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Expand Collapse Colorectal Cancer  - General Description Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the chromosomal instability pathway (CIN) as well as microsatellite instability pathway (MSI). Both of these are recognized pathways in the development of CRC. These types of genetic instability lead to activation of proto-oncogenes such as KRAS, and the inactivation of tumor suppressors mentioned below.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated in abnormal patterns, this prevents the production of tumor suppressor proteins that are important in controlling or stopping cell growth. When these are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, and loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; AKT, APC, beta-catenin, BRAF, EGFR, ERBB2, ERBB3, IDH2, KRAS, NRAS, PIk3CA, PTEN, TP53,TRK 1, 2 and 3, and others still being identified.

Finally, distinct familial syndromes of CRC such as Lynch syndrome have been studied, and in these patients, the normal proof-reading of DNA during cell replication is found to be deficient. While DNA polymerase enzyme is replicating DNA before cells divide (with both daughter cells having a full complement of DNA), it occasionally makes errors. In a process of proof-reading behind this enzyme, several proteins form a complex to find and repair these mistakes. The process of proof-reading and restoring the DNA to the correct sequence is called mismatch repair (MMR). In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. The accumulation of these mistakes or mutations leads to cancer. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic CRC. DNA repair machinery in the cell is important in keeping the genome stable and accurate. Defects in MMR also contribute to microsatellite instability (MIS), described above.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC are available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017
Genetic Alterations in CRC; Gastrointestinal Cancer Research; Amaghany T, et al.
Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the chromosomal instability pathway (CIN) as well as microsatellite instability pathway (MSI). Both of these are recognized pathways in the development of CRC. These types of genetic instability lead to activation of proto-oncogenes such as KRAS, and the inactivation of tumor suppressors mentioned below.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated in abnormal patterns, this prevents the production of tumor suppressor proteins that are important in controlling or stopping cell growth. When these are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, and loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; AKT, APC, beta-catenin, BRAF, EGFR, ERBB2, ERBB3, IDH2, KRAS, NRAS, PIk3CA, PTEN, TP53,TRK 1, 2 and 3, and others still being identified.

Finally, distinct familial syndromes of CRC such as Lynch syndrome have been studied, and in these patients, the normal proof-reading of DNA during cell replication is found to be deficient. While DNA polymerase enzyme is replicating DNA before cells divide (with both daughter cells having a full complement of DNA), it occasionally makes errors. In a process of proof-reading behind this enzyme, several proteins form a complex to find and repair these mistakes. The process of proof-reading and restoring the DNA to the correct sequence is called mismatch repair (MMR). In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. The accumulation of these mistakes or mutations leads to cancer. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic CRC. DNA repair machinery in the cell is important in keeping the genome stable and accurate. Defects in MMR also contribute to microsatellite instability (MIS), described above.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC are available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017
Genetic Alterations in CRC; Gastrointestinal Cancer Research; Amaghany T, et al.
Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the chromosomal instability pathway (CIN) as well as microsatellite instability pathway (MSI). Both of these are recognized pathways in the development of CRC. These types of genetic instability lead to activation of proto-oncogenes such as KRAS, and the inactivation of tumor suppressors mentioned below.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated in abnormal patterns, this prevents the production of tumor suppressor proteins that are important in controlling or stopping cell growth. When these are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, and loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; AKT, APC, beta-catenin, BRAF, EGFR, ERBB2, ERBB3, IDH2, KRAS, NRAS, PIk3CA, PTEN, TP53,TRK 1, 2 and 3, and others still being identified.

Finally, distinct familial syndromes of CRC such as Lynch syndrome have been studied, and in these patients, the normal proof-reading of DNA during cell replication is found to be deficient. While DNA polymerase enzyme is replicating DNA before cells divide (with both daughter cells having a full complement of DNA), it occasionally makes errors. In a process of proof-reading behind this enzyme, several proteins form a complex to find and repair these mistakes. The process of proof-reading and restoring the DNA to the correct sequence is called mismatch repair (MMR). In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. The accumulation of these mistakes or mutations leads to cancer. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic CRC. DNA repair machinery in the cell is important in keeping the genome stable and accurate. Defects in MMR also contribute to microsatellite instability (MIS), described above.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC are available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017
Genetic Alterations in CRC; Gastrointestinal Cancer Research; Amaghany T, et al.
Colorectal Cancer (CRC) is cancer that initiates in the colon or rectum-the lower part of the digestive system in the body. During digestion, food moves through the stomach and small intestine into the colon. The colon absorbs water and nutrients from food, and stores waste matter (stool) that moves from the colon through the rectum before leaving the body.

