The CpG island methylator phenotype in colorectal cancer: Progress and problems

Hughes, Lesley; Bakker, Carolina A.J. Khalid-de; Smits, Kim M.; Brandt, Piet A. van den; Jonkers, Daisy; Ahuja, Nita; Herman, James G.; Weijenberg, Matty P.; Engeland, Manon van

doi:10.1016/j.bbcan.2011.10.005

Cited by 95 publications

(96 citation statements)

References 105 publications

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“…Conversely, the lower incidence of CIMP can be attributed to many factors that could possibly be genetic and/or environmental. 26 A published association of CIMP-high tumors included right-sided tumors, older age, physical inactivity, and smoking. 27,28 The current study population was at least a decade younger compared with Western populations studied, 83.3% of the tumors were left sided, and the patients belonged to a distinct ethnic group.…”

Section: Survival Analysismentioning

confidence: 99%

Molecular markers and pathway analysis of colorectal carcinoma in the Middle East

Beg

Siraj

Prabhakaran

et al. 2015

Cancer

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BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers in the world. A newly proposed integrated pathway comprising traditional, alternate, and serrated pathways by genetic and epigenetic factors was defined recently and hypothesized to play a role in the pathogenesis of CRC; however, to the authors' knowledge, there is a paucity of information regarding these proposed molecular pathways in different ethnic groups. METHODS: Molecular characterization of 770 CRC specimens was performed for microsatellite instability, BRAF, and KRAS by polymerase chain reaction and 500 cases for CpG island methylator phenotype (CIMP) high phenotype by MethyLight technology. Tumors were assigned to different molecular pathways and examined for clinicopathological correlation and survival analysis. RESULTS: The traditional pathway constituted 33.4% of CRC cases, the alternate pathway comprised 11.6%, and the serrated molecular pathway accounted for only 0.8% of Middle Eastern CRC cases. Approximately 54.2% of CRC cases did not qualify to fit into any pathway and thus were designated as an unassigned group. Molecular pathways were found to be significantly associated with tumor site and grade. A subset of cases with an uncategorized pathway demonstrated a significant survival difference (P 5 .0079). CONCLUSIONS: The serrated pathway was found to account for a very low percentage of the CRC patient cohort in the current study. The unassigned group accounted for the majority of Middle Eastern CRC cases, and therefore methods of CRC pathway analysis might not be applicable to this ethnic group. The current study demonstrates the need to unravel the molecular genetic basis of this disease to further subcategorize these CRC cases. It also identifies a need for further studies on different populations for a better understanding of their exact role and incidence. Cancer 2015;121:3799-808.

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Section: Survival Analysismentioning

confidence: 99%

Molecular markers and pathway analysis of colorectal carcinoma in the Middle East

Beg

Siraj

Prabhakaran

et al. 2015

Cancer

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“…A panel of genes, including the mismatch repair gene MLH1, have been identified as commonly being hypermethylated in CRC giving rise to a third molecular subtype of CRC known as the CpG island methylator phenotype (8) .…”

Section: Colorectal Cancer and Its Molecular Classificationmentioning

confidence: 99%

Folate, colorectal cancer and the involvement of DNA methylation

Williams

2012

Proc. Nutr. Soc.

