Accumulated Clonal Genetic Alterations in Familial and Sporadic Colorectal Carcinomas with Widespread Instability in Microsatellite Sequences

Fujiwara, Takanori; Stolker, Joshua M.; Watanabe, Toshiaki; Rashid, Asif; Longo, Patti A.; Eshleman, James R.; Booker, Susan V.; Lynch, Henry T.; Jass, Jeremy R.; Green, Jane S.; Kim, Hoguen; Jen, Jin; Vogelstein, Bert; Hamilton, Stanley R.

doi:10.1016/s0002-9440(10)65651-9

Cited by 178 publications

(150 citation statements)

References 94 publications

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“…There is a reported association between Ki-ras mutations and highly methylated tumours (Toyota et al, 2000;Hawkins et al, 2002), however, codon 12 mutations are the predominating type in these studies of sporadic colorectal tumours. A high frequency of codon 13 mutations has only been reported once before, in a set of HNPCC tumours with MSI (Fujiwara et al, 1998). This is reflected in the germline-derived cell lines in this study; however, a significant proportion of codon 13 mutations also occurred in Ki-ras of nongermline cell lines.…”

Section: Mwcontrasting

confidence: 58%

CpG island methylation is a common finding in colorectal cancer cell lines

Suter

Norrie

et al. 2003

Br J Cancer

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Tumour cell lines are commonly used in colorectal cancer (CRC) research, including studies designed to assess methylation defects. Although many of the known genetic aberrations in CRC cell lines have been comprehensively described, no studies have been performed on their methylation status. In this study, 30 commonly used CRC cell lines as well as seven primary tumours from individuals with hereditary nonpolyposis colorectal cancer (HNPCC) were assessed for methylation at six CpG islands known to be hypermethylated in colorectal cancer: hMLH1, p16, methylated in tumour (MINT-)-1, -2, -12 and -31. The cell lines were also assessed for microsatellite instability (MSI), ploidy status, hMLH1 expression, and mutations in APC and Ki-ras. Methylation was frequently observed at all examined loci in most cell lines, and no differences were observed between germline-derived and sporadic cell lines. Methylation was found at MINT 1 in 63%, MINT 2 in 57%, MINT 12 in 71%, MINT 31 in 53%, p16 in 71%, and hMLH1 in 30% of cell lines. Overall only one cell line, SW1417, did not show methylation at any locus. Methylation was found with equal frequency in MSI and chromosomally unstable lines. MSI was over-represented in the cell lines relative to sporadic CRC, being detected in 47% of cell lines. The rate of codon 13 Ki-ras mutations was also over three times that expected from in vivo studies. We conclude that CpG island hypermethylation, whether acquired in vivo or in culture, is a ubiquitous phenomenon in CRC cell lines. We suggest that CRC cell lines may be only representative of a small subset of real tumours, and this should be taken into account in the use of CRC cell lines for epigenetic studies.

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Section: Mwcontrasting

confidence: 58%

CpG island methylation is a common finding in colorectal cancer cell lines

Suter

Norrie

et al. 2003

Br J Cancer

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“…This finding leads to the hypothesis that pERK is involved in the mechanism of tumor progression of MMR-proficient CRC and Lynch syndrome by interacting with the wnt signaling pathway and RHAMM: (1) KRAS mutation is found in approximately 35% of unselected CRCs, whereas it is mutated at a particularly low frequency in sporadic MSI-H cancers. [38][39][40][41][42] (2) The molecule ERK, a member of the MAPK pathway, is activated by a cascade of phophorylation events downstream from the ras proto-oncogene. 8 (3) Intracellular and cell surface RHAMM isoforms are important for the activation of ERK by PDGF (platelet-derived growth factor) and mutant (activated) RAS, respectively, while intracellular RHAMMv4 overexpression activates ERK.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer

