Bone and Soft Tissue Sarcoma, ATM, all mutations

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Expand Collapse Bone and Soft Tissue Sarcoma  - General Description This year about 12,000 people in the U.S. will be told by a doctor that they have cancer of the soft tissue. Sarcomas develop more commonly in adults, although certain types of sarcoma are found more typically in children.

Soft tissue sarcomas can form almost anywhere in the body, including cartilage, fat, muscle, fibrous tissue, blood vessels, and other connective or supportive tissues; osteosarcomas develop in bone, liposarcomas form in fat; rhabdomyosarcomas form in muscle; Ewing sarcomas form in bone and soft tissue; Kaposi sarcoma and uterine sarcoma are other types of soft tissue sarcomas. Because there are many types of soft tissue sarcoma, the cell type must be identified before treatment decisions are made. There are ongoing clinical trials using many forms of therapy in specific types of sarcoma.

Source: National Cancer Institute, 2017
This year about 12,000 people in the U.S. will be told by a doctor that they have cancer of the soft tissue. Sarcomas develop more commonly in adults, although certain types of sarcoma are found more typically in children.

Soft tissue sarcomas can form almost anywhere in the body, including cartilage, fat, muscle, fibrous tissue, blood vessels, and other connective or supportive tissues; osteosarcomas develop in bone, liposarcomas form in fat; rhabdomyosarcomas form in muscle; Ewing sarcomas form in bone and soft tissue; Kaposi sarcoma and uterine sarcoma are other types of soft tissue sarcomas. Because there are many types of soft tissue sarcoma, the cell type must be identified before treatment decisions are made. There are ongoing clinical trials using many forms of therapy in specific types of sarcoma.

Source: National Cancer Institute, 2017
This year about 12,000 people in the U.S. will be told by a doctor that they have cancer of the soft tissue. Sarcomas develop more commonly in adults, although certain types of sarcoma are found more typically in children.

Soft tissue sarcomas can form almost anywhere in the body, including cartilage, fat, muscle, fibrous tissue, blood vessels, and other connective or supportive tissues; osteosarcomas develop in bone, liposarcomas form in fat; rhabdomyosarcomas form in muscle; Ewing sarcomas form in bone and soft tissue; Kaposi sarcoma and uterine sarcoma are other types of soft tissue sarcomas. Because there are many types of soft tissue sarcoma, the cell type must be identified before treatment decisions are made. There are ongoing clinical trials using many forms of therapy in specific types of sarcoma.

Source: National Cancer Institute, 2017
This year about 12,000 people in the U.S. will be told by a doctor that they have cancer of the soft tissue. Sarcomas develop more commonly in adults, although certain types of sarcoma are found more typically in children.

Soft tissue sarcomas can form almost anywhere in the body, including cartilage, fat, muscle, fibrous tissue, blood vessels, and other connective or supportive tissues; osteosarcomas develop in bone, liposarcomas form in fat; rhabdomyosarcomas form in muscle; Ewing sarcomas form in bone and soft tissue; Kaposi sarcoma and uterine sarcoma are other types of soft tissue sarcomas. Because there are many types of soft tissue sarcoma, the cell type must be identified before treatment decisions are made. There are ongoing clinical trials using many forms of therapy in specific types of sarcoma.

Source: National Cancer Institute, 2017
Expand Collapse ATM  - General Description
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The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the rate at which cells grow and divide. This protein also plays an important role in the normal development and activity of several body systems, including the nervous system and the immune system. Additionally, the ATM protein assists cells in recognizing damaged or broken DNA strands. The ATM protein coordinates DNA repair by activating enzymes that cause a delay in the cell cycle, enabling cells to repair the broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic information.

The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB's). There are two main pathways used by cells to repair DSB's in their DNA, one is Homologous Recombination (HR), the other is Non-Homologous End Joining (NHEJ). This page of our website focuses on the HR pathway (there is a separate web page for NHEJ repair found if you select PKcs on the list of genes when you sign onto the web-page).

Many proteins are involved in the complex HR pathway to repair DSB's in DNA. There is a graphic above that depicts the HR pathway (if you click on the graphic, it will enlarge and become a bit easier to follow). While complicated, the DSB at the top right of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete and accurate repair of the DSB in the DNA.

Some of the proteins involved in the HR DSB repair pathway are MRE11, NBS1, RAD50. These three proteins make up the MRN complex. This complex detects DSB's in the DNA. Once the DSB is found by the MRN complex, the MRN complex functions with BRCA1 and CtIP to resect the DSB’s to form single stranded DNA “tails”. Meanwhile, DSB's also activate the ATM protein, which can act upon CHK2 to activate it, as well as directly activating the tumor suppressor TP53. TP53 can cause cell cycle delay, giving the cell time to repair DNA breaks or mistakes before the cell cycle leading to division resumes. In the next step, RPA binds to the single stranded DNA "tails" that have been created by BRCA1 and CtIP in conjunction with the MRN. The binding of RPA activates another protein called ATR. ATR has many important functions, including activating CHK1, which can cause cell cycle delay giving cells time to repair DNA. ATR also regulates BRCA1 which recruits a bound group of proteins including PALB2/BRCA2/RAD51. In the next step, RAD51 displaces the RPA that is on the single stranded DNA, with the involvement of BRCA2/PALB2 and RAD51c. BRCA1/BARD1 helps RAD51 coated single stranded DNA to invade double stranded DNA with homologous sequences to form a DNA repair loop. With the help of DNA polymerases, the repair loop creates the opportunity to use the intact homologous DNA as a template to correctly repair DSB’s. Enzymes called ligases reconnect the ends of the DNA, leading to complete and accurate repair of the DSB in DNA.

