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Targeted therapies in colorectal cancer-an integrative view by PPPM.

Hagan S, Orr MC, Doyle B - EPMA J (2013)

Bottom Line: KRAS and BRAF mutations have been shown to predict response to anti-EGFR therapy.As EGFR can also signal via the phosphatidylinositol 3-kinase (PI3K) kinase pathway, there is considerable interest in the potential roles of members of this pathway (such as PI3K and PTEN) in predicting treatment response.Therefore, a combined approach of new techniques that allow identification of these biomarkers alongside interdisciplinary approaches to the treatment of advanced CRC will aid in the treatment decision-making process and may also serve to guide future therapeutic approaches.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Life Sciences Glasgow, Caledonian University, Glasgow, G4 0BA, UK. suzanne.hagan@gcu.ac.uk.

ABSTRACT
In developed countries, colorectal cancer (CRC) is the third most common malignancy, but it is the second most frequent cause of cancer-related death. Clinicians are still faced with numerous challenges in the treatment of this disease, and future approaches which target the molecular features of the disorder will be critical for success in this disease setting. Genetic analyses of many solid tumours have shown that up to 100 protein-encoding genes are mutated. Within CRC, numerous genetic alterations have been identified in a number of pathways. Therefore, understanding the molecular pathology of CRC may present information on potential routes for treatment and may also provide valuable prognostic information. This will be particularly pertinent for molecularly targeted treatments, such as anti-vascular endothelial growth factor therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. KRAS and BRAF mutations have been shown to predict response to anti-EGFR therapy. As EGFR can also signal via the phosphatidylinositol 3-kinase (PI3K) kinase pathway, there is considerable interest in the potential roles of members of this pathway (such as PI3K and PTEN) in predicting treatment response. Therefore, a combined approach of new techniques that allow identification of these biomarkers alongside interdisciplinary approaches to the treatment of advanced CRC will aid in the treatment decision-making process and may also serve to guide future therapeutic approaches.

No MeSH data available.


Related in: MedlinePlus

Molecular classification of CRC as described by Jass [17]. Tumours are divided primarily on the basis of CIMP status and microsatellite stability. Group 1 tumours show methylation of MLH1 and B-Raf mutations. They are characterised by CIMP+ and MSI-H, arise from serrated polyps and account for approximately 12% of CRC. Group 2 tumours are similar, but show only partial methylation of MSH1 associated with B-Raf mutation. They are CIMP+, MSS/microsatellite instable-low (MSI-L), arise from serrated polyps and account for approximately 8% of CRC. Group 3 tumours show not only mutations in APC, Kras and/or p53 but also methylation of MGMT. These tumours are CIMP-L and MSS/MSI-L, and show CIS. They can arise in either serrated or classical adenomas, and account for approximately 20% of CRC. Group 4 tumours are the classical type described in Vogelstein's original model [20], which show mutations in APC, Kras and/or p53. These tumours demonstrate CIS and are CIMP- and MSS. They arise in classical adenomas and make up approximately 57% of CRC. Group 5 tumours are those tumours arising in the familial cancer syndrome, HNPCC. They show mutations in one of the DNA MMR genes, are CIMP-, but MSI-H and account for approximately 3% of CRC (adapted from Ibrahim and Arends, [146]).
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Figure 1: Molecular classification of CRC as described by Jass [17]. Tumours are divided primarily on the basis of CIMP status and microsatellite stability. Group 1 tumours show methylation of MLH1 and B-Raf mutations. They are characterised by CIMP+ and MSI-H, arise from serrated polyps and account for approximately 12% of CRC. Group 2 tumours are similar, but show only partial methylation of MSH1 associated with B-Raf mutation. They are CIMP+, MSS/microsatellite instable-low (MSI-L), arise from serrated polyps and account for approximately 8% of CRC. Group 3 tumours show not only mutations in APC, Kras and/or p53 but also methylation of MGMT. These tumours are CIMP-L and MSS/MSI-L, and show CIS. They can arise in either serrated or classical adenomas, and account for approximately 20% of CRC. Group 4 tumours are the classical type described in Vogelstein's original model [20], which show mutations in APC, Kras and/or p53. These tumours demonstrate CIS and are CIMP- and MSS. They arise in classical adenomas and make up approximately 57% of CRC. Group 5 tumours are those tumours arising in the familial cancer syndrome, HNPCC. They show mutations in one of the DNA MMR genes, are CIMP-, but MSI-H and account for approximately 3% of CRC (adapted from Ibrahim and Arends, [146]).

Mentions: This molecular sub-typing of CRC has advanced to the stage where we can now begin to consider a molecular classification-based approach for CRC. Jass suggested one such classification and proposed five molecular sub-classifications (see Figure 1), based on levels of MSI and CIMP [17].


