Bladder Cancer, ATM

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Expand Collapse Bladder Cancer  - General Description This year about 74,000 people in the U.S. (76% of them men and half will be over the age of 73 years old) will be told by a doctor that they have cancer of the urinary bladder. With significant improvements in the treatment of this malignancy, about 550,000 of them remain alive today.

Bladder cancer begins in different types of cells found in the inner lining of the bladder, the flexible muscular organ that stores urine. Transitional cells, which stretch or shrink as the bladder fills or empties, account for 90% of bladder cancers in the United States. Less commonly (in 6-8% of U.S. bladder cancers), the cancer begins in squamous cells that may form in response to irritation or infection that has lasted a long time. Adenocarcinoma begins in cells that make mucous and accounts for only about 2% of U.S. bladder cancers. Adenocarcinoma of the bladder is also believed to be a result of long-lasting irritation or inflammation.

If the cancer stays in the lining of the bladder, it is called superficial bladder cancer. Sometimes, though, transitional cell cancer spreads through the lining and breaks into the muscular wall beneath it or spreads to nearby organs and lymph nodes. In this case it is known as invasive bladder cancer.

Bladder 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, bladder 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 blood stream and go to other places in the body. In these distant places, the bladder cancer cells cause secondary (metastatic) tumors to grow, in the bones, for example. To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a lymph node and a pathologist inspects it under a microscope. Several kinds of imaging can also be performed to determine if bladder cancer has spread. These include CT scans, MRI, chest x-rays and bone scans.

Source: National Cancer Institute, 2012
This year about 74,000 people in the U.S. (76% of them men and half will be over the age of 73 years old) will be told by a doctor that they have cancer of the urinary bladder. With significant improvements in the treatment of this malignancy, about 550,000 of them remain alive today.

Bladder cancer begins in different types of cells found in the inner lining of the bladder, the flexible muscular organ that stores urine. Transitional cells, which stretch or shrink as the bladder fills or empties, account for 90% of bladder cancers in the United States. Less commonly (in 6-8% of U.S. bladder cancers), the cancer begins in squamous cells that may form in response to irritation or infection that has lasted a long time. Adenocarcinoma begins in cells that make mucous and accounts for only about 2% of U.S. bladder cancers. Adenocarcinoma of the bladder is also believed to be a result of long-lasting irritation or inflammation.

If the cancer stays in the lining of the bladder, it is called superficial bladder cancer. Sometimes, though, transitional cell cancer spreads through the lining and breaks into the muscular wall beneath it or spreads to nearby organs and lymph nodes. In this case it is known as invasive bladder cancer.

Bladder 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, bladder 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 blood stream and go to other places in the body. In these distant places, the bladder cancer cells cause secondary (metastatic) tumors to grow, in the bones, for example. To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a lymph node and a pathologist inspects it under a microscope. Several kinds of imaging can also be performed to determine if bladder cancer has spread. These include CT scans, MRI, chest x-rays and bone scans.

Source: National Cancer Institute, 2012
This year about 74,000 people in the U.S. (76% of them men and half will be over the age of 73 years old) will be told by a doctor that they have cancer of the urinary bladder. With significant improvements in the treatment of this malignancy, about 550,000 of them remain alive today.

Bladder cancer begins in different types of cells found in the inner lining of the bladder, the flexible muscular organ that stores urine. Transitional cells, which stretch or shrink as the bladder fills or empties, account for 90% of bladder cancers in the United States. Less commonly (in 6-8% of U.S. bladder cancers), the cancer begins in squamous cells that may form in response to irritation or infection that has lasted a long time. Adenocarcinoma begins in cells that make mucous and accounts for only about 2% of U.S. bladder cancers. Adenocarcinoma of the bladder is also believed to be a result of long-lasting irritation or inflammation.

If the cancer stays in the lining of the bladder, it is called superficial bladder cancer. Sometimes, though, transitional cell cancer spreads through the lining and breaks into the muscular wall beneath it or spreads to nearby organs and lymph nodes. In this case it is known as invasive bladder cancer.

Bladder 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, bladder 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 blood stream and go to other places in the body. In these distant places, the bladder cancer cells cause secondary (metastatic) tumors to grow, in the bones, for example. To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a lymph node and a pathologist inspects it under a microscope. Several kinds of imaging can also be performed to determine if bladder cancer has spread. These include CT scans, MRI, chest x-rays and bone scans.

Source: National Cancer Institute, 2012
This year about 74,000 people in the U.S. (76% of them men and half will be over the age of 73 years old) will be told by a doctor that they have cancer of the urinary bladder. With significant improvements in the treatment of this malignancy, about 550,000 of them remain alive today.

Bladder cancer begins in different types of cells found in the inner lining of the bladder, the flexible muscular organ that stores urine. Transitional cells, which stretch or shrink as the bladder fills or empties, account for 90% of bladder cancers in the United States. Less commonly (in 6-8% of U.S. bladder cancers), the cancer begins in squamous cells that may form in response to irritation or infection that has lasted a long time. Adenocarcinoma begins in cells that make mucous and accounts for only about 2% of U.S. bladder cancers. Adenocarcinoma of the bladder is also believed to be a result of long-lasting irritation or inflammation.

If the cancer stays in the lining of the bladder, it is called superficial bladder cancer. Sometimes, though, transitional cell cancer spreads through the lining and breaks into the muscular wall beneath it or spreads to nearby organs and lymph nodes. In this case it is known as invasive bladder cancer.

Bladder 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, bladder 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 blood stream and go to other places in the body. In these distant places, the bladder cancer cells cause secondary (metastatic) tumors to grow, in the bones, for example. To find out whether the cancer has entered the lymph system, a surgeon removes all or part of a lymph node and a pathologist inspects it under a microscope. Several kinds of imaging can also be performed to determine if bladder cancer has spread. These include CT scans, MRI, chest x-rays and bone scans.

Source: National Cancer Institute, 2012
Expand Collapse ATM  - General Description
CLICK IMAGE FOR MORE INFORMATION
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 ATM  in Bladder Cancer
Genetic alterations in DNA repair genes such as ATM have been found in cancer of the bladder. 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 cancer of the bladder. 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.

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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