Most CRC's and rectal cancers are adenocarcinomas, meaning that they originate in cells that make and release mucus and other fluids. CRC often begins as a growth called a polyp, which may form on the inner wall of the colon or rectum. Over time, some polyps become cancerous. This highlights the importance of colonoscopy screening to find and remove polyps before they become cancerous.

CRC is the fourth most common type of cancer diagnosed in the U.S. Deaths from CRC have decreased with the use of colonoscopies and fecal occult blood tests, which check for blood in the stool. Disparities in survival have been observed between African American and other populations. This may be due to factors such as access to colonoscopy screening, or to other factors not yet identified.

Because of its prevalence, scientists have studied CRC extensively, even creating models of how cancer develops using CRC as an example. There are also families with a very high incidence of CRC occurrence. When these families were studied, certain conditions that create instability in the whole genome were identified that predispose people to CRC. These include what is called the chromosomal instability pathway (CIN) as well as microsatellite instability pathway (MSI). Both of these are recognized pathways in the development of CRC. These types of genetic instability lead to activation of proto-oncogenes such as KRAS, and the inactivation of tumor suppressors mentioned below.

Other genetic alterations in how the DNA in cells is organized have been found to contribute to CRC in families and individuals. These are called epigenetic changes. Normal DNA has methyl groups added in specific regions that regulate gene expression. When the genes that suppress growth-called tumor suppressors-are methylated in abnormal patterns, this prevents the production of tumor suppressor proteins that are important in controlling or stopping cell growth. When these are missing, unregulated growth occurs, contributing to the development of cancer. Some tumor suppressor proteins that are frequently inactivated in CRC are APC, TP53, and loss of one arm of chromosome 18 that contains a tumor suppressor.

The study of families with a high prevalence of CRC have lead scientists to discover genetic changes that contribute to the development of CRC in sporadic cases occurring in patients. Mutations in the genes encoding the following proteins have now been associated with subsets of CRC; AKT, APC, beta-catenin, BRAF, EGFR, ERBB2, ERBB3, IDH2, KRAS, NRAS, PIk3CA, PTEN, TP53,TRK 1, 2 and 3, and others still being identified.

Finally, distinct familial syndromes of CRC such as Lynch syndrome have been studied, and in these patients, the normal proof-reading of DNA during cell replication is found to be deficient. While DNA polymerase enzyme is replicating DNA before cells divide (with both daughter cells having a full complement of DNA), it occasionally makes errors. In a process of proof-reading behind this enzyme, several proteins form a complex to find and repair these mistakes. The process of proof-reading and restoring the DNA to the correct sequence is called mismatch repair (MMR). In Lynch syndrome, one or more of the proteins involved in MMR is mutated, and the mistakes in the DNA do not get corrected. The accumulation of these mistakes or mutations leads to cancer. Mutations in MMR proteins are not only found in familial cases of CRC, but also in patients with sporadic CRC. DNA repair machinery in the cell is important in keeping the genome stable and accurate. Defects in MMR also contribute to microsatellite instability (MIS), described above.

Testing for the mutations and genomic conditions that contribute to the development or progression of CRC are available at MGH in the sophisticated CLIA certified genomic testing lab, and in other large Centers and some private testing companies used by physicians. Validated treatments as well as clinical trials investigating improved targeted and immunologic therapies are available to patients at MGH.

NIH/NCI Cancer Website www.cancer.gov 2017
Genetic Alterations in CRC; Gastrointestinal Cancer Research; Amaghany T, et al.
PubMed ID's
2188735,
Expand Collapse BRAF  - General Description
CLICK IMAGE FOR MORE INFORMATION
The BRAF gene encodes a serine/threonine kinase that activates the growth-promoting MAP kinase signaling cascade. BRAF is commonly activated by somatic point mutations in human cancers, most frequently by mutations located within the kinase domain at amino acid positions G466, G469, L597 and V600.

In regards to treatment, the Food and Drug Administration (FDA) approved the BRAF inhibitor, vemurafenib, for the treatment of unresectable or metastatic melanoma patients harboring specifically the BRAF V600E mutation, as detected by an FDA-approved test. In addition, there are a growing number of targeted agents that are being evaluated for the treatment of various BRAF-mutant advanced cancers, including other RAF kinase inhibitors and/or MEK inhibitors. 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.

Tumor mutation profiling performed clinically at the MGH Cancer Center has identified the highest incidence of BRAF mutations in thyroid cancer (30-40%), melanoma (20-30%) and colon cancer (10-15%).

To read more about the various BRAF based trials ongoing at the MGH Cancer Center, click on the "disease-gene-mutation" tab on the web page, and select relevant information. Current trials will appear as a ist under the posted information.


