Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell 4, 121-31

The Burnham Institute, La Jolla Cancer Center, Cancer Genetics and Epigenetics Program, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cancer Cell (Impact Factor: 23.89). 09/2003; 4(2):121-31. DOI: 10.1016/S1535-6108(03)00190-9
Source: PubMed

ABSTRACT A CpG island DNA methylator phenotype has been postulated to explain silencing of the hMLH1 DNA mismatch repair gene in cancer of the microsatellite mutator phenotype. To evaluate this model, we analyzed methylation in CpG islands from six mutator and suppressor genes, and thirty random genomic sites, in a panel of colorectal cancers. Tumor-specific somatic hypermethylation was a widespread age-dependent process that followed a normal Gaussian distribution. Because there was no discontinuity in methylation rate, our results challenge the methylator phenotype hypothesis and its hypothetical pathological underlying defect. We also show that the mutator phenotype dominates over the gradual accumulation of DNA hypermethylation in determining the genotypic features that govern the phenotypic peculiarities of colon cancer of the mutator pathway.

Download full-text


Available from: Kentaro Yamashita, Aug 24, 2015
  • Source
    • "The notion of CpG island methylator phenotype (CIMP) arose from the initial observation that a subset of colorectal cancers has higher frequency of DNA hypermethylation at candidate tumor-suppressor promoters ( Toyota et al. 1999). Thus far, the hypermethylated sites used to characterize CIMP have not been standardized, leading to inconsistencies in whether a colon cancer is appropriately described as CIMP ( Yamashita et al. 2003; Issa 2004; Anacleto et al. 2005). Consequently, clinical studies attempting to correlate CIMP with prognosis and responsiveness to 5-fluorouracil chemotherapy have produced contradicting results ( Van Rijnsoever et al. 2003; Shen et al. 2007; Barault et al. 2008; Lee et al. 2008; Kim et al. 2009; Ogino et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: A subset of colorectal cancers was postulated to have the CpG island methylator phenotype (CIMP), a higher propensity for CpG island DNA methylation. The validity of CIMP, its molecular basis, and its prognostic value remain highly controversial. Using MBD-isolated genome sequencing, we mapped and compared genome-wide DNA methylation profiles of normal, non-CIMP, and CIMP colon specimens. Multidimensional scaling analysis revealed that each specimen could be clearly classified as normal, non-CIMP, and CIMP, thus signifying that these three groups have distinctly different global methylation patterns. We discovered 3780 sites in various genomic contexts that were hypermethylated in both non-CIMP and CIMP colon cancers when compared with normal colon. An additional 2026 sites were found to be hypermethylated in CIMP tumors only; and importantly, 80% of these sites were located in CpG islands. These data demonstrate on a genome-wide level that the additional hypermethylation seen in CIMP tumors occurs almost exclusively at CpG islands and support definitively that these tumors were appropriately named. When these sites were examined more closely, we found that 25% were adjacent to sites that were also hypermethylated in non-CIMP tumors. Thus, CIMP is also characterized by more extensive methylation of sites that are already prone to be hypermethylated in colon cancer. These observations indicate that CIMP tumors have specific defects in controlling both DNA methylation seeding and spreading and serve as an important first step in delineating molecular mechanisms that control these processes.
    Genome Research 02/2012; 22(2):283-91. DOI:10.1101/gr.122788.111 · 13.85 Impact Factor
  • Source
    • "Other studies showed that MSI CRCs can display the epigenetic signature of a widespread hypermethylation of the CpG islands in gene promoters (Ahuja et al., 1997). It was later shown that some overlap exists between the sporadic CRC with the microsatellite mutator phenotype and a hypermethylator phenotype (Toyota et al., 1999; Samowitz et al., 2005), which would be inversely correlated with chromosomal instability and would precede MSI (Goel et al., 2007), although other data challenge the concept of a methylator phenotype as the molecular ground for MSI development in sporadic CRCs (Yamashita et al., 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Microsatellite instability (MSI) originates from the systematic accumulation of uncorrected deletion/insertion in repetitive DNA tracts in cancer cells with a deficient mismatch repair system. Among colorectal cancers, the MSI signature identifies hereditary cases arising in patients with germline mutations in hMLH1, hMSH2, PMS2 and a fraction of those with hMSH6 mutations, as well as sporadic cancers with epigenetic hMLH1 promoter hypermethylation. Considering the specific pathogenesis, pathological features, natural history and response to 5-fluoro-uracil-based chemotherapy of the MSI cancers, confusion about the genetic markers for MSI recognition seems surprising. In this clinically relevant field, an agreement has not been reached concerning the use of di- or mononucleotide markers for MSI assessment. The Revised Bethesda Guidelines still recommend a panel of markers consisting of mono- and dinucleotides, despite being questioned whether it is congruous to continue to use dinucleotide markers for MSI identification. In any event, no single marker is accurate enough for MSI testing, and an awareness of their pros and cons is required for proper interpretation of results. In recent years, several papers have reported different prevalence of MSI in unrelated series, largely depending on the detection and classification method, suggesting that MSI test interpretation also requires the understanding of the phenomenon rather than simply the crude satisfaction of panel recommendations. Inaccuracies can otherwise lead to under- or overdiagnosis and inaccurate disease classification, which always have a negative impact on the clinical practice of medicine.
    Oncogene 09/2008; 27(49):6313-21. DOI:10.1038/onc.2008.217 · 8.56 Impact Factor
  • Source
    • "In 1999, Toyota et al. proposed that a subset of sporadic CRCs display a promoter CpG island methylator phenotype (CIMP), which manifests itself as an exceptionally high frequency of methylation of discrete CpG islands (Toyota et al. 1999b). Although the existence of CIMP has not been detected in CRCs associated with the CpG island methylation of a number of genes across the genome by some investigators (Yamashita et al. 2003; Anacleto et al. 2005), subsequent population-based studies have confirmed the presence of a subset (Samowitz et al. 2005; Ogino et al. 2006a). In 2006, Weisenberger et al., studying a large carefully selected marker panel in a cohort of sporadic CRCs, definitively confirmed the existence of CIMP. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A body of evidence accumulated over the past decade suggests that epigenetic mechanisms play an essential role in maintaining important cellular functions. Changes in epigenetic patterns (mainly DNA hyper- and hypomethylation and, more recently, histone modifications) may contribute to the development of cancer. Aberrant epigenetic events expand thorough tumor progression from the earliest to latest stages, therefore they can serve as convenient markers for detection and prognosis of cancer. The potential reversibility of epigenetic states in the tumor cell is an attractive target for cancer therapy. Much of our current knowledge on epigenetic alternations in cancer comes from studies on gastrointestinal malignancies, mainly on colorectal cancer, which currently serves as a model for epigenetic tumorigenesis. This review summarizes the current knowledge of epigenetic changes in gastrointestinal cancers and how this relates directly to disease progression and prognosis.
    Journal of applied genetics 02/2008; 49(1):1-10. DOI:10.1007/BF03195243 · 1.90 Impact Factor
Show more