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

When mutated, KRAS can act as an oncogene, causing normal cells to become cancerous. The mutations can shift the KRAS protein into the "on" position all the time. KRAS mutations are common in pancreatic, lung and colorectal cancers. These KRAS 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 KRAS mutations across a broad-spectrum of cancer types. The highest incidence of KRAS mutations have been found in pancreatic cancer (70%), colon cancer (30%), lung cancer (25%), cholangiocarcinoma (15-20%), acute myeloid leukemia (15-20%) and endometrial cancer (15-20%). Across the other major tumor types, KRAS mutations have been found in less than 10% of cases that have been tested.

Source: Genetics Home Reference
KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is a member of the closely related RAS gene family that includes NRAS and HRAS. These RAS members are small GTPases that transduce 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 and are tumorigenic, each oncogene exerts clear phenotypic differences. KRAS is the most frequently mutated gene from the RAS family, occurring in approximately 20% of all human cancers. Mutational hotspots in KRAS reside primarily in amino acid residues 12, 13 or 61 and function to promote hyperproliferation and suppress differentiation.

Tumor mutation profiling performed clinically at the MGH Cancer Center has identified KRAS mutations across a broad-spectrum of cancer types. The highest incidence of KRAS mutations have been found in pancreatic cancer (70%), colon cancer (30%), lung cancer (25%), cholangiocarcinoma (15-20%), acute myeloid leukemia (15-20%) and endometrial cancer (15-20%). Across the other major tumor types, KRAS mutations have been found in less than 10% of cases that have been tested.

Source: Genetics Home Reference
Expand Collapse G13V (c.38G>T)  in KRAS
The KRAS G13V mutation arises from a single nucleotide change (c.38G>T) and results in an amino acid substitution of the glycine (G) at position 13 by a valine (V).
The KRAS G13V mutation arises from a single nucleotide change (c.38G>T) and results in an amino acid substitution of the glycine (G) at position 13 by a valine (V).

There is no clear association between activating KRAS mutations and poor prognosis in colorectal cancer. This may be attributed to allele-specific differences, as the KRAS G12V mutation has specifically been associated with worse survival. In addition, the presence of BRAF mutations significantly worsens the prognosis and clinical trials looking for the effect of KRAS on long-term outcomes should control for this factor.

Currently, the presence of KRAS mutations in colorectal cancer is used more as a negative marker of treatment selection. Based on FDA guidelines, metastatic colorectal patients harboring a KRAS mutation should NOT be treated with the anti-EGFR agent cetuximab or panitumumab, regardless of EGFR expression status. Furthermore, preclinical studies have strongly indicated that clinical BRAF inhibitors should NOT be used in the treatment of KRAS-mutant colorectal cancer, due to unexpected compensatory mechanisms.

The role of KRAS mutations in predicting response to other targeted therapies has not yet been determined. While it remains unclear whether KRAS mutation will predict response to current MEK and/or ERK inhibitors being tested in clinical trials, a combination therapy approach that additionally targets the PI3K/AKT/mTOR or insulin growth factor receptor pathways may confer more robust treatment effects.

There is no clear association between activating KRAS mutations and poor prognosis in colorectal cancer. This may be attributed to allele-specific differences, as the KRAS G12V mutation has specifically been associated with worse survival. In addition, the presence of BRAF mutations significantly worsens the prognosis and clinical trials looking for the effect of KRAS on long-term outcomes should control for this factor.

Currently, the presence of KRAS mutations in colorectal cancer is used more as a negative marker of treatment selection. Based on FDA guidelines, metastatic colorectal patients harboring a KRAS mutation should NOT be treated with the anti-EGFR agent cetuximab or panitumumab, regardless of EGFR expression status. Furthermore, preclinical studies have strongly indicated that clinical BRAF inhibitors should NOT be used in the treatment of KRAS-mutant colorectal cancer, due to unexpected compensatory mechanisms.

The role of KRAS mutations in predicting response to other targeted therapies has not yet been determined. While it remains unclear whether KRAS mutation will predict response to current MEK and/or ERK inhibitors being tested in clinical trials, a combination therapy approach that additionally targets the PI3K/AKT/mTOR or insulin growth factor receptor pathways may confer more robust treatment effects.

PubMed ID's
20133499, 19934290, 20008640, 11531254, 18316791, 18946061, 19339720, 19114683, 20921465, 19884549, 20130576, 19194827, 20179705, 18946061, 1911468
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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
NCT02079740 Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors 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
Trial Status: Showing Results: 1-10 of 31 Per Page:
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