Bone and Soft Tissue Sarcoma, TP53

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Expand Collapse Bone and Soft Tissue Sarcoma  - General Description This year about 11,000 people in the U.S. will be told by a doctor that they have cancer of the soft tissue. Half of these patients will be at least 58 years old. Among the many types of soft tissue sarcoma, the more common ones are gastrointestinal stromal tumors (GIST), Kaposi sarcoma and uterine sarcoma.

Soft tissue sarcomas can form almost anywhere in the body, including muscles, tendons, fat, blood vessels, lymph vessels, nerves and tissues around joints. In adults, they are most common in the legs and arms (about 50% of all cases), the trunk (about 30% of all cases) and the head and neck (about 10% of cases). Based on the type of soft tissue in which the cancer began, each sarcoma appears different under the microscope.

GIST can occur anywhere along the gastrointestinal tract, including the stomach (about 60% of all cases), small intestine (about 30% of all cases), and large intestine (colon). The FDA has approved the targeted therapies imatinib (Gleevec) and sunitinib (Sutent) in the treatment of certain kinds of GIST.

Kaposi sarcoma causes abnormal tissue (lesions) to grow in the skin; mucous membranes lining the mouth, nose, and throat; lymph nodes; and other organs. Kaposi sarcoma differs from other cancers in that these lesions may begin in more than one place in the body at the same time.

Uterine sarcoma is a rare cancer that forms in the muscles of the uterus or tissues that support the uterus, a hollow organ in the pelvis where a baby (fetus) develops. Uterine sarcoma is different from endometrial cancer, which begins in the lining of the uterus known as the endometrium.

Soft tissue sarcoma (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.

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, MRI, bone scans, CT scans and PET scans.

Despite significant improvements in the treatment of sarcoma and soft tissue tumors, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2012
Sarcomas are a heterogenous group of malignancies derived from mesenchymal tissue. There are more than 50 subtypes of sarcomas that can arise from virtually all sites of the human body. The two most common types of soft tissue sarcoma are tumors that differentiate into fat-like cells (liposarcoma) and smooth muscle-like cells (leiomyosarcoma). Many sarcomas are defined by chromosomal translocations that underlie its tumorigenesis, but these are generally not known to be heritable diseases. The risk of sporadic soft tissue sarcomas is increased by prior radiation therapy and, in the case of lymphangiosarcoma, by chronic lymphedema. The chemicals Thorotrast, vinyl chloride and arsenic are also established carcinogens for hepatic angiosarcomas.

Soft tissue sarcomas occur with greater frequency in patients with the following inherited syndromes:

- Nevoid basal cell carcinoma syndrome (Gorlin syndrome: PTCH1 gene mutation)
- Gardner syndrome (APC mutation).
- Li-Fraumeni syndrome (TP53 mutation)
- Tuberous sclerosis (Bourneville disease: TSC1 or TSC2 mutation)
- von Recklinghausen disease (neurofibromatosis type 1: NF1 mutation)
- Werner syndrome (adult progeria: WRN mutation)

Source: National Cancer Institute, 2012
This year about 11,000 people in the U.S. will be told by a doctor that they have cancer of the soft tissue. Half of these patients will be at least 58 years old. Among the many types of soft tissue sarcoma, the more common ones are gastrointestinal stromal tumors (GIST), Kaposi sarcoma and uterine sarcoma.

Soft tissue sarcomas can form almost anywhere in the body, including muscles, tendons, fat, blood vessels, lymph vessels, nerves and tissues around joints. In adults, they are most common in the legs and arms (about 50% of all cases), the trunk (about 30% of all cases) and the head and neck (about 10% of cases). Based on the type of soft tissue in which the cancer began, each sarcoma appears different under the microscope.

GIST can occur anywhere along the gastrointestinal tract, including the stomach (about 60% of all cases), small intestine (about 30% of all cases), and large intestine (colon). The FDA has approved the targeted therapies imatinib (Gleevec) and sunitinib (Sutent) in the treatment of certain kinds of GIST.

Kaposi sarcoma causes abnormal tissue (lesions) to grow in the skin; mucous membranes lining the mouth, nose, and throat; lymph nodes; and other organs. Kaposi sarcoma differs from other cancers in that these lesions may begin in more than one place in the body at the same time.

