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Expand Collapse Colorectal Cancer  - General Description A cancer that begins in the colon is often called colon cancer and a cancer that begins in the rectum is often called rectal cancer, but sometimes the term colorectal cancer is used for a cancer that begins in either place. This year about 132,700 people in the U.S. will be diagnosed with cancer of the colon or rectum. However, nearly 1.1 million remain alive today after having been diagnosed with colorectal cancer.

The colon and rectum are parts of the large intestine. In the colon, which accounts for most of the length of the large intestine, water and nutrients are extracted from partly-digested food before the food is turned into waste. The waste then enters the rectum before being pushed out of the body, leaving via the short anal canal and the anus (cancers also develop in the anus and anal canal, but they aren't classified as colorectal cancers). Most colon cancers and rectal cancers are adenocarcinomas, tumors that begin in gland-like cells lining the colon or rectum. Other types of cancerous tissues account for only 2% to 5% of colorectal cancers.

Colorectal 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, 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 colon/rectal cancer cells cause secondary tumors to grow. The main sites to which colorectal cancer spreads are the liver, lungs and peritoneum. 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 examines it to see if cancer cells are present. Several kinds of imaging also can be performed to determine if the cancer has spread. These include chest x-rays, MRI, CT scans and PET scans.

The FDA has approved several targeted therapies for treatment of patients with metastatic colorectal cancer. These include bevacizumab (Avastin), cetuximab (Erbitux), panitumumab (Vectibix) and ziv-afibercept (Zaltrap).

Despite significant improvements in the treatment of colorectal cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2015
The prognosis of patients with colon cancer is clearly related to the degree of tumor penetration through the bowel wall, the presence or absence of nodal involvement, and the presence or absence of distant metastases. These three characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. The American Joint Committee on Cancer and a National Cancer Institute-sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor. This recommendation takes into consideration that the number of lymph nodes examined is a reflection of the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.

Many other prognostic markers have been evaluated retrospectively for patients with colon cancer, though most have not been prospectively validated (including allelic loss of chromosome 18q or thymidylate synthase expression). Microsatellite instability, also associated with hereditary nonpolyposis colon cancer (HNPCC), has been associated with improved survival (independent of tumor stage) in a population-based series of 607 patients younger than 50 years of age with colorectal cancer. Treatment decisions generally depend on factors such as physician/patient preferences and the stage of the disease, rather than the age of the patient. Racial differences in overall survival after adjuvant therapy have been observed (although not in disease-free survival), suggesting that comorbid conditions play a role in survival outcome in different patient populations.

Source: National Cancer Institute, 2012
A cancer that begins in the colon is often called colon cancer and a cancer that begins in the rectum is often called rectal cancer, but sometimes the term colorectal cancer is used for a cancer that begins in either place. This year about 132,700 people in the U.S. will be diagnosed with cancer of the colon or rectum. However, nearly 1.1 million remain alive today after having been diagnosed with colorectal cancer.

The colon and rectum are parts of the large intestine. In the colon, which accounts for most of the length of the large intestine, water and nutrients are extracted from partly-digested food before the food is turned into waste. The waste then enters the rectum before being pushed out of the body, leaving via the short anal canal and the anus (cancers also develop in the anus and anal canal, but they aren't classified as colorectal cancers). Most colon cancers and rectal cancers are adenocarcinomas, tumors that begin in gland-like cells lining the colon or rectum. Other types of cancerous tissues account for only 2% to 5% of colorectal cancers.

Colorectal 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, 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 colon/rectal cancer cells cause secondary tumors to grow. The main sites to which colorectal cancer spreads are the liver, lungs and peritoneum. 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 examines it to see if cancer cells are present. Several kinds of imaging also can be performed to determine if the cancer has spread. These include chest x-rays, MRI, CT scans and PET scans.

The FDA has approved several targeted therapies for treatment of patients with metastatic colorectal cancer. These include bevacizumab (Avastin), cetuximab (Erbitux), panitumumab (Vectibix) and ziv-afibercept (Zaltrap).

Despite significant improvements in the treatment of colorectal cancers, novel therapies and treatment strategies are needed.

Source: National Cancer Institute, 2015
The prognosis of patients with colon cancer is clearly related to the degree of tumor penetration through the bowel wall, the presence or absence of nodal involvement, and the presence or absence of distant metastases. These three characteristics form the basis for all staging systems developed for this disease. Bowel obstruction and bowel perforation are indicators of poor prognosis. Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance. The American Joint Committee on Cancer and a National Cancer Institute-sponsored panel recommended that at least 12 lymph nodes be examined in patients with colon and rectal cancer to confirm the absence of nodal involvement by tumor. This recommendation takes into consideration that the number of lymph nodes examined is a reflection of the aggressiveness of lymphovascular mesenteric dissection at the time of surgical resection and the pathologic identification of nodes in the specimen. Retrospective studies demonstrated that the number of lymph nodes examined in colon and rectal surgery may be associated with patient outcome.

