Refining molecular analysis in the pathways of colorectal carcinogenesis.
BACKGROUND and AIMS: In the stepwise model, specific genetic and epigenetic changes accumulate as colorectal adenomas progress to carcinomas (CRCs). CRCs also acquire global phenotypes, particularly microsatellite instability (MSI) and aneuploidy/polyploidy (chromosomal instability, CIN). Few chang...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2005
|
| _version_ | 1826289626716831744 |
|---|---|
| author | Rowan, A Halford, S Gaasenbeek, M Kemp, Z Sieber, O Volikos, E Douglas, E Fiegler, H Carter, N Talbot, I Silver, A Tomlinson, I |
| author_facet | Rowan, A Halford, S Gaasenbeek, M Kemp, Z Sieber, O Volikos, E Douglas, E Fiegler, H Carter, N Talbot, I Silver, A Tomlinson, I |
| author_sort | Rowan, A |
| collection | OXFORD |
| description | BACKGROUND and AIMS: In the stepwise model, specific genetic and epigenetic changes accumulate as colorectal adenomas progress to carcinomas (CRCs). CRCs also acquire global phenotypes, particularly microsatellite instability (MSI) and aneuploidy/polyploidy (chromosomal instability, CIN). Few changes specific to MSI-low or CIN+ cancers have been established. METHODS: We investigated 100 CRCs for: mutations and loss of heterozygosity (LOH) where appropriate, of APC, K-ras, BRAF, SMAD4, and p53; deletion on 5q around APC and 18q around SMAD4; total chromosomal-scale losses and gains; MSI; and CIN. RESULTS: As expected, CIN- cancers had fewer chromosomal changes overall than CIN+ lesions, but after correcting for this, 5q deletions alone predicted CIN+ status. 5q deletions were not, however, significantly associated with APC mutations, which were equally frequent in CIN+ and CIN- tumors. We therefore found no evidence to show that mutant APC promotes CIN. p53 mutations/LOH were more common in CIN+ than CIN- lesions, and all chromosomal amplifications were in CIN+ tumors. CIN- cancers could be subdivided according to the total number of chromosomal-scale changes into CIN-low and CIN-stable groups; 18q deletion was the best predictor, being present in nearly all CIN-low lesions and almost no CIN-stable tumors. MSI-low was not associated with CIN, any specific mutation, a mutational signature, or clinicopathologic characteristic. CONCLUSIONS: Overall, the components of the stepwise model (APC, K-ras, and p53 mutations, plus 18q LOH) tended to co-occur randomly. We propose an updated version of this model comprising 4 pathways of CRC pathogenesis, on the basis of 5q/18q deletions, MSI (high/low), and CIN (high/low/stable). |
| first_indexed | 2024-03-07T02:31:45Z |
| format | Journal article |
| id | oxford-uuid:a777bba9-5c25-4a90-9aa3-3d03c843c97a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:31:45Z |
| publishDate | 2005 |
| record_format | dspace |
| spelling | oxford-uuid:a777bba9-5c25-4a90-9aa3-3d03c843c97a2022-03-27T02:54:52ZRefining molecular analysis in the pathways of colorectal carcinogenesis.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a777bba9-5c25-4a90-9aa3-3d03c843c97aEnglishSymplectic Elements at Oxford2005Rowan, AHalford, SGaasenbeek, MKemp, ZSieber, OVolikos, EDouglas, EFiegler, HCarter, NTalbot, ISilver, ATomlinson, I BACKGROUND and AIMS: In the stepwise model, specific genetic and epigenetic changes accumulate as colorectal adenomas progress to carcinomas (CRCs). CRCs also acquire global phenotypes, particularly microsatellite instability (MSI) and aneuploidy/polyploidy (chromosomal instability, CIN). Few changes specific to MSI-low or CIN+ cancers have been established. METHODS: We investigated 100 CRCs for: mutations and loss of heterozygosity (LOH) where appropriate, of APC, K-ras, BRAF, SMAD4, and p53; deletion on 5q around APC and 18q around SMAD4; total chromosomal-scale losses and gains; MSI; and CIN. RESULTS: As expected, CIN- cancers had fewer chromosomal changes overall than CIN+ lesions, but after correcting for this, 5q deletions alone predicted CIN+ status. 5q deletions were not, however, significantly associated with APC mutations, which were equally frequent in CIN+ and CIN- tumors. We therefore found no evidence to show that mutant APC promotes CIN. p53 mutations/LOH were more common in CIN+ than CIN- lesions, and all chromosomal amplifications were in CIN+ tumors. CIN- cancers could be subdivided according to the total number of chromosomal-scale changes into CIN-low and CIN-stable groups; 18q deletion was the best predictor, being present in nearly all CIN-low lesions and almost no CIN-stable tumors. MSI-low was not associated with CIN, any specific mutation, a mutational signature, or clinicopathologic characteristic. CONCLUSIONS: Overall, the components of the stepwise model (APC, K-ras, and p53 mutations, plus 18q LOH) tended to co-occur randomly. We propose an updated version of this model comprising 4 pathways of CRC pathogenesis, on the basis of 5q/18q deletions, MSI (high/low), and CIN (high/low/stable). |
| spellingShingle | Rowan, A Halford, S Gaasenbeek, M Kemp, Z Sieber, O Volikos, E Douglas, E Fiegler, H Carter, N Talbot, I Silver, A Tomlinson, I Refining molecular analysis in the pathways of colorectal carcinogenesis. |
| title | Refining molecular analysis in the pathways of colorectal carcinogenesis. |
| title_full | Refining molecular analysis in the pathways of colorectal carcinogenesis. |
| title_fullStr | Refining molecular analysis in the pathways of colorectal carcinogenesis. |
| title_full_unstemmed | Refining molecular analysis in the pathways of colorectal carcinogenesis. |
| title_short | Refining molecular analysis in the pathways of colorectal carcinogenesis. |
| title_sort | refining molecular analysis in the pathways of colorectal carcinogenesis |
| work_keys_str_mv | AT rowana refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis AT halfords refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis AT gaasenbeekm refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis AT kempz refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis AT siebero refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis AT volikose refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis AT douglase refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis AT fieglerh refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis AT cartern refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis AT talboti refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis AT silvera refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis AT tomlinsoni refiningmolecularanalysisinthepathwaysofcolorectalcarcinogenesis |