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• W1969178571 abstract "EpigenomicsVol. 5, No. 2 EditorialFree AccessClinical applications of DNA methylation biomarkers in colorectal cancerChristopher PE Lange & Peter W LairdChristopher PE LangeLeiden University Medical Center, Department of Surgery, Albinusdreef 2, 2333 ZA Leiden, The NetherlandsSearch for more papers by this author & Peter W Laird* Author for correspondenceDepartment of Surgery, Biochemistry & Molecular Biology, Keck School of Medicine of University of Southern California, Norris Comprehensive Cancer Center, 1450 Biggy Street, Room G511B, Los Angeles, CA 90089-9601, USA. Search for more papers by this authorEmail the corresponding author at plaird@usc.eduPublished Online:8 Apr 2013https://doi.org/10.2217/epi.13.4AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: biomarkerscolorectal cancerDNA methylationepigeneticsepigenomicsColorectal cancer (CRC) is a common disease that results in significant morbidity and mortality worldwide. CRC is the second leading cause of cancer mortality worldwide, and accounts for over 600,000 deaths annually [1]. Biomarkers are molecules or substances found in blood, other bodily fluids or tissues that reflect a particular biological or pathological state. Blood- or stool-based biomarkers have the potential to revolutionize CRC diagnostics by providing noninvasive, patient-friendly and cost-effective early detection of CRC. Cancer biomarkers may have broader applications, including disease risk analysis in otherwise healthy people, molecular classification, therapy response prediction, disease prognostics and recurrence monitoring in patients who have been treated for cancer. In recent years, abnormal patterns of DNA methylation have emerged as candidate cancer biomarkers [2]. Here, we will summarize recent advances in the use of DNA methylation biomarkers in CRC clinical applications.Germline mutations in hereditary CRC syndromes have proven valuable in identifying individuals at high risk of developing CRC, enabling personalized surveillance and early intervention. These classic high-risk alleles are mostly caused by loss-of-function coding-region mutations. By contrast, germline polymorphisms in regulatory regions of the MLH1 gene have been found to result in a higher likelihood of epigenetic silencing from the affected MLH1 allele, thereby increasing the risk of developing mismatch-repair-deficient CRC [3,4]. In rare cases, the effect of the polymorphism is strong enough to cause constitutional silencing of the MLH1 allele [3], which would be detectable in a blood-based MLH1 DNA methylation assay. Another example of a systemic epigenetic alteration is loss of imprinting of the IGF2 gene, which results in the activation of the normally silent allele of the IGF2 gene, an epigenetic phenomenon associated with various types of cancer, including CRC. Systemic loss of imprinting can be determined in peripheral blood and may be associated with an increased risk of developing CRC [5].Epigenetic biomarkers have also been explored as cost-effective and noninvasive alternatives to colonoscopy for the early detection of CRC. An ideal early detection DNA methylation biomarker would be present in the targeted malignancy at high frequency and detectable in bodily fluids or secretions despite the presence of background DNA from normal tissues. The most recent DNA methylation biomarker studies show promising results that have the potential to impact the way CRC patients will be treated in the future. The field of DNA methylation biomarker research is evolving rapidly and organized efforts are being made to structure biomarker research and development [6]. In the past, however, many studies have been performed without employing clear rules of evidence, using small sample sizes and relying on candidate gene approaches and nonquantitative detection methods. It has long been known that aberrant patterns of DNA methylation from CRC cells can be detected in tumor-derived cell-free DNA (cfDNA) found in plasma, serum or feces of cancer patients [7]. It is thought that cfDNA in cancer patients is a result of direct shedding from the primary tumor through apoptosis, necrosis or secretion, or potentially originates from free circulating tumor cells or metastatic cell deposits [7]. Studies have reported the existence of specific hypermethylated genes in blood and stool of patients with CRC and their associations with clinical disease and prognosis [8–10]. It has not yet been determined whether the use of a blood-based test or a stool-based test for early CRC detection is more efficient and more accepted by the public. DNA methylation biomarkers for early detection of CRC have been studied in both blood and feces. A blood-based test has the advantage that it can be used for primary detection, as well as postoperative follow-up for local and distant recurrences. In addition, the