After studying familial cancer syndromes, BRCA1 and BRCA2 were identified a while ago as inherited genes that when altered by mutation, cause certain cancers. Some BRCA1 and BRCA2 genes become mutated somatically, meaning in a non-inherited way. When either gene is mutated, the resulting protein cannot perform its role in DNA repair correctly. This turns out to be true for other proteins in the HR pathway as well. Recently, scientists have found mutations in many of the other genes that encode the proteins involved in the HR pathway as well. Mutations in HR pathway members include MRE11, NBS1, RAD50, ATM, CHK2, BRCA1, PALB2, RAD51, BRCA2, BARD1, and RAD51c (these are depicted in red in the above graphic). This remarkable number of mutations highlights how important the HR DSB DNA repair pathway is in cells. The results of any of the mutations in HR pathway proteins results in proteins that do not function properly in their role in DNA repair. Without proper function of the proteins involved in DNA repair, DNA mistakes or breaks are not properly repaired, and the damaged DNA contributes to the development of cancer.

Many mutations in the ATM gene have been identified in different types of cancer. This leaves the cells totally reliant on the ATR pathway to delay the cell cycle so that DNA repair can be accomplished. Dependence on the ATR DNA repair pathway has therapeutic implications for patients whose tumors have mutations in ATM, or mutations in other proteins in the HR pathway.

Testing for mutations in the many genes (ATM and the other genes depicted in red in the graphic above) is available in the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in the DNA repair proteins-including strategies for cancers that have mutated ATM-are available at the MGH Cancer Center.
The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the rate at which cells grow and divide. This protein also plays an important role in the normal development and activity of several body systems, including the nervous system and the immune system. Additionally, the ATM protein assists cells in recognizing damaged or broken DNA strands. The ATM protein coordinates DNA repair by activating enzymes that cause a delay in the cell cycle, enabling cells to repair the broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic information.

The maintenance of intact, correctly sequenced DNA is vital to the life of a cell. If there are mistakes made in replicating DNA before cell division, subsequent daughter cells will have inaccurate DNA, and may either die or carry mutations that can contribute to the development of cancer. For this reason, cells have evolved multiple pathways to repair mistakes in-or damage to- DNA. The specific repair pathway used by the cell depends on the type of DNA damage that has occurred. The types of DNA repair that we are focusing on relate directly to cancer. These involve a break in BOTH strands of DNA, which can be the result of ionizing radiation or other DNA damaging agents. This type of DNA damage is called Double Strand Breaks (DSB's). There are two main pathways used by cells to repair DSB's in their DNA, one is Homologous Recombination (HR), the other is Non-Homologous End Joining (NHEJ). This page of our website focuses on the HR pathway (there is a separate web page for NHEJ repair found if you select PKcs on the list of genes when you sign onto the web-page).

Many proteins are involved in the complex HR pathway to repair DSB's in DNA. There is a graphic above that depicts the HR pathway (if you click on the graphic, it will enlarge and become a bit easier to follow). While complicated, the DSB at the top right of the graphic is acted upon by a series of proteins in the circle of steps shown that ultimately lead to the complete and accurate repair of the DSB in the DNA.

Some of the proteins involved in the HR DSB repair pathway are MRE11, NBS1, RAD50. These three proteins make up the MRN complex. This complex detects DSB's in the DNA. Once the DSB is found by the MRN complex, the MRN complex functions with BRCA1 and CtIP to resect the DSB’s to form single stranded DNA “tails”. Meanwhile, DSB's also activate the ATM protein, which can act upon CHK2 to activate it, as well as directly activating the tumor suppressor TP53. TP53 can cause cell cycle delay, giving the cell time to repair DNA breaks or mistakes before the cell cycle leading to division resumes. In the next step, RPA binds to the single stranded DNA "tails" that have been created by BRCA1 and CtIP in conjunction with the MRN. The binding of RPA activates another protein called ATR. ATR has many important functions, including activating CHK1, which can cause cell cycle delay giving cells time to repair DNA. ATR also regulates BRCA1 which recruits a bound group of proteins including PALB2/BRCA2/RAD51. In the next step, RAD51 displaces the RPA that is on the single stranded DNA, with the involvement of BRCA2/PALB2 and RAD51c. BRCA1/BARD1 helps RAD51 coated single stranded DNA to invade double stranded DNA with homologous sequences to form a DNA repair loop. With the help of DNA polymerases, the repair loop creates the opportunity to use the intact homologous DNA as a template to correctly repair DSB’s. Enzymes called ligases reconnect the ends of the DNA, leading to complete and accurate repair of the DSB in DNA.

