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Revista Española de Enfermedades Digestivas

versión impresa ISSN 1130-0108

Rev. esp. enferm. dig. vol.104 no.3  mar. 2012

http://dx.doi.org/10.4321/S1130-01082012000300001 

EDITORIAL

 

Methylation in colorectal cancer

Metilación en el cáncer colorrectal

 

 

José Perea1 and Daniel Rueda2

1Department of General Surgery B. 2Laboratory of Molecular Biology.
Hospital Universitario 12 de Octubre. Madrid, Spain

 

 

The emerging relevance of colorectal cancer (CRC) in the last few years is well known. In Spain, this is the most prevalent malignancy and the second cause of cancer-related mortality. Focusing on both genders, over 25,000 new cases are diagnosed in Spain, and around 13,000 individuals die from this condition every year (1). Thus, more than ever, this unquestionable significance makes our deeper understanding mandatory, which has evolved on an ongoing basis ever since Fearon and Vogelstein defined their colorectal carcinogenesis model back in 1990 (2). Today, the hypothesis that most CRCs emerge from adenomas via the suppressor -also referred to as chromosome instability (CI)- route, which is initiated by a mutation in gene APC -this is the classical description of colorectal carcinogenesis corresponding to the adenoma-carcinoma sequence (2)-, is only met by 60% of cases (3), and two additional alternative, non -excluding routes, are now considered- the microsatellite instability (MSI) pathway, associated with Lynch syndrome and a small proportion of sporadic cases, and the methylator phenotype pathway, most recently identified and referred to as CIMP (CpG Island Methylator Phenotype) in the English-language literature. Advances occurred in the understanding of the molecular basis of CRC are doubtless the strongest drive towards a more rational, specific management for this condition via the identification of new, more specific therapy targets, as well as markers to describe the various behaviors of the disease.

Epigenetics is a term used to describe the mechanisms than may modify at various levels the expression of specific genes without altering the corresponding DNA sequence, including DNA methylation, chromatin remodeling, and other processes mediated by non-coding RNA molecules (4). From a general perspective, a tumor would originate from multiple, cumulative changes in the genome of its cells, both epigenetic and DNA sequence changes. These sequence changes include deletions in chromosome regions with gene loss that may be associated with negative cell-cycle regulation (tumor suppressor genes), mutations that may activate or inactivate a number of proteins, gene amplifications entailing an overexpression of specific genes, and even loss or gain of entire chromosomes.

As mentioned above, colorectal carcinogenesis pathways are sometimes mutually excluding, as is the case with MSI and CI, whereas on other occasions there may be some overlap, as occurs with CIMP. CRC is being increasingly classified into various phenotypes according to its molecular profiles (5). Thus, its classification from a molecular viewpoint is based on the predominant cell event (CI, MSI, CIMP) or, equivalently, according to the event-initiating factor (suppressor pathway for CI; mutation pathway for MSI; methylator pathway for CIMP).

CIMP relates to changes at the epigenetic level, more specifically at the DNA methylation level. CpG islands are DNA regions that conform around 40% of gene promoters in mammals. In these regions there is a high concentration of cytosine-guanine pairs linked with phosphate bonds. These CpG sites are unmethylated when genes are expressed; hence their methylation in gene promoters may inhibit genic expression by inactivating the genes involved. Transcriptional inactivation by methylating CpG islands in tumor suppressor gene promoters is a relevant carcinogenesis mechanism, what is usually referred to as methylator phenotype. The mechanism through which methylation occurs in the promoter regions of various genes has been shown to play a role in a proportion of CRCs nearing 35% (6). This is also designated the "serrated pathway to colorectal carcinogenesis", as it seemingly emerges from a serrated precursor lesion (whose histology may include hyperplastic polyps, sessile serrated polyps, and serrated adenomas). In contrast to microsatellite status screening, where Bethesda's panel is used by consensus (7), there is still no agreement on an optimal panel for CpG islands or sites regarding CIMP characterization.

A number of differentiating features may be identified in these tumors. Thus, they seem to prefer the proximal colon, female gender, and older age; poorly differentiated tumors are more common and, from a molecular viewpoint, there is a wider presence of BRAF mutations, whereas the mutation rate for TP53 is lower (8-10).

The mechanisms for CRCs emerging via this pathway seem to stem from a BRAF activating mutation, which inhibits physiological apoptosis at the level of epithelial cells in the colon. From this event serrated lesions may give rise to hyperplastic polyps or sessile serrated polyps. These lesions are susceptible to CpG island methylation in the promoter regions of multiple genes, hence they may induce epigenetic silencing -an initially random indirect inactivation of genes. Methylation of the MLH1 promoter, which is very common in these cases, would originate sporadic CRCs with MSI. In this respect the fact that most sporadic cases with MSI are CIMP positive should be highlighted, whereas the presence of this phenotype in Lynch syndrome patients is uncommon (11,12).

From a clinical standpoint the diagnostic, prognostic, and therapeutic implications of the CIMP pathway are under analysis today. Certain papers focus on the utility of methylated gene identification in plasma or fecal samples for the early diagnosis of CRC (13-18), even in an attempt to predict, from the mucosal wash fluid during colonoscopy, CRC cases with a higher degree of invasiveness at the colonic wall (19). From a prognostic point of view a number of approaches have been essayed. On the one hand, trying to relate the methylation status of certain genes to outcome (for example, IGF2, which seems to suggest a poor prognosis) (20). Another instance is the paper reported in this issue of Revista Española de Enfermedades Digestivas, by Vengazones et al. (21), where the clinical and prognostic implications of p16 methylation in CRCs are discussed. Overall studies have also been undertaken to assess the prognosis of tumors with CIMP, which remains blurry given the bias of a common association with mutations in BRAF, suggestive of a poor prognosis on their own (22). As can be surmised, also the various epigenetic forms of CRC have been studied regarding the sensitivity-resistance to chemotherapy, but little is known because most studies were performed in vitro, among other reasons (23).

