Molecular interactions in the Vogelstein model of colorectal carcinoma

Arends, Jan Willem

doi:10.1002/(sici)1096-9896(200003)190:4<412::aid-path533>3.0.co;2-p

Cited by 157 publications

(47 citation statements)

References 32 publications

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“…By utilizing quantitative means applied to multiple microdissection targets, the temporal profile can be developed generating patient specific information at the individual patient level. [31][32][33][34][35] In conclusion, we believed that the determination of sequential timing of mutational damage in cytologic material could be incorporated in the work-up and help to make more definitive diagnosis of malignancy in pancreatobiliary cytology specimens Figure 3 The temporal profile of sequential mutation acquisition can be represented by a schematic diagram highlighting the order to mutation accumulation. Mutations acquired early are present in multiple microdissection targets and at a higher proportion of affected cells.…”

Section: Discussionmentioning

confidence: 99%

Determination of sequential mutation accumulation in pancreas and bile duct brushing cytology

et al. 2006

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Neoplastic progression is characterized by clonal expansion of tumor cells associated with accumulation of mutational damage. The timing of mutation acquisition could be of value in distinguishing preneoplastic conditions from early and advanced cancer as well as characterizing tumor aggressiveness and treatment response. Using quantitative methods applied to microdissected cell clusters selected according to cytomorphologic features, we sought to demonstrate the feasibility and efficacy for determining the time and course of mutation accumulation in pancreatobiliary cytology specimens. In all, 40 pancreatic duct and 21 biliary brushing cytology specimens were retrieved from the cytology database. Xylene-resistant markings were placed on the slide underside and coverslips removed. Clusters of benign, atypical and malignant cells were manually microdissected and DNA extracted. Mutations (allelic imbalance) (loss of heterozygosity) were quantitatively determined for a broad panel of 15 markers (1p, 3p, 5q, 9p, 10q, 17p, 17q, 21q, 22q) as well as point mutation in K-ras-2 using PCR/capillary electrophoresis. Time course was based on earlier mutations having a higher proportion of mutant DNA for a particular marker. The descending frequency of detectable mutational involvement in pancreatic cytology was K-ras-2 point mutation (58%), 3p25-26 and 17q21 (35%), 5q23 (33%), 1p36 (28%), followed by the remaining molecular markers. The descending frequency of mutational content in bile duct cytology was 17p13, 1p36, 3p25-26, and 5q23 followed by remaining molecular markers. K-ras-2 point mutation was not seen in bile duct specimens. While there was overlap in the spectrum of mutational markers in pancreatic duct and biliary brushing cytology, the temporal profile was significantly different (Po0.001). Pancreatic and biliary neoplasia progression involves distinct subset of accumulated defined mutations. Determination of timing of the mutational damage in cytologic material could be incorporated in the work-up and help in making a more definitive diagnosis of malignancy in pancreatobiliary cytology specimens.

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Section: Discussionmentioning

confidence: 99%

Determination of sequential mutation accumulation in pancreas and bile duct brushing cytology

et al. 2006

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“…Although the importance of ACF as biomarkers of colon cancer risk is well established (5,10,36,46,47), few studies have attempted to additionally stratify these lesions at the molecular/genetic level. The incipient and dynamic nature of ACF is likely to complicate histologybased methods of prognostication.…”

Section: Discussionmentioning

confidence: 99%

Genetic signatures of High- and Low-Risk Aberrant Crypt Foci in a Mouse Model of Sporadic Colon Cancer

et al. 2004

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To determine whether cancer risk is related to histopathological features of preneoplastic aberrant crypt foci (ACF), gene expression analysis was performed on ACF from two mouse strains with differing tumor sensitivity to the colonotropic carcinogen, azoxymethane. ACF from sensitive A/J mice were considered at high risk, whereas ACF from resistant AKR/J mice were considered at low risk for tumorigenesis. A/J and AKR/J mice received weekly injections of azoxymethane (10 mg/kg body weight), and frozen colon sections were prepared 6 weeks later. Immunohistochemistry was performed using biomarkers associated with colon cancer, including adenomatous polyposis coli, ␤-catenin, p53, c-myc, cyclin D1, and proliferating cell nuclear antigen. Hyperplastic ACF, dysplastic ACF, microadenomas, adjacent normal-appearing epithelium, and vehicle-treated colons were laser captured, and RNA was linearly amplified (LCM-LA) and subjected to cDNA microarray-based expression analysis. Patterns of gene expression were identified using adaptive centroid algorithm. ACF from low-and high-risk colons were not discriminated by immunohistochemistry, with the exception of membrane staining of ␤-catenin. To develop genetic signatures that predict cancer risk, LCM-LA RNA from ACF was hybridized to cDNA arrays. Of 4896 interrogated genes, 220 clustered into six broad clusters. A total of 226 and 202 genes was consistently altered in lesions from A/J and AKR/J mice, respectively. Although many alterations were common to both strains, expression profiles stratified high-and low-risk lesions. These data demonstrate that ACF with distinct tumorigenic potential have distinguishing molecular features. In addition to providing insight into colon cancer promotion, our data identify potential biomarkers for determining colon cancer risk in humans.

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“…Crucial molecular events involve alteration and mutation of adenomatous polyposis coli (APC) and Kirsten-ras (K-ras) genes. In addition, mutations in the tumor-suppressor gene p53 appear to be a late phenomenon in CRC, which may allow the growing tumor with multiple genetic alterations to evade cell-cycle arrest and apoptosis (Gryfe et al, 1997;Arends, 2000). Nowadays, it is largely assumed that in addition to being directly responsible for the antitumor effect, agents damaging DNA may initiate postdamage responses by activating cell-cycle checkpoints (Johnstone et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line

et al. 2004

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Molecular interactions in the Vogelstein model of colorectal carcinoma

Cited by 157 publications

References 32 publications

Determination of sequential mutation accumulation in pancreas and bile duct brushing cytology

Determination of sequential mutation accumulation in pancreas and bile duct brushing cytology

Genetic signatures of High- and Low-Risk Aberrant Crypt Foci in a Mouse Model of Sporadic Colon Cancer

Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53-deficient HT29 human colon cancer cell line

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