After studying familial cancer syndromes, BRCA1 and BRCA2 were identified a while ago as inherited genes that when altered by mutation, cause certain cancers. Some BRCA1 and BRCA2 genes become mutated somatically, meaning in a non-inherited way. When either gene is mutated, the resulting protein cannot perform its role in DNA repair correctly. This turns out to be true for other proteins in the HR pathway as well. Recently, scientists have found mutations in many of the other genes that encode the proteins involved in the HR pathway as well. Mutations in HR pathway members include MRE11, NBS1, RAD50, ATM, CHK2, BRCA1, PALB2, RAD51, BRCA2, BARD1, and RAD51c (these are depicted in red in the above graphic). This remarkable number of mutations highlights how important the HR DSB DNA repair pathway is in cells. The results of any of the mutations in HR pathway proteins results in proteins that do not function properly in their role in DNA repair. Without proper function of the proteins involved in DNA repair, DNA mistakes or breaks are not properly repaired, and the damaged DNA contributes to the development of cancer.

Many mutations in the ATM gene have been identified in different types of cancer. This leaves the cells totally reliant on the ATR pathway to delay the cell cycle so that DNA repair can be accomplished. Dependence on the ATR DNA repair pathway has therapeutic implications for patients whose tumors have mutations in ATM, or mutations in other proteins in the HR pathway.

Testing for mutations in the many genes (ATM and the other genes depicted in red in the graphic above) is available in the MGH genetics lab. Treatment as well as clinical trials studying new drugs that target defects in the DNA repair proteins-including strategies for cancers that have mutated ATM-are available at the MGH Cancer Center.

PubMed ID's
27617969, 24003211, PMC2988877
Expand Collapse all mutations  in ATM
Changes in the gene encoding ATM often involve alterations in the nucleotide sequence of the DNA, called mutations. Mutations in the gene result in an abnormal ATM protein, one that can no longer cause cell cycle arrest through CHK2 and TP53. Without this pause, cell cycle delay for DNA repair can only occur through an alternate pathway induced by ATR. The tumor cell dependence on ATR provides therapeutic opportunities for patients with mutations in ATM (or other proteins in the DNA repair pathway). Without a delay in the cell cycle, damaged DNA cannot be repaired, leading to death of tumor cells.
Changes in the gene encoding ATM often involve alterations in the nucleotide sequence of the DNA, called mutations. Mutations in the gene result in an abnormal ATM protein, one that can no longer cause cell cycle arrest through CHK2 and TP53. Without this pause, cell cycle delay for DNA repair can only occur through an alternate pathway induced by ATR. The tumor cell dependence on ATR provides therapeutic opportunities for patients with mutations in ATM (or other proteins in the DNA repair pathway). Without a delay in the cell cycle, damaged DNA cannot be repaired, leading to death of tumor cells.

Genetic alterations in DNA repair genes such as ATM have been found in sarcomas. Mutations in the ATM gene result in an altered ATM protein, that does not function normally. If ATM can no longer activate CHK2 or TP53 (see graphic above), then there is no Cell cycle arrest. Cell cycle arrest is a pause in the cell cycle that allows cells to repair damaged DNA. An accumulation of damaged DNA can lead to the development of cancer.

Genetic alterations in DNA repair genes such as ATM have been found in sarcomas. Mutations in the ATM gene result in an altered ATM protein, that does not function normally. If ATM can no longer activate CHK2 or TP53 (see graphic above), then there is no Cell cycle arrest. Cell cycle arrest is a pause in the cell cycle that allows cells to repair damaged DNA. An accumulation of damaged DNA can lead to the development of cancer.

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 23 Per Page:
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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
NCT02659020 A Study of Olaratumab (LY3012207) in Participants With Advanced Soft Tissue Sarcoma A Study of Olaratumab (LY3012207) in Participants With Advanced Soft Tissue Sarcoma MGH Open D
NCT03126591 A Study of Olaratumab (LY3012207) Plus Pembrolizumab in Participants With Advanced or Metastatic Soft Tissue Sarcoma A Study of Olaratumab (LY3012207) Plus Pembrolizumab in Participants With Advanced or Metastatic Soft Tissue 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
NCT02748135 A Two-Part Study of TB-403 in Pediatric Subjects With Relapsed or Refractory Medulloblastoma A Two-Part Study of TB-403 in Pediatric Subjects With Relapsed or Refractory Medulloblastoma MGH Open D
NCT02278250 An Open-Label Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of VX-803/M4344 as a Single Agent and in Combination With Cytotoxic Chemotherapy in Subjects With Advanced Solid Tumors An Open-Label Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of VX-803/M4344 as a Single Agent and in Combination With Cytotoxic Chemotherapy in Subjects 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
NCT02454972 Clinical Trial of Lurbinectedin (PM01183) in Selected Advanced Solid Tumors Clinical Trial of Lurbinectedin (PM01183) in Selected Advanced Solid Tumors MGH Open D
NCT02306161 Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma MGH Open D
NCT02567435 Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma MGH Open D
Trial Status: Showing Results: 1-10 of 23 Per Page:
123Next »

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