Melanoma, ATM, all mutations

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Expand Collapse Melanoma  - General Description Skin cancer is a malignant tumor that grows in the skin cells and accounts for more than 50 percent of all cancers. There are generally three different types of skin cancer: basal cell carcinoma, squamous cell carcinoma and melanoma.

Basal cell carcinoma and squamous cell carcinoma usually appear on sun-exposed areas of the body. Prognosis is generally good and both of these cancer types can usually be effectively treated through surgery, with a minority of cases requiring radiation treatment.

Melanoma is the most aggressive form of skin cancer and arises in the cells that produce pigment (color) in the skin. BRAF is the gene that is most frequently activated by mutation in this malignancy and the common BRAF V600E and V600K mutations have been associated with a more aggressive clinical course and shorter survival. Vemurafenib is a new and effective FDA-approved targeted agent that is available to treat unresectable or metastatic melanoma based on the presence of a BRAF V600E mutation. Preclinical data has indicated that the rare BRAF V600R mutation may also be sensitive to vemurafenib. Also, the BRAF L597R mutation has been found to confer sensitivity to downstream MEK inhibitors. Most recently, the combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib was approved by FDA for the treatment of patients with BRAF V600E or V600K mutations. While less frequent, mutations in cancer genes such as NRAS, MEK, PTEN, PIK3CA and KIT may provide opportunities for enrollment into ongoing clinical trials.

Skin cancer is a malignant tumor that grows in the skin cells and accounts for more than 50 percent of all cancers. There are generally three different types of skin cancer: basal cell carcinoma, squamous cell carcinoma and melanoma.

Basal cell carcinoma and squamous cell carcinoma usually appear on sun-exposed areas of the body. Prognosis is generally good and both of these cancer types can usually be effectively treated through surgery, with a minority of cases requiring radiation treatment.

Melanoma is the most aggressive form of skin cancer and arises in the cells that produce pigment (color) in the skin. BRAF is the gene that is most frequently activated by mutation in this malignancy and the common BRAF V600E and V600K mutations have been associated with a more aggressive clinical course and shorter survival. Vemurafenib is a new and effective FDA-approved targeted agent that is available to treat unresectable or metastatic melanoma based on the presence of a BRAF V600E mutation. Preclinical data has indicated that the rare BRAF V600R mutation may also be sensitive to vemurafenib. Also, the BRAF L597R mutation has been found to confer sensitivity to downstream MEK inhibitors. Most recently, the combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib was approved by FDA for the treatment of patients with BRAF V600E or V600K mutations. While less frequent, mutations in cancer genes such as NRAS, MEK, PTEN, PIK3CA and KIT may provide opportunities for enrollment into ongoing clinical trials.

Skin cancer is a malignant tumor that grows in the skin cells and accounts for more than 50 percent of all cancers. There are generally three different types of skin cancer: basal cell carcinoma, squamous cell carcinoma and melanoma.

Basal cell carcinoma and squamous cell carcinoma usually appear on sun-exposed areas of the body. Prognosis is generally good and both of these cancer types can usually be effectively treated through surgery, with a minority of cases requiring radiation treatment.

Melanoma is the most aggressive form of skin cancer and arises in the cells that produce pigment (color) in the skin. BRAF is the gene that is most frequently activated by mutation in this malignancy and the common BRAF V600E and V600K mutations have been associated with a more aggressive clinical course and shorter survival. Vemurafenib is a new and effective FDA-approved targeted agent that is available to treat unresectable or metastatic melanoma based on the presence of a BRAF V600E mutation. Preclinical data has indicated that the rare BRAF V600R mutation may also be sensitive to vemurafenib. Also, the BRAF L597R mutation has been found to confer sensitivity to downstream MEK inhibitors. Most recently, the combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib was approved by FDA for the treatment of patients with BRAF V600E or V600K mutations. While less frequent, mutations in cancer genes such as NRAS, MEK, PTEN, PIK3CA and KIT may provide opportunities for enrollment into ongoing clinical trials.

Skin cancer is a malignant tumor that grows in the skin cells and accounts for more than 50 percent of all cancers. There are generally three different types of skin cancer: basal cell carcinoma, squamous cell carcinoma and melanoma.

Basal cell carcinoma and squamous cell carcinoma usually appear on sun-exposed areas of the body. Prognosis is generally good and both of these cancer types can usually be effectively treated through surgery, with a minority of cases requiring radiation treatment.