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Diet is a major factor in the aetiology of colorectal cancer (CRC). Epidemiological evidence suggests that folate confers a modest protection against CRC risk. However, the relationship is complex, and evidence from human intervention trials and animal studies suggests that a highdose of folic acid supplementation may enhance the risk of colorectal carcinogenesis in certain circumstances. The molecular mechanisms underlying the apparent dual modulatory effect of folate on colorectal carcinogenesis are not fully understood. Folate is central to C 1 metabolism and is needed for both DNA synthesis and DNA methylation, providing plausible biological mechanisms through which folate could modulate cancer risk. Aberrant DNA methylation is an early event in colorectal carcinogenesis and is typically associated with the transcriptional silencing of tumour suppressor genes. Folate is required for the production of S-adenosyl methionine, which serves as a methyl donor for DNA methylation events; thereby folate availability is proposed to modulate DNA methylation status. The evidence for an effect of folate on DNA methylation in the human colon is limited, but a modulation of DNA methylation in response to folate has been demonstrated. More research is required to clarify the optimum intake of folate for CRC prevention and to elucidate the effect of folate availability on DNA methylation and the associated impact on CRC biology.Colorectal cancer: Folate: Folic acid: DNA methylation Colorectal cancer (CRC) occurs as a consequence of a complex series of genetic and epigenetic events leading to uncontrolled cell proliferation of malignant cells. Although the genetic events leading to neoplasia are well defined, an appreciation of the importance of epigenetic factors is relatively recent. Aberrant DNA methylation has been recognised as an early event in CRC and has been the focus of considerable research. As with other epigenetic events, DNA methylation is potentially reversible making aberrant DNA methylation in cancer a particularly attractive target for chemotherapeutics and chemoprevention. Diet is known to have a significant impact on risk of CRC and there is some suggestion of an inverse association between folate and CRC risk. Folate is a methyl donor for DNA methylation and consequently DNA methylation has received attention in attempts to elucidate the mechanism whereby folate may modify CRC risk. This review focuses on our current knowledge and understanding of the interaction between folate, CRC and the possible involvement of DNA methylation. Colorectal cancer and its molecular classificationCRC is the third most common cancer in the world, accounting for 10% of all cancers and for approximately 20% of all deaths in the developed world (1) . It is an agerelated disease with peak incidence in the seventh decade of life. The majority of CRC cases are sporadic; however, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer are two forms of early onset hereditary CRC that account for approxi...

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“…A CIMP-útvonal a CRC-k hozzávetőleg 30%-ában megjelenik, s a proximalis colontumorok kb. 30-40%-a, a distalis colon-és rectumtumorok 5-15%-a CIMP-pozitív [10]. A CIMP-pozitív tumorok közel 90%-ára jellemző a BRAF-vagy a KRAS-mutáció is [11].…”

Section: Cimp (Metilációs Fenotípus)unclassified

Heterogén vastagbéldaganat: a fogazott útvonalon kialakuló, sporadikus laesiók jelentősége a klinikai gyakorlatban

et al. 2018

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A colorectalis daganatra ma már igen heterogén betegségként tekintünk, mely heterogenitást a kialakulásában szerepet játszó genetikai faktorok, molekuláris eltérések, különböző jelátviteli útvonalak, valamint mikro-és makrokörnye-zeti tényezők okoznak. A korábban ismert ,,klasszikus" adenoma-carcinoma szekvencia mellett az elmúlt évtizedben egy másik, alternatív útvonal is felismerésre került. Ezt ,,fogazott" útvonalnak nevezzük, mely az elváltozások kb. egyharmadáért felelős. Ezek a laesiók a molekuláris tulajdonságaikon felül makroszkópos és mikroszkópos képükben és progressziós hajlamukban, illetve prognózisukban is eltérnek a klasszikus útvonal daganataitól. Az alábbi összefog-laló közlemény ezen eltérések molekuláris tulajdonságait, makroszkópos és szövettani jellegzetességeit, illetve klinikai jelentőségét szemlélteti. Orv Hetil. 2018; 159(6): 206-214. Kulcsszavak: vastagbéldaganat, fogazott útvonal, polip, prognózis Colorectal cancer heterogeneity: the clinical impact of sporadic lesions arising via the serrated pathwayToday, colorectal cancer is regarded as a heterogeneous disease. Its heterogeneity is caused by genetic alterations, molecular aberrations, different developing pathways as well as by micro-and macroenviromental agents. In the last decade, beside the classic genetic model for colorectal tumuorgenesis that follows the adenoma-carcinoma sequence, an alternative pathway has been identified. This pathway is called the serrated pathway and it is responsible for approximately one third of all colorectal lesions. Beyond their dissimilar molecular characteristics, these tumours also show different macroscopic and histologic appearance. Moreover, their malignant potency and progressive ability distinguish them from tumours of the classic genetic model. The aim of this review is to summarize the molecular and pathologic features of serrated lesions and the serrated pathway to colorectal cancer and to highlight their clinical impact. Keywords

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The CpG island methylator phenotype in colorectal cancer: Progress and problems

Cited by 95 publications

References 105 publications

Molecular markers and pathway analysis of colorectal carcinoma in the Middle East

Molecular markers and pathway analysis of colorectal carcinoma in the Middle East

Folate, colorectal cancer and the involvement of DNA methylation

Heterogén vastagbéldaganat: a fogazott útvonalon kialakuló, sporadikus laesiók jelentősége a klinikai gyakorlatban

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