Many other prognostic markers have been evaluated retrospectively for patients with colon cancer, though most have not been prospectively validated (including allelic loss of chromosome 18q or thymidylate synthase expression). Microsatellite instability, also associated with hereditary nonpolyposis colon cancer (HNPCC), has been associated with improved survival (independent of tumor stage) in a population-based series of 607 patients younger than 50 years of age with colorectal cancer. Treatment decisions generally depend on factors such as physician/patient preferences and the stage of the disease, rather than the age of the patient. Racial differences in overall survival after adjuvant therapy have been observed (although not in disease-free survival), suggesting that comorbid conditions play a role in survival outcome in different patient populations.

Source: National Cancer Institute, 2012
Expand Collapse APC  - General Description
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Adenomatous Polyposis Coli (APC) is a regulator of several fundamental cellular processes, including cell division, cell attachment, cell migration, cell polarization, and chromosome segregation during division. In these complex functions, APC activity is essential for the prevention of cancer (in other words, APC acts as a tumor suppressor). APC is involved in these cellular functions through interactions with other cellular proteins. One of the most recognized functions of APC is in regulating levels of beta-catenin, which is part of the WNT signal pathway in cells.

The WNT signal pathway is important in a variety of cellular processes. In the left hand cell in the graphic above, one can see that when there is no WNT ligand to bind to the extracellular WNT receptor, APC exists in a complex with other proteins. The complex is known as the “destruction complex”, and acts to destroy beta-catenin in the cell cytoplasm. This keeps levels of beta-catenin in the cell very low. Beta-catenin also binds to E-cadherin at the cell membrane, and is involved in cell to cell contacts (see graphic).

When WNT ligand binds to the extracellular WNT receptor, as is depicted in the right hand cell in the graphic above, it activates the receptor to send a signal that causes the dissociation of the destruction complex including APC. Without the destruction complex, beta-catenin builds up in the cytoplasm of the cells. In the cytoplasm, beta-catenin binds to T-cell factor (TCF), and together they translocate into the nucleus. They then bind to DNA and activate the transcription of genes that promote cell growth, such as c-Myc and cyclin D1. In the presence of WNT ligand binding, normal cells proliferate and divide.

In some cancers, APC is genetically altered, either through mutation or actual loss of the gene. Mutations in APC have been found in most colon cancers, whether familial (inherited genetic alterations) or spontaneous (somatic gene mutation). Mutations in APC have also been found in other cancers, including in adenocarcinoma of the lung. When APC is missing or mutated it cannot function in the destruction complex, and beta-catenin builds up in the cytoplasm even in the absence of WNT signaling. This unregulated high level of beta-catenin binds to TCF, moves into the nucleus of cancer cells, and binds to DNA to stimulate transcription of c-Myc and cyclin D1, causing cells to grow and divide.

Another way that APC function can be disrupted is through changes in E-cadherin, a protein that binds to beta-catenin, and mediates cell to cell contact (see graphic above). In many cancers, E-cadherin expression is lost, and without E-cadherin interacting with beta-catenin, cell to cell contact becomes dysregulated. Other genetic changes in E-cadherin can be inherited. The gene that encodes E-cadherin is called CDH1. Inherited germline mutations in CDH1 result in an E-cadherin protein that does not function normally, and these inherited mutations in CDH1/E-cadherin have been found to be associated with Hereditary Diffuse Gastric cancer/Lobular Breast Cancer Syndrome. The fact that so many genetic alterations in the pathways associated with APC highlight the importance of the APC tumor suppressor in normally preventing cancer.


Sources:
Graphic adapted from slideshareecdn.com 02-cat-neoplasia-5081/95/02-cat-neoplasia-14-728.jpg?cb=124463107
Valeria Bugos, Camila Guezada, Nicolas Briceno
Text sources PMID#17881494 Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene

Adenomatous Polyposis Coli (APC) is a regulator of several fundamental cellular processes, including cell division, cell attachment, cell migration, cell polarization, and chromosome segregation during division. In these complex functions, APC activity is essential for the prevention of cancer (in other words, APC acts as a tumor suppressor). APC is involved in these cellular functions through interactions with other cellular proteins. One of the most recognized functions of APC is in regulating levels of beta-catenin, which is part of the WNT signal pathway in cells.

