Serrated Polyps and Colorectal Cancer: New Pathway to Malignancy

Department of Pathology, The University of Chicago, Chicago, IL 60637, USA.
Annual Review of Pathology Mechanisms of Disease (Impact Factor: 18.75). 02/2009; 4(1):343-64. DOI: 10.1146/annurev.pathol.4.110807.092317
Source: PubMed


Until recently, two major forms of colorectal epithelial polyp were recognized: the adenoma and the hyperplastic polyp. Adenomas were perceived to represent the precursor to colorectal cancer, whereas hyperplastic polyps were viewed as innocuous lesions with no potential for progression to malignancy. We now recognize, however, that the lesions formerly classified as hyperplastic actually represent a heterogeneous group of polyps, some of which have a significant risk for neoplastic transformation. These serrated polyps include not only hyperplastic polyps but also traditional serrated adenomas and sessile serrated adenomas. These polyps demonstrate characteristic molecular alterations not commonly seen in colorectal adenomas, and they probably progress to colorectal cancer by means of a new pathway: the serrated neoplasia pathway. The morphologic features of serrated colorectal lesions, the molecular alterations that characterize them, and their role in colorectal cancer development are discussed herein.

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    • "A subset of colon cancers exhibits widespread promoter methylation, referred to as the CpG island methylator phenotype (CIMP) [43–46]. CRC tumors characterized by CIMP are thought to arise via the serrated neoplasia pathway [47]. An early event in CIMP tumors appears to be a mutation in the BRAF protooncogene, which inhibits normal apoptosis of colonic epithelial cells [48]. "
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    ABSTRACT: Purpose: To investigate the association between CpG island methylator phenotype (CIMP) and the overall survival of sporadic colorectal cancer (CRC) in Northeast China. Methods: 282 sporadic CRC patients were recruited in this study. We selected MLH1, MGMT, p16, APC, MINT1, MINT31, and RUNX3 as the CIMP panel markers. The promoter methylation was assessed by methylation sensitive high resolution melting (MS-HRM). Proportional hazards-regression models were fitted with computing hazard ratios (HR) and the corresponding 95% confidence intervals (95% CI). Results: 12.77% (36/282) of patients were CIMP-0, 74.1% (209/282) of patients were CIMP-L, and 13.12% (37/282) of patients were CIMP-H. The five-year survival of the 282 CRC patients was 58%. There was significant association between APC gene promoter methylation and CRC overall survival (HR = 1.61; 95% CI: 1.05-2.46; P = 0.03). CIMP-H was significantly associated with worse prognosis compared to CIMP-0 (HR = 3.06; 95% CI: 1.19-7.89; P = 0.02) and CIMP-L (HR = 1.97; 95% CI: 1.11-3.48; P = 0.02), respectively. While comparing with the combine of CIMP-L and CIMP-0 (CIMP-L/0), CIMP-H also presented a worse prognosis (HR = 2.31; 95% CI: 1.02-5.24; P = 0.04). Conclusion: CIMP-H may be a predictor of a poor prognosis of CRC in Northeast China patients.
    Full-text · Article · Aug 2014 · BioMed Research International
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    • "The well-known Vogelstein model has long hypothesized that germline or somatic mutations are required for malignant transformation, and the accumulation of multiple mutations determines the biological behavior of the tumor.2 Furthermore, three molecular pathways have been implicated in colorectal tumorigenesis, and these include the chromosomal instability pathway,3 the mutator-phenotype/DNA mismatch repair pathway,4 and the hypermethylation phenotype, or hyperplastic/serrated polyp pathway.5 While a detailed description of these pathways is outside the scope of this article, it is important to recognize that distinctive molecular characteristics of these pathways have implications for targeted therapies and their potential efficacy. "
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    ABSTRACT: Metastatic colorectal cancer is a significant cause of morbidity and mortality in the US and around the world. While several novel cytotoxic and biologic therapies have been developed and proven efficacious in the past two decades, their optimal use in terms of patient selection, drug combinations, and regimen sequences has yet to be defined. Recent investigations regarding anti-epidermal growth factor receptor therapies include the comparison of single-agent panitumumab and cetuximab, the benefit of adding cetuximab to chemotherapy in the conversion therapy setting, the comparison of cetuximab and bevacizumab when added to first-line chemotherapy, and predictive biomarkers beyond KRAS exon 2 (codons 12 and 13) mutations. With respect to anti-vascular endothelial growth factor therapies, new data on continuing bevacizumab beyond disease progression on a bevacizumab-containing chemotherapy regimen, the addition of bevacizumab to triplet chemotherapy in the first-line setting, maintenance therapy with bevacizumab plus either capecitabine or erlotinib, the addition of aflibercept to chemotherapy, and regorafenib as monotherapy have emerged. Recent scientific and technologic advances in the field of metastatic colorectal cancer promise to elucidate the biological underpinnings of this disease and its therapies for the goal of improving personalized treatments for patients with metastatic colorectal cancer.
    Full-text · Article · Jul 2014 · Pharmacogenomics and Personalized Medicine
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    • "Moreover, promoter methylation was also referred to as the CpG island methylator phenotype (CIMP) [14,15]. CIMP-positive CRC was distinguished from CIMP-negative CRC patients by clinicopathological factors [16], and CIMP was associated with development of the serrated pathway of CRC [17]. Clinically, several CIMPs containing MLH1 (a mismatch repair gene), and microsatellite instability were characterized to be associated with CRC prognosis [18,19]. "
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    ABSTRACT: Colorectal cancer (CRC) arises as a consequence of genetic events such as gene mutation and epigenetic alteration. The aim of this study was to identify new hypermethylated candidate genes and methylation-based therapeutic targets using vincristine in CRC. We analyzed the methylation status of 27,578 CpG sites spanning more than 14,000 genes in CRC tissues compared with adjacent normal tissues and normal colon tissues using Illumina bead chip array. Twenty-one hypermethylated genes and 18 CpG island methylator phenotype markers were selected as candidate genes. The methylation status of 39 genes was validated by quantitative methylation-specific polymerase chain reaction in CRC tissues, adjacent normal tissues, normal colon cells, and three CRC cell lines. Of these, 29 hypermethylated candidate genes were investigated using the demethylating effects of 5-aza-2[prime]-deoxycytidine (5-aza-dC) and vincristine in CRC cells. Thirty-two out of 39 genes were hypermethylated in CRC tissues compared with adjacent normal tissues. Vincristine induced demethylation of methylated genes in CRC cells to the same extent as 5-aza-dC. The mRNA expression of AKR1B1, CHST10, ELOVL4, FLI1, SOX5, STK33, and ZNF304 was restored by treatment with 5-aza-dC and vincristine. These results suggest that these novel hypermethylated genes AKR1B1, CHST10, ELOVL4, SOX5, STK33, and ZNF304 may be potential methylation biomarkers and therapeutic targets of vincristine in CRC.
    Full-text · Article · Jan 2014 · Journal of Experimental & Clinical Cancer Research
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