Melanoma is the most aggressive form of skin cancer and arises in the cells that produce pigment (color) in the skin. BRAF is the gene that is most frequently activated by mutation in this malignancy and the common BRAF V600E and V600K mutations have been associated with a more aggressive clinical course and shorter survival. Vemurafenib is a new and effective FDA-approved targeted agent that is available to treat unresectable or metastatic melanoma based on the presence of a BRAF V600E mutation. Preclinical data has indicated that the rare BRAF V600R mutation may also be sensitive to vemurafenib. Also, the BRAF L597R mutation has been found to confer sensitivity to downstream MEK inhibitors. Most recently, the combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib was approved by FDA for the treatment of patients with BRAF V600E or V600K mutations. While less frequent, mutations in cancer genes such as NRAS, MEK, PTEN, PIK3CA and KIT may provide opportunities for enrollment into ongoing clinical trials.

PubMed ID's
21343559, 22798288, 20551065
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 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. Mutations in HR pathway members that have now been identified in certain cancers 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 result of mutations in proteins involved in the HR pathway results in proteins that do not function properly in their role in DNA repair. Without proper function of all 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 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. Mutations in HR pathway members that have now been identified in certain cancers 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 result of mutations in proteins involved in the HR pathway results in proteins that do not function properly in their role in DNA repair. Without proper function of all 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
Genetic alterations in DNA repair genes such as ATM have been found in many cancers. These mutations often involve alterations in the nucleotide sequence of the DNA, or other changes. Mutations in the ATM gene result in an abnormal ATM protein that is unable to perform its normal function.
Genetic alterations in DNA repair genes such as ATM have been found in many cancers. These mutations often involve alterations in the nucleotide sequence of the DNA, or other changes. Mutations in the ATM gene result in an abnormal ATM protein that is unable to perform its normal function.

Genetic alterations in DNA repair genes such as ATM have been found in melanomas. 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 melanomas. 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 45 Per Page:
12345Next »
Protocol # Title Location Status Match
NCT02637531 A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IPI-549 A Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IPI-549 MGH Open D
NCT03192345 A First-in-human Study of the Safety, Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity of SAR439459 Monotherapy and Combination of SAR439459 and REGN2810 in Patients With Advanced Solid Tumors A First-in-human Study of the Safety, Pharmacokinetics, Pharmacodynamics and Anti-tumor Activity of SAR439459 Monotherapy and Combination of SAR439459 and REGN2810 in Patients With Advanced Solid Tumors MGH Open D
NCT02561234 A Multiple Dose, Dose Escalation Trial of AEB1102 in Patients With Advanced Solid Tumors A Multiple Dose, Dose Escalation Trial of AEB1102 in Patients With Advanced Solid Tumors MGH Open D
NCT02897765 A Personal Cancer Vaccine (NEO-PV-01) w/ Nivolumab for Patients With Melanoma, Lung Cancer or Bladder Cancer A Personal Cancer Vaccine (NEO-PV-01) w/ Nivolumab for Patients With Melanoma, Lung Cancer or Bladder Cancer MGH Open D
NCT02817633 A Phase 1 Study of TSR-022, an Anti-TIM-3 Monoclonal Antibody, in Patients With Advanced Solid Tumors A Phase 1 Study of TSR-022, an Anti-TIM-3 Monoclonal Antibody, in Patients With Advanced Solid Tumors MGH Open D
NCT02110355 A Phase 1b/2a Study Evaluating AMG 232 in Metastatic Melanoma A Phase 1b/2a Study Evaluating AMG 232 in Metastatic Melanoma MGH Open D
NCT03417739 A Phase II Study of BVD-523 in Metastatic Uveal Melanoma A Phase II Study of BVD-523 in Metastatic Uveal Melanoma MGH Open D
NCT03148418 A Study in Participants Previously Enrolled in a Genentech− and/or F. Hoffmann-La Roche Ltd-Sponsored Atezolizumab Study (IMbrella A) A Study in Participants Previously Enrolled in a Genentech− and/or F. Hoffmann-La Roche Ltd-Sponsored Atezolizumab Study (IMbrella A) MGH Open D
NCT01714739 A Study of an Anti-KIR Antibody Lirilumab in Combination With an Anti-PD1 Antibody Nivolumab and Nivolumab Plus an Anti-CTLA-4 Ipilimumab Antibody in Patients With Advanced Solid Tumors A Study of an Anti-KIR Antibody Lirilumab in Combination With an Anti-PD1 Antibody Nivolumab and Nivolumab Plus an Anti-CTLA-4 Ipilimumab Antibody in Patients With Advanced Solid Tumors MGH Open D
NCT02880371 A Study of ARRY-382 in Combination With Pembrolizumab for the Treatment of Patients With Advanced Solid Tumors A Study of ARRY-382 in Combination With Pembrolizumab for the Treatment of Patients With Advanced Solid Tumors MGH Open D
Trial Status: Showing Results: 1-10 of 45 Per Page:
12345Next »
Our Melanoma Team

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