Bladder Cancer, BRCA1 and BRCA2, Sporadic Somatic Mutations

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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 BRCA1 and BRCA2  - General Description
BRCA1 and BRCA2 are genes that encode proteins that play an important role in DNA repair. DNA is damaged in organisms through various means-UV from the sunlight, and exposure to other substances that cause breaks or cross-links in the DNA. DNA breaks also occur when cells are dividing and chromosomes need to separate, especially in cells that will eventually have half the number of chromosomes-the egg and sperm-during a process called meiosis. When the proteins that are involved in DNA repair are mutated or missing, breaks in the DNA do not get repaired, resulting in an accumulation of DNA that is incorrectly arranged, which leads to cancer. For this reason, BRCA1 and BRCA2 are called tumor suppressor genes, because when they function correctly, they participate in repairing DNA and preventing cancers.

When both strands of the DNA helix are disrupted, a process called Double Stranded DNA Repair takes place through a process called Homologous Recombination. This process involves a complex-or group-of many different proteins, some that attach onto the broken ends of DNA and then recruit other proteins to the site that are able to repair double strand breaks (DSB's) in the DNA so that the genes they encode are correctly sequenced when the repair is complete. Along with the BRCA proteins, proteins called RAD50 and RAD51 are part of the complex of proteins involved in DNA repair. During the DNA repair process, BRCA2 recruits RAD51 into the complex that is responsible for DNA repair.

BRCA1 and BRCA2 are genes that were discovered in families that had a high incidence of breast cancer. In these families, the genetic alterations in BRCA1 or BRCA2 are present in the germ-line, which means they are inherited. Inherited germ-line mutations in BRCA1 or BRCA2 greatly increase the likelihood of developing cancer of the breast or ovary, as well as prostate cancer in men. BRCA1 has many functions in the cell. It is involved in transcription of genes, targeting proteins for degradation in the cell, cell cycle regulation, and homologous recombination to repair DNA. BRCA2 is involved in homologous recombination to repair DNA. When either BRCA gene is missing or inactivated, the result is hereditary breast and ovarian cancer (HBOC). BRCA2 mutations confer a 50-60% lifetime risk of breast cancer, a 30% lifetime risk of ovarian cancer, a 20 fold risk of prostate cancer, a tenfold risk of pancreatic cancer, and potentially increased frequency of other cancers as well.

Patients can also develop somatic mutations or deletions of the BRCA1 or BRCA2 gene during their lifetime, instead of inheriting these mutations. Spontaneous mutations in BRCA1 or BRCA2 in an individual are called sporadic mutations. As more patients with different tumor types are tested for BRCA1 and BRCA2, it is becoming evident that multiple tumor types can harbor BRCA1 or BRCA2 mutations or deletions of the gene. Mutations in other genes involved in DNA repair can also contribute to the development of tumors. Testing is available for BRCA1 and BRCA2 mutations at MGH, where there are established treatments such as PARP inhibitors in use, and clinical trials ongoing for improved treatments for patients carrying these mutations.

Sources:
The DNA Damage Response: Ten Years After, J. Wade Harper, Stephen J. Elledge, Molecular Cell, Vol.28, Issue 5, 2007, pages 739-745.

DNA repair targeted therapy: The past or future of cancer treatment? 2017
Science Direct article pii/S0163725816000322
BRCA1 and BRCA2 are genes that encode proteins that play an important role in DNA repair. DNA is damaged in organisms through various means-UV from the sunlight, and exposure to other substances that cause breaks or cross-links in the DNA. DNA breaks also occur when cells are dividing and chromosomes need to separate, especially in cells that will eventually have half the number of chromosomes-the egg and sperm-during a process called meiosis. When the proteins that are involved in DNA repair are mutated or missing, breaks in the DNA do not get repaired, resulting in an accumulation of DNA that is incorrectly arranged, which leads to cancer. For this reason, BRCA1 and BRCA2 are called tumor suppressor genes, because when they function correctly, they participate in repairing DNA and preventing cancers.

When both strands of the DNA helix are disrupted, a process called Double Stranded DNA Repair takes place through a process called Homologous Recombination. This process involves a complex-or group-of many different proteins, some that attach onto the broken ends of DNA and then recruit other proteins to the site that are able to repair double strand breaks (DSB's) in the DNA so that the genes they encode are correctly sequenced when the repair is complete. Along with the BRCA proteins, proteins called RAD50 and RAD51 are part of the complex of proteins involved in DNA repair. During the DNA repair process, BRCA2 recruits RAD51 into the complex that is responsible for DNA repair.

BRCA1 and BRCA2 are genes that were discovered in families that had a high incidence of breast cancer. In these families, the genetic alterations in BRCA1 or BRCA2 are present in the germ-line, which means they are inherited. Inherited germ-line mutations in BRCA1 or BRCA2 greatly increase the likelihood of developing cancer of the breast or ovary, as well as prostate cancer in men. BRCA1 has many functions in the cell. It is involved in transcription of genes, targeting proteins for degradation in the cell, cell cycle regulation, and homologous recombination to repair DNA. BRCA2 is involved in homologous recombination to repair DNA. When either BRCA gene is missing or inactivated, the result is hereditary breast and ovarian cancer (HBOC). BRCA2 mutations confer a 50-60% lifetime risk of breast cancer, a 30% lifetime risk of ovarian cancer, a 20 fold risk of prostate cancer, a tenfold risk of pancreatic cancer, and potentially increased frequency of other cancers as well.