Targeted therapies in colorectal cancer-an integrative view by PPPM.

Hagan S, Orr MC, Doyle B - EPMA J (2013)

Molecular classification of CRC as described by Jass [17]. Tumours are divided primarily on the basis of CIMP status and microsatellite stability. Group 1 tumours show methylation of MLH1 and B-Raf mutations. They are characterised by CIMP+ and MSI-H, arise from serrated polyps and account for approximately 12% of CRC. Group 2 tumours are similar, but show only partial methylation of MSH1 associated with B-Raf mutation. They are CIMP+, MSS/microsatellite instable-low (MSI-L), arise from serrated polyps and account for approximately 8% of CRC. Group 3 tumours show not only mutations in APC, Kras and/or p53 but also methylation of MGMT. These tumours are CIMP-L and MSS/MSI-L, and show CIS. They can arise in either serrated or classical adenomas, and account for approximately 20% of CRC. Group 4 tumours are the classical type described in Vogelstein's original model [20], which show mutations in APC, Kras and/or p53. These tumours demonstrate CIS and are CIMP- and MSS. They arise in classical adenomas and make up approximately 57% of CRC. Group 5 tumours are those tumours arising in the familial cancer syndrome, HNPCC. They show mutations in one of the DNA MMR genes, are CIMP-, but MSI-H and account for approximately 3% of CRC (adapted from Ibrahim and Arends, [146]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3584939&req=5

Figure 1: Molecular classification of CRC as described by Jass [17]. Tumours are divided primarily on the basis of CIMP status and microsatellite stability. Group 1 tumours show methylation of MLH1 and B-Raf mutations. They are characterised by CIMP+ and MSI-H, arise from serrated polyps and account for approximately 12% of CRC. Group 2 tumours are similar, but show only partial methylation of MSH1 associated with B-Raf mutation. They are CIMP+, MSS/microsatellite instable-low (MSI-L), arise from serrated polyps and account for approximately 8% of CRC. Group 3 tumours show not only mutations in APC, Kras and/or p53 but also methylation of MGMT. These tumours are CIMP-L and MSS/MSI-L, and show CIS. They can arise in either serrated or classical adenomas, and account for approximately 20% of CRC. Group 4 tumours are the classical type described in Vogelstein's original model [20], which show mutations in APC, Kras and/or p53. These tumours demonstrate CIS and are CIMP- and MSS. They arise in classical adenomas and make up approximately 57% of CRC. Group 5 tumours are those tumours arising in the familial cancer syndrome, HNPCC. They show mutations in one of the DNA MMR genes, are CIMP-, but MSI-H and account for approximately 3% of CRC (adapted from Ibrahim and Arends, [146]).
Mentions: This molecular sub-typing of CRC has advanced to the stage where we can now begin to consider a molecular classification-based approach for CRC. Jass suggested one such classification and proposed five molecular sub-classifications (see Figure 1), based on levels of MSI and CIMP [17].

Bottom Line: KRAS and BRAF mutations have been shown to predict response to anti-EGFR therapy.As EGFR can also signal via the phosphatidylinositol 3-kinase (PI3K) kinase pathway, there is considerable interest in the potential roles of members of this pathway (such as PI3K and PTEN) in predicting treatment response.Therefore, a combined approach of new techniques that allow identification of these biomarkers alongside interdisciplinary approaches to the treatment of advanced CRC will aid in the treatment decision-making process and may also serve to guide future therapeutic approaches.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Life Sciences Glasgow, Caledonian University, Glasgow, G4 0BA, UK. suzanne.hagan@gcu.ac.uk.

ABSTRACT
In developed countries, colorectal cancer (CRC) is the third most common malignancy, but it is the second most frequent cause of cancer-related death. Clinicians are still faced with numerous challenges in the treatment of this disease, and future approaches which target the molecular features of the disorder will be critical for success in this disease setting. Genetic analyses of many solid tumours have shown that up to 100 protein-encoding genes are mutated. Within CRC, numerous genetic alterations have been identified in a number of pathways. Therefore, understanding the molecular pathology of CRC may present information on potential routes for treatment and may also provide valuable prognostic information. This will be particularly pertinent for molecularly targeted treatments, such as anti-vascular endothelial growth factor therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy. KRAS and BRAF mutations have been shown to predict response to anti-EGFR therapy. As EGFR can also signal via the phosphatidylinositol 3-kinase (PI3K) kinase pathway, there is considerable interest in the potential roles of members of this pathway (such as PI3K and PTEN) in predicting treatment response. Therefore, a combined approach of new techniques that allow identification of these biomarkers alongside interdisciplinary approaches to the treatment of advanced CRC will aid in the treatment decision-making process and may also serve to guide future therapeutic approaches.

No MeSH data available.


Related in: MedlinePlus