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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 NRAS  - General Description
CLICK IMAGE FOR MORE INFORMATION
NRAS is a gene that provides the code for making NRAS, a GTPase that converts GTP to GDP. This protein is part of the MAP kinase signaling cascade that relays chemical signals from the outside of the cell to the cell's nucleus, and is primarily involved in controlling cell division. When NRAS is attached (bound) to GDP, it is in its “off” position and can't send signals to the nucleus. But when a GTP molecule arrives and binds to NRAS, NRAS is activated and sends its signal, and then it converts the GTP into GDP and returns to the "off" position. HRAS and KRAS are other GTPases that are similar to NRAS.

When mutated, however, NRAS can act as an oncogene, causing normal cells to become cancerous. The mutations can shift the NRAS protein into the "on" position all the time. These NRAS mutations are said to be somatic, because instead of coming from a parent and being present in every cell (hereditary), they are acquired during the course of a person's life and are found only in cells that become cancerous.

Tumor mutation profiling performed clinically at the MGH Cancer Center has identified the highest incidence of NRAS mutations in melanoma (~30%), acute myeloid leukemia (~15%) and thyroid carcinoma (5-10%).

Source: Genetics Home Reference
NRAS (neuroblastoma RAS viral oncogene homolog) is a member of the closely related RAS gene family that also includes KRAS and HRAS. These RAS members are small GTPases that mediate extracellular signals to the downstream effectors RAF, PI3K and RALGDS. RAS members are involved in regulating diverse cellular processes including survival, proliferation and differentiation. While activating mutations in the RAS genes lead to sustained GTPase activation that contributes to oncogenesis, each oncogene exerts clear differences. Mutational hotspots in NRAS reside primarily in amino acid residues 12, 13 or 61 and function to suppress apoptosis.

Clinical tumor genotyping performed at the MGH Cancer Center has identified the highest incidence of NRAS mutations in melanoma (~30%), acute myeloid leukemia (~15%) and thyroid carcinoma (5-10%).

Source: Genetics Home Reference
PubMed ID's
18372904, 21779495
Expand Collapse Q61R (c.182A>G)  in NRAS
The NRAS Q61R mutation arises from a single nucleotide change (c.182A>G) and results in an amino acid substitution of the glutamine (Q) at position 61 by an arginine (R).
The NRAS Q61R mutation arises from a single nucleotide change (c.182A>G) and results in an amino acid substitution of the glutamine (Q) at position 61 by an arginine (R).

The large randomized MRC COIN trial reported that the presence of an NRAS mutation was associated with worse prognosis in advanced colorectal patients.

The role of NRAS mutations for selecting anti-cancer targeted agents is unknown at this time. Unlike its closely-related family member KRAS, the frequency of NRAS mutation is low in colorectal cancer (4%) and this has precluded its determination as a biomarker of drug resistance to the anti-EGFR agent cetuximab or panitumumab. However, a single multi-center retrospective study has reported that the presence of an NRAS mutation was associated with significantly lower response to treatment with cetuximab plus chemotherapy in patients with chemotherapy-refractory, metastatic colorectal cancer.

Based on clinical evidence obtained in melanoma, downstream pathway MEK inhibitors may be a feasible treatment strategy for the treatment of NRAS-mutant tumors, citing an approximate 20% response rate to single-agent MEK162 treatment in patients with malignant melanoma. While it remains unclear whether NRAS mutations will predict response to current MEK inhibitors in colorectal cancer, a combination therapy approach that additionally targets the PI3K/AKT/mTOR pathway may confer a more robust treatment effect.

The large randomized MRC COIN trial reported that the presence of an NRAS mutation was associated with worse prognosis in advanced colorectal patients.

The role of NRAS mutations for selecting anti-cancer targeted agents is unknown at this time. Unlike its closely-related family member KRAS, the frequency of NRAS mutation is low in colorectal cancer (4%) and this has precluded its determination as a biomarker of drug resistance to the anti-EGFR agent cetuximab or panitumumab. However, a single multi-center retrospective study has reported that the presence of an NRAS mutation was associated with significantly lower response to treatment with cetuximab plus chemotherapy in patients with chemotherapy-refractory, metastatic colorectal cancer.

Based on clinical evidence obtained in melanoma, downstream pathway MEK inhibitors may be a feasible treatment strategy for the treatment of NRAS-mutant tumors, citing an approximate 20% response rate to single-agent MEK162 treatment in patients with malignant melanoma. While it remains unclear whether NRAS mutations will predict response to current MEK inhibitors in colorectal cancer, a combination therapy approach that additionally targets the PI3K/AKT/mTOR pathway may confer a more robust treatment effect.

PubMed ID's
20619739, 20141835, 16273091, 19805051, 21641636, 23414587
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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
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
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
Trial Status: Showing Results: 1-10 of 31 Per Page:
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