Patients can also develop somatic mutations or deletions of the BRCA1 or BRCA2 gene during their lifetime, instead of inheriting these mutations. Spontaneous mutations in BRCA1 or BRCA2 in an individual are called sporadic mutations. As more patients with different tumor types are tested for BRCA1 and BRCA2, it is becoming evident that multiple tumor types can harbor BRCA1 or BRCA2 mutations or deletions of the gene. Mutations in other genes involved in DNA repair can also contribute to the development of tumors. Testing is available for BRCA1 and BRCA2 mutations at MGH, where there are established treatments such as PARP inhibitors in use, and clinical trials ongoing for improved treatments for patients carrying these mutations.

Sources:
The DNA Damage Response: Ten Years After, J. Wade Harper, Stephen J. Elledge, Molecular Cell, Vol.28, Issue 5, 2007, pages 739-745.

DNA repair targeted therapy: The past or future of cancer treatment? 2017
Science Direct article pii/S0163725816000322
PubMed ID's
19553641,
Expand Collapse Sporadic Somatic Mutations  in BRCA1 and BRCA2
The loss or inactivation of BRCA1 or BRCA2 genes have a serious impact on the cells ability to repair DNA damage when it occurs. In some cases, sporadic genetic alterations can occur in an individuals BRCA1 or BRCA2 genes. These somatic mutations cause a loss or impairment in the function of the proteins encoded by the BRCA1 or BRCA2 genes. Sporadic somatic mutations in BRCA1 or BRCA2 impair DNA damage repair, resulting in an increased risk of developing cancer.
The loss or inactivation of BRCA1 or BRCA2 genes have a serious impact on the cells ability to repair DNA damage when it occurs. In some cases, sporadic genetic alterations can occur in an individuals BRCA1 or BRCA2 genes. These somatic mutations cause a loss or impairment in the function of the proteins encoded by the BRCA1 or BRCA2 genes. Sporadic somatic mutations in BRCA1 or BRCA2 impair DNA damage repair, resulting in an increased risk of developing cancer.

The loss or inactivation of BRCA1 or BRCA2 genes have a serious impact on the cells ability to repair DNA damage when it occurs. In familial cancer syndromes, BRCA1 or BRCA2 genes are lost or impaired in the germline, meaning the defect in the gene is inherited. Inherited BRCA1 or BRCA2 impairment causes an increased risk of developing cancer.

The loss or inactivation of BRCA1 or BRCA2 genes have a serious impact on the cells ability to repair DNA damage when it occurs. In familial cancer syndromes, BRCA1 or BRCA2 genes are lost or impaired in the germline, meaning the defect in the gene is inherited. Inherited BRCA1 or BRCA2 impairment causes an increased risk of developing cancer.

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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 19 Per Page:
12Next »
Protocol # Title Location Status Match
NCT02052778 A Dose Finding Study Followed by a Safety and Efficacy Study in Patients With Advanced Solid Tumors or Multiple Myeloma With FGF/FGFR-Related Abnormalities A Dose Finding Study Followed by a Safety and Efficacy Study in Patients With Advanced Solid Tumors or Multiple Myeloma With FGF/FGFR-Related Abnormalities MGH Open D
NCT02897765 A Personalized Cancer Vaccine (NEO-PV-01) w/ Nivolumab for Patients With Melanoma, Lung Cancer or Bladder Cancer A Personalized Cancer Vaccine (NEO-PV-01) w/ Nivolumab for Patients With Melanoma, Lung Cancer or Bladder Cancer MGH Open D
NCT02450331 A Study of Atezolizumab Versus Observation as Adjuvant Therapy in Participants With High-Risk Muscle-Invasive Urothelial Carcinoma (UC) After Surgical Resection A Study of Atezolizumab Versus Observation as Adjuvant Therapy in Participants With High-Risk Muscle-Invasive Urothelial Carcinoma (UC) After Surgical Resection MGH Open D
NCT02603432 A Study Of Avelumab In Patients With Locally Advanced Or Metastatic Urothelial Cancer (JAVELIN Bladder 100) A Study Of Avelumab In Patients With Locally Advanced Or Metastatic Urothelial Cancer (JAVELIN Bladder 100) MGH Open D
NCT02323191 A Study of Emactuzumab and Atezolimumab Administered in Combination in Participants With Advanced Solid Tumors A Study of Emactuzumab and Atezolimumab Administered in Combination in Participants With Advanced Solid Tumors MGH Open D
NCT01953926 An Open-label, Phase 2 Study of Neratinib in Patients With Solid Tumors With Somatic Human Epidermal Growth Factor Receptor (EGFR, HER2, HER3) Mutations or EGFR Gene Amplification An Open-label, Phase 2 Study of Neratinib in Patients With Solid Tumors With Somatic Human Epidermal Growth Factor Receptor (EGFR, HER2, HER3) Mutations or EGFR Gene Amplification MGH Open D
NCT01948297 Debio 1347-101 Phase I Trial in Advanced Solid Tumours With Fibroblast Growth Factor Receptor (FGFR) Alterations Debio 1347-101 Phase I Trial in Advanced Solid Tumours With Fibroblast Growth Factor Receptor (FGFR) Alterations MGH Open D
NCT02989064 MAGE-A10ᶜ⁷⁹⁶T for Urothelial Cancer, Melanoma or Head and Neck Cancers MAGE-A10ᶜ⁷⁹⁶T for Urothelial Cancer, Melanoma or Head and Neck Cancers MGH Open D
NCT02465060 NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma MGH Open D
NCT02655822 Phase 1/1b Study to Evaluate the Safety and Tolerability of CPI-444 Alone and in Combination With Atezolizumab in Advanced Cancers Phase 1/1b Study to Evaluate the Safety and Tolerability of CPI-444 Alone and in Combination With Atezolizumab in Advanced Cancers MGH Open D
Trial Status: Showing Results: 1-10 of 19 Per Page:
12Next »
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