The WNT signal pathway is important in a variety of cellular processes. In the left hand cell in the graphic above, one can see that when there is no WNT ligand to bind to the extracellular WNT receptor, APC exists in a complex with other proteins. The complex is known as the “destruction complex”, and acts to destroy beta-catenin in the cell cytoplasm. This keeps levels of beta-catenin in the cell very low. Beta-catenin also binds to E-cadherin at the cell membrane, and is involved in cell to cell contacts (see graphic).

When WNT ligand binds to the extracellular WNT receptor, as is depicted in the right hand cell in the graphic above, it activates the receptor to send a signal that causes the dissociation of the destruction complex including APC. Without the destruction complex, beta-catenin builds up in the cytoplasm of the cells. In the cytoplasm, beta-catenin binds to T-cell factor (TCF), and together they translocate into the nucleus. They then bind to DNA and activate the transcription of genes that promote cell growth, such as c-Myc and cyclin D1. In the presence of WNT ligand binding, normal cells proliferate and divide.

In some cancers, APC is genetically altered, either through mutation or actual loss of the gene. Mutations in APC have been found in most colon cancers, whether familial (inherited genetic alterations) or spontaneous (somatic gene mutation). Mutations in APC have also been found in other cancers, including in adenocarcinoma of the lung. When APC is missing or mutated it cannot function in the destruction complex, and beta-catenin builds up in the cytoplasm even in the absence of WNT signaling. This unregulated high level of beta-catenin binds to TCF, moves into the nucleus of cancer cells, and binds to DNA to stimulate transcription of c-Myc and cyclin D1, causing cells to grow and divide.

Another way that APC function can be disrupted is through changes in E-cadherin, a protein that binds to beta-catenin, and mediates cell to cell contact (see graphic above). In many cancers, E-cadherin expression is lost, and without E-cadherin interacting with beta-catenin, cell to cell contact becomes dysregulated. Other genetic changes in E-cadherin can be inherited. The gene that encodes E-cadherin is called CDH1. Inherited germline mutations in CDH1 result in an E-cadherin protein that does not function normally, and these inherited mutations in CDH1/E-cadherin have been found to be associated with Hereditary Diffuse Gastric cancer/Lobular Breast Cancer Syndrome. The fact that so many genetic alterations in the pathways associated with APC highlight the importance of the APC tumor suppressor in normally preventing cancer.


Sources:
Graphic adapted from slideshareecdn.com 02-cat-neoplasia-5081/95/02-cat-neoplasia-14-728.jpg?cb=124463107
Valeria Bugos, Camila Guezada, Nicolas Briceno
Text sources PMID#17881494 Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene

PubMed ID's
1788494
Expand Collapse APC  in Colorectal Cancer
New information on cancer, genes, and mutations is being discovered each day. Currently, researchers have not found any information on the gene and disease you have chosen. Please check back as new data may be available soon.
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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 Results: 1-10 of 27 Per Page:
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Protocol # Title Location Status Match
NCT02279433 A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b MGH Open D
NCT02099058 A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors A Phase 1/1b Study With ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Cancer Tumors MGH Open D
NCT02327169 A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Patients With Advanced Nonhematologic Malignancies A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Patients With Advanced Nonhematologic Malignancies MGH Open D
NCT02365662 A Study Evaluating Safety and Pharmacokinetics of ABBV-221 in Subjects With Advanced Solid Tumor Types Likely to Exhibit Elevated Levels of Epidermal Growth Factor Receptor A Study Evaluating Safety and Pharmacokinetics of ABBV-221 in Subjects With Advanced Solid Tumor Types Likely to Exhibit Elevated Levels of Epidermal Growth Factor Receptor MGH Open D
NCT01714739 A Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors A Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors MGH Open D
NCT01633970 A Study of Atezolizumab Administered in Combination With Bevacizumab and/or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors A Study of Atezolizumab Administered in Combination With Bevacizumab and/or With Chemotherapy in Participants With Locally Advanced or Metastatic Solid Tumors MGH Open D
NCT02467361 A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers A Study of BBI608 Administered in Combination With Immune Checkpoint Inhibitors in Adult Patients With Advanced Cancers MGH Open D
NCT02228811 A Study of DCC-2701 in Participants With Advanced Solid Tumors A Study of DCC-2701 in Participants With Advanced Solid Tumors MGH Open D
NCT02082210 A Study of LY2875358 in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer A Study of LY2875358 in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer MGH Open D
NCT02060188 A Study of Nivolumab and Nivolumab Plus Ipilimumab in Recurrent and Metastatic Colon Cancer (CheckMate 142) A Study of Nivolumab and Nivolumab Plus Ipilimumab in Recurrent and Metastatic Colon Cancer (CheckMate 142) MGH Open D
Trial Status: Showing Results: 1-10 of 27 Per Page:
123Next »
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