the importance of P53 to normal cell growth. P53 is found to be mutated in over half of cancers studied, including ovarian cancer, colon and esophageal cancer, and many other types of cancer. Because p53 plays so many complex roles in the cell, we do not depict it in a simple graphic as we have with other proteins on this web site in which genetic alterations have been found in specific tumors that lead to dysregulation of these proteins. Rather, P53 as a negative regulator of cell growth under important circumstances plays this role at the center of a complex network of pathways within the cell. Many of the proteins involved in the pathways that regulate P53 and its responses are also found to be genetically altered in some cancers.

As we have seen, the P53 protein has many functions in the cell, and because of these many roles, its location in the nucleus or cytoplasm varies, depending on the function and when it exerts its effect during the cell cycle. One important protein that regulates P53 is called HDM2/MDM2, depicted in the graphic above. The HDM2/MDM2 protein contains a p53 binding domain, and once bound to p53, it inhibits the activation of the P53 protein, and thereby prevents P53 from regulating growth arrest, even when there is damage to the DNA. Some cancers have been found to overexpress HDM2/MDM2, meaning there is an excess of the protein which binds to P53, preventing it from exerting its important role in regulating growth arrest. Cell division that occurs despite damage to the DNA can lead to cancer. Interestingly, those cancers that have been found to over-express HDM2/MDM2 typically are not found to have p53 mutations. This provides scientists with evidence that by whatever means, either through increasing the amount of the P53 inhibitor HDM2/MDM2, or, through mutations in P53 that prevent the normal activities of the protein, the normal function of P53 is important in preventing cancer. MDM2 was named after its discovery in studies on laboratory mice. The human version of the gene is designated HumanDM2, or HDM2. Genetic alterations leading to over-expression of MDM2 are observed most commonly in sarcomas, but have also been observed in endometrial cancer, colon cancer, and stomach cancer.

Source: Molecular Genetics of Cancer, Second Edition
Chapter No. 2, Section No. 12
Leif W. Ellisen, MD, PhD
Expand Collapse All Mutations  in TP53
TP53 Mutations that are associated with many cancer types result in the loss of function of the P53 proteins' tumor suppressor activity. Mutations in P53 that have been studied in tumors prevent P53 from acting to stop growth, or in other words, to cause cell cycle arrest. Cell cycle arrest mediated by P53 is necessary to give cells time to repair damaged DNA. P53 is also involved in other functions in the cell that cause cells that have suffered more damage than can be repaired to undergo apoptosis or autophagy, leading to deliberate cell death. When P53 normal function is debilitated through genetic mutations, the development of cancer is more likely than in cells that have intact and fully functional P53.
TP53 Mutations that are associated with many cancer types result in the loss of function of the P53 proteins' tumor suppressor activity. Mutations in P53 that have been studied in tumors prevent P53 from acting to stop growth, or in other words, to cause cell cycle arrest. Cell cycle arrest mediated by P53 is necessary to give cells time to repair damaged DNA. P53 is also involved in other functions in the cell that cause cells that have suffered more damage than can be repaired to undergo apoptosis or autophagy, leading to deliberate cell death. When P53 normal function is debilitated through genetic mutations, the development of cancer is more likely than in cells that have intact and fully functional P53.

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing all 2 results Per Page:
Protocol # Title Location Status Match
NCT00585195 A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer MGH Open D
NCT02568267 Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions) Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions) MGH Open D
MGH has many open clinical trials for other cancers not shown on the Targeted Cancer Care website. They can be found on the MassGeneral.org clinical trials search page.

Additional clinical trials may be applicable to your search criteria, but they may not be available at MGH. These clinical trials can typically be found by searching the clinicaltrials.gov website.
Trial Status: Showing all 2 results Per Page:

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