Uterine sarcoma is a rare cancer that forms in the muscles of the uterus or tissues that support the uterus, a hollow organ in the pelvis where a baby (fetus) develops. Uterine sarcoma is different from endometrial cancer, which begins in the lining of the uterus known as the endometrium.

Soft tissue sarcoma (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.

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, MRI, bone scans, CT scans and PET scans.

Despite significant improvements in the treatment of sarcoma and soft tissue tumors, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2012
Sarcomas are a heterogenous group of malignancies derived from mesenchymal tissue. There are more than 50 subtypes of sarcomas that can arise from virtually all sites of the human body. The two most common types of soft tissue sarcoma are tumors that differentiate into fat-like cells (liposarcoma) and smooth muscle-like cells (leiomyosarcoma). Many sarcomas are defined by chromosomal translocations that underlie its tumorigenesis, but these are generally not known to be heritable diseases. The risk of sporadic soft tissue sarcomas is increased by prior radiation therapy and, in the case of lymphangiosarcoma, by chronic lymphedema. The chemicals Thorotrast, vinyl chloride and arsenic are also established carcinogens for hepatic angiosarcomas.

Soft tissue sarcomas occur with greater frequency in patients with the following inherited syndromes:

- Nevoid basal cell carcinoma syndrome (Gorlin syndrome: PTCH1 gene mutation)
- Gardner syndrome (APC mutation).
- Li-Fraumeni syndrome (TP53 mutation)
- Tuberous sclerosis (Bourneville disease: TSC1 or TSC2 mutation)
- von Recklinghausen disease (neurofibromatosis type 1: NF1 mutation)
- Werner syndrome (adult progeria: WRN mutation)

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 TP53  in Bone and Soft Tissue Sarcoma
The therapeutic implications of TP53 mutations in sarcomas are currently not known.

Despite extensive study there is no consensus in regards to the prognostic implications of TP53 mutations in sarcomas.

The therapeutic implications of TP53 mutations in sarcomas are currently not known.

Despite extensive study there is no consensus in regards to the prognostic implications of TP53 mutations in sarcomas.

Expand Collapse No mutation selected
The mutation of a gene provides clinicians with a very detailed look at your cancer. Knowing this information could change the course of your care. To learn how you can find out more about genetic testing please visit http://www.massgeneral.org/cancer/news/faq.aspx or contact the Cancer Center.

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene
Trial Status: Showing all 10 results Per Page:
Protocol # Title Location Status Match
NCT02601950 A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma MGH Open D
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
NCT02642016 A Study to Evaluate the Safety and Pharmacokinetics of KTN0158 in Adult Patients With Advanced Solid Tumors A Study to Evaluate the Safety and Pharmacokinetics of KTN0158 in Adult Patients With Advanced Solid Tumors 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
NCT02611024 Pharmacokinetic Study of PM01183 in Combination With Irinotecan in Patients With Selected Solid Tumors Pharmacokinetic Study of PM01183 in Combination With Irinotecan in Patients With Selected Solid Tumors MGH Open D
NCT01858168 Phase I Study of Olaprib and Temozolomide for Ewings Sarcoma Phase I Study of Olaprib and Temozolomide for Ewings Sarcoma MGH Open D
NCT02180867 Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Non-Rhabdomyosarcoma Soft Tissue Sarcomas That Can Be Removed by Surgery Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Non-Rhabdomyosarcoma Soft Tissue Sarcomas That Can Be Removed by Surgery MGH Open D
NCT02576431 Study of LOXO-101 in Subjects With NTRK Fusion Positive Solid Tumors (NAVIGATE) Study of LOXO-101 in Subjects With NTRK Fusion Positive Solid Tumors (NAVIGATE) MGH Open D
NCT02660034 The Safety, Pharmacokinetics and Antitumor Activity of the BGB-A317 in Combination With the BGB-290 in Subjects With Advanced Solid Tumors The Safety, Pharmacokinetics and Antitumor Activity of the BGB-A317 in Combination With the BGB-290 in Subjects With Advanced Solid Tumors MGH Open D
NCT02609984 Trial of CMB305 and Atezolizumab in Patients With Sarcoma Trial of CMB305 and Atezolizumab in Patients With Sarcoma 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.
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