et al. 2006

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RHAMM, a member of the microtubule-associated protein family that interacts with the mitogen-activated protein kinase pathway, is associated with tumor progression, aggressive disease and shortened survival in several tumor types. This study aimed to determine the prognostic value of RHAMM in colorectal cancer (CRC). A series of 1420 unselected, nonconsecutive CRC resections were subdivided into three groups: (1) DNA mismatch repair (MMR)-proficient, (2) MLH1 negative and (3) presumed Lynch syndrome. Immunohistochemical analysis of RHAMM expression (0 vs 40%), increasing expression (increasing percentage positivity) and complete expression (100 vs o100%) was performed using tissue microarray technique and the results were correlated with clinicopathological parameters. Fifty-seven tissue samples of normal colonic mucosa were included as a control group. In a univariate analysis increasing and complete expression of RHAMM were associated with higher N stage (P ¼ 0.023 and 0.021) and worse survival (Po0.0001) in MMR-proficient CRC. Complete expression of RHAMM was associated with worse survival in presumed Lynch syndrome (P ¼ 0.016). In MLH1-negative CRC there was no association between RHAMM expression and the clinicopathological features. In a multivariate analysis, increasing RHAMM expression was an independent adverse prognostic factor in MMR-proficient CRC (Po0.0001) and complete expression in MMR-proficient CRC and presumed Lynch syndrome (Po0.0001 and P ¼ 0.031, respectively). Nuclear pERK expression was associated with increasing RHAMM expression in MMR-proficient CRC (P ¼ 0.012) and with complete RHAMM expression in presumed HNPCC (P ¼ 0.03). Increasing and complete RHAMM expressions are independent adverse prognostic factors in MMR-proficient CRC and presumed Lynch syndrome.

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“…Eighteen cases of colon cancer previously characterized by RMo-PAGE 23 (SR Hamilton, submitted) for the presence (14 cases) or absence (4 cases) of MSI were analyzed using the technique reported herein. Of the 14 cases diagnosed as MSI by RMo-PAGE, all 14 were diagnosed as MSI-H by FM-CE.…”

Section: A Cross-validation Study Establishes the Validity Of The Flumentioning

confidence: 99%

Detection of Microsatellite Instability by Fluorescence Multiplex Polymerase Chain Reaction

Berg

Glaser

Thompson

et al. 2000

The Journal of Molecular Diagnostics

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We have created a clinical molecular diagnostic assay to test for microsatellite instability (MSI) at multiple loci simultaneously in paraffin-embedded surgical pathology colon resection specimens. This fluorescent multiplex polymerase chain reaction (PCR) assay analyzes the five primary microsatellite loci recommended at the 1997 National Cancer Institute-sponsored conference on MSI for the identification of MSI or replication errors in colorectal cancer: Bat-25, Bat-26, D2S123, D5S346, and D17S250. Amplicon detection is accomplished by capillary electrophoresis using the ABI 310 Genetic Analyzer. Assay validation compared 18 specimens previously assessed by radioactive PCR and polyacrylamide gel electrophoresis detection to results generated by the reported assay. Germline and tumor DNA samples were amplified in separate multiplex PCR reactions, sized in separate capillary electrophoresis runs, and compared directly to identify novel length alleles in tumor tissue. A concordance of 100% between the two modalities was achieved. The multiplex assay routinely detected a subpopulation of 10% tumor alleles in the presence of 90% normal alleles. A novel statistical model was generated that corroborates the validity of using results generated by analysis of five independent microsatellites to achieve a single overall MSI diagnosis. The assay presented is superior to standard radioactive monoplex PCR, polyacrylamide gel electrophoretic analysis, primarily due to the multiplex PCR format. (J Mol Diag 2000, 2:20 -28)Microsatellite instability (MSI), or replication error, is a manifestation of genomic instability arising in a variety of human neoplasms where tumor cells have a decreased overall ability to faithfully replicate DNA. This phenomenon has been shown to be a frequent, if not obligatory, surrogate marker of underlying functional inactivation of one of the human DNA mismatch repair (MMR) genes. [1][2][3][4][5][6]

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Accumulated Clonal Genetic Alterations in Familial and Sporadic Colorectal Carcinomas with Widespread Instability in Microsatellite Sequences

Cited by 178 publications

References 94 publications

CpG island methylation is a common finding in colorectal cancer cell lines

CpG island methylation is a common finding in colorectal cancer cell lines

Overexpression of the receptor for hyaluronic acid mediated motility is an independent adverse prognostic factor in colorectal cancer

Detection of Microsatellite Instability by Fluorescence Multiplex Polymerase Chain Reaction

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