As pointed out above, the need to understand the molecular basis of CRC is of paramount importance to correctly design both diagnostic and therapeutic strategies. In this regard, CIMP screening is most relevant, even more so given it is the most recently identified carcinogenesis pathway, as is the screening for specific CpG island methylations in the genes associated with colorectal carcinogenesis, hence the interest arisen by the paper by Vengazones et al. (21), which is an additional contribution in this regard.

 

References

1. Quintero E, Andréu M, Lanas A, et al. Estrategias para la detección precoz del cáncer colorrectal. En: Bandrés F, Castells A, Morillas JD, editor. La prevención del cáncer colorectal en España. Fundación Tejerina, 2009.         [ Links ]

2. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-67.         [ Links ]

3. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007;50:223-30.         [ Links ]

4. Bonasio R, Tu S, Reinberg D. Molecular signals of epigenetic states. Science 2010;330:612-6.         [ Links ]

5. Perea J, Lomas M, Hidalgo M. Bases moleculares del cáncer colorrectal: ¿Hacia un manejo individualizado? Rev Esp Enferm Dig 2011;103:29-35.         [ Links ]

6. Snover DC. Update on serrated pathway to colorectal carcinoma. Hum Pathol 2011;42:1-10.         [ Links ]

7. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998 58:5248-57.         [ Links ]

8. van Rinjsoever M, Grieu F, Eisaleh H, Joseph D, Iacopetta B. Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands. Gut 2002;51:797-802.         [ Links ]

9. Samowitz W, Albertsen H, Herrick J, Levin TR, Sweeny C, Murtaugh MA, et al. Evaluation of a large, population-based sample supports a CpG island methylator phenotype (CIMP) in colon cancer. Gastroenterology 2005;129:837-45.         [ Links ]

10. Ogino S, Cantor M, Kawasaki T, Brahmandam M, Kirkner GJ, Weisenberger DJ, et al. CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies. Gut 2006;55:1000-6.         [ Links ]

11. Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nature Genetics 2006;38:787-93.         [ Links ]

12. McGivern A, Wynter CVA, Whitehall VLJ, Kambara T, Spring KJ, Walsh MD, et al. Promote hyper methy,lation frecuency and BRAF mutations distinguis hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer. Familial Cancer 2004;3:101-7.         [ Links ]

13. Lofton-Day C, Model F, Devos T, Tetzner R, Distler J, Schuster M, et al. DNA methylation biomarkers for blood-based colorectal cancer screening. Clin Chem 2008;54:414-23.         [ Links ]

14. deVos T, Tetzner R, Model F, Weiss G, Schuster M, Distler J, et al. Circulating methylated SEPT9 DNA in plasma is a biomarker for colorectal cancer. Clin Chem 2009;55:1337-46.         [ Links ]

15. Grützmann R, Molnar B, Pilarsky C, Habermann JK, Schlag PM, Saeger HD, et al. Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay. PLoS One 2008;3:e3759.         [ Links ]

16. Tänzer M, Balluff B, Distler J, Hale K, Leodolter A, Röcken C, et al. Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection ofcolorectal precancerous lesions. PLoS One 2010;5:e9061.         [ Links ]

17. Kostin PA, Zakharzhevskaia NB, Generozov EV, Govorun VM, Chernyshov SV, Shchelygin IuA. Hypermethylation of the CDH1, SEPT9, HLTF and ALX4 genes and their diagnostic significance in colorectal cancer. Vopr Onkol 2010;56:162-8.         [ Links ]

18. Itzkowitz S, Brand R, Jandorf L, Durkee K, Millholland J, Rabeneck L, et al. A simplified, noninvasive stool DNA test for colorectal cancer detection. Am J Gastroenterol 2008;103:2862-70.         [ Links ]

19. Kamimae S, Yamamoto E, Yamano HO, Nojima M, Suzuki H, Ashida M, et al. Epigenetic alteration of DNA in mucosal wash fluid predicts invasiveness of colorectal tumors. Cancer Prev Res (Phila) 2011;4:674-83.         [ Links ]

20. Baba Y, Nosho K, Shima K, Huttenhower C, Tanaka N, Hazra A, et al. Hypomethylation of the IGF2 DMR in colorectal tumors, detected by bisulfite pyrosequencing, is associated with poor prognosis. Gastroenterology 2010;139:1855-64.         [ Links ]

21. Veganzones S, Rafael S, Vidaurreta M, de la Orden V, Mediero B, Fernández C, et al. p16 gene methylation in colorectal cancer patients with long-term follow-up. Rev Esp Enferm Dig 2012;104(3):111-7.         [ Links ]

22. Curtin K, Slattery ML, Samowitz. CpG Island methylation in colorectal cancer: Past, present and future. Patholog Res Int 2011 Apr 12;2011:902674.         [ Links ]

23. Coppedè F. Epigenetic biomarkers of colorectal cancer: focus on DNA methylation. Cancer Letters (2011), doi:10.1016/j.canlet.2011.12.030.         [ Links ]

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