Source: Genetics Home Reference
The BRAF gene encodes a serine/threonine kinase that activates the growth-promoting MAP kinase signaling cascade. BRAF is commonly activated by somatic point mutations in human cancers, most frequently by mutations located within the kinase domain at amino acid positions G466, G469, L597 and V600.

In regards to treatment, the Food and Drug Administration (FDA) approved the BRAF inhibitor, vemurafenib, for the treatment of unresectable or metastatic melanoma patients harboring specifically the BRAF V600E mutation, as detected by an FDA-approved test. In addition, there are a growing number of targeted agents that are being evaluated for the treatment of various BRAF-mutant advanced cancers, including other RAF kinase inhibitors and/or MEK inhibitors. 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.

Tumor mutation profiling performed clinically at the MGH Cancer Center has identified the highest incidence of BRAF mutations in thyroid cancer (30-40%), melanoma (20-30%) and colon cancer (10-15%).

To read more about the various BRAF based trials ongoing at the MGH Cancer Center, click on the "disease-gene-mutation" tab on the web page, and select relevant information. Current trials will appear as a ist under the posted information.

Source: Genetics Home Reference
PubMed ID's
12068308, 15947100, 20401974, 20425073, 21606968
Expand Collapse V600R (c.1798_1799GT>AG)  in BRAF
The BRAF V600R mutation arises from a double nucleotide change (c.1798_1799GT>AG) and results in an amino acid substitution of the valine (V) at position 600 by an arginine (R).
The BRAF V600R mutation arises from a double nucleotide change (c.1798_1799GT>AG) and results in an amino acid substitution of the valine (V) at position 600 by an arginine (R).

BRAF mutations are found in approximately 10% of colorectal cancers, mainly in sporadic tumors with the CpG island methylator phenotype (CIMP+) and high microsatellite instability (MSI-H).

It has not been determined whether non-V600E BRAF mutations in metastatic colorectal cancer are similarly associated with poor prognosis as the predominant BRAF V600E mutation.

Activating BRAF mutations (more specifically V600E) have been linked to resistance to anti-EGFR therapies panitumumab or cetuximab. In addition, it has been demonstrated that BRAF-mutant colorectal carcinomas do not respond similarly to BRAF inhibitors as do malignant melanomas with a BRAF V600E mutation. However, correlative and genotype-directed studies will be required to determine whether non-V600E mutations in colorectal cancer predict response to other matched targeted therapies. For instance, preclinical and early clinical studies in melanoma have demonstrated that some BRAF mutations (L597, V600K) confer increased sensitivity to novel RAF and MEK inhibitors. Additional clinical trials are currently underway to test these treatment approaches in other tumor types, including colorectal cancer.

BRAF mutations are found in approximately 10% of colorectal cancers, mainly in sporadic tumors with the CpG island methylator phenotype (CIMP+) and high microsatellite instability (MSI-H).

It has not been determined whether non-V600E BRAF mutations in metastatic colorectal cancer are similarly associated with poor prognosis as the predominant BRAF V600E mutation.

Activating BRAF mutations (more specifically V600E) have been linked to resistance to anti-EGFR therapies panitumumab or cetuximab. In addition, it has been demonstrated that BRAF-mutant colorectal carcinomas do not respond similarly to BRAF inhibitors as do malignant melanomas with a BRAF V600E mutation. However, correlative and genotype-directed studies will be required to determine whether non-V600E mutations in colorectal cancer predict response to other matched targeted therapies. For instance, preclinical and early clinical studies in melanoma have demonstrated that some BRAF mutations (L597, V600K) confer increased sensitivity to novel RAF and MEK inhibitors. Additional clinical trials are currently underway to test these treatment approaches in other tumor types, including colorectal cancer.

PubMed ID's
19001320, 19603018, 20619739, 20413299, 19884556, 17363584, 12198537, 16804544, 12068308, 21426297, 22281684, 22448344, 22798288
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing Results: 1-10 of 31 Per Page:
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Protocol # Title Location Status Match
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 DGM
NCT01351103 A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands MGH Open DG
NCT02857270 A Study of LY3214996 Administered Alone or in Combination With Other Agents in Participants With Advanced/Metastatic Cancer A Study of LY3214996 Administered Alone or in Combination With Other Agents in Participants With Advanced/Metastatic Cancer MGH Open DG
NCT02335918 A Dose Escalation and Cohort Expansion Study of Anti-CD27 (Varlilumab) and Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors A Dose Escalation and Cohort Expansion Study of Anti-CD27 (Varlilumab) and Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors MGH Open D
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
NCT02715284 A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors 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
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
Trial Status: Showing Results: 1-10 of 31 Per Page:
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