processing of a relatively small amount of blood may be preferred in laboratories above handling bulky feces. However, stool-based biomarkers may have some advantages over blood-based tests. Because colorectal adenomas and early CRCs are situated in the inner lining of the colorectum and are in direct contact with feces, tumor secretions and shed cells mix directly with colorectal content. Although it is difficult to estimate whether the half-life of tumor DNA is longer or shorter in feces than in blood, it seems conceivable that the concentration of tumor-derived DNA is higher in the intestine than in the bloodstream. Indeed, reported sensitivities for blood-based CRC DNA methylation biomarkers range up to 90% with a specificity of 88% [11]. In stool, sensitivities of 95% with specificities of 94% have been published [12]. A recent study by Ahlquist et al. reported a DNA stool test that detects methylated BMP3, NDRG4, vimentin and TFPI2, mutant KRAS, the ACTB gene and the quantity of hemoglobin [13]. This assay detected adenomas larger then 2 cm with a sensitivity of 82% and CRC with a sensitivity of 91% at a specificity of 93%.Little is known about the exact mechanism of tumor cfDNA derivation and spread and its relationship to biomarker detection. Factors that might influence diagnostic performance of a CRC DNA methylation biomarker include tumor, host and test characteristics. It is likely that tumor biology affects detectability. For instance, CpG island methylator phenotype (CIMP) tumors harbor high frequencies of DNA methylation and could therefore be more amenable to detection using DNA methylation biomarkers compared with tumors with lower frequencies of aberrant DNA methylation (as is the case for rectal tumors). Furthermore, the total amount of DNA shed by the tumor is likely to influence test performance. In general, biomarker studies show that stage IV CRC tumors, which usually have a higher total tumor burden, are detected more frequently than stage I CRC tumors or adenomas. Although it is known that cfDNA concentrations can vary significantly between individuals, the exact reason why is not clear. Besides individual variances in tumor biology, cfDNA spread and clearance by the liver and kidneys, as well as the wide-ranging diversity of the way samples are treated in different laboratories, may contribute to this variation. With the very low concentrations of tumor-derived DNA in the bloodstream, the volume of blood used in the analysis will affect assay sensitivity. Indeed, most DNA methylation-based detection assays use volumes in the ml range, rather than the µl range [2]. For example, the recently commercialized DNA methylation marker SEPT9 is assayed in 4 ml of plasma and yields a sensitivity of 90% for the detection of CRC at a specificity of 88% [11,14]. Methylated SFRP2, on the other hand, was reported to detect 67% of CRCs at a specificity of 94% using only 200 µl of serum [15]. In a recently published study we demonstrated that methylated THBD detects 74% of stage I/II CRCs at a specificity of 80% using 1 ml of serum [16]. It is difficult to compare these markers without considering the large difference in volume. It is possible that SFRP2 or THBD would outperform SEPT9 at equal volumes. Future studies will have to point out if increasing test volume also increases sensitivity without loss of specificity.Molecular classification of CRC is possible using various molecular traits identified in CRC tumor samples. Some commonly used classifications are microsatellite instability (MSI), mutations of the TP53, KRAS and BRAF genes. Although chromosomal instability status also reflects a molecular characteristic and is associated with worse prognosis in CRC, it is usually not used as a molecular classifier owing to its heterogeneity and poorly defined characterization. CIMP is seen in a subset of CRC tumors with unusually frequent DNA hypermethylation of a defined set of loci, and was first described in colon cancers more then a decade ago [17]. Although the exact molecular mechanisms and causes of CIMP are unknown, this phenomenon in CRC is associated with a specific phenotype (older age, female sex, family history of CRC, proximal location in the colon, mucinous cell differentiation, specific precursor lesions and smoking) and is tightly associated with sporadic MSI, BRAF and KRAS mutations and MLH1 promotor methylation [18,19]. CIMP is a CRC classifier, but also has prognostic meaning, and has been studied as a predictive marker in CRC. A prognostic biomarker gives information on tumor biology; a predictive marker tells us how a specific tumor responds to drug treatment. Although studies have suggested that MSI as well as CIMP have a disadvantageous effect on adjuvant fluorouracil (5-FU)-based treatment in CRC patients (predictive), in general MSI+CIMP+ status is associated with better clinical outcome (prognostic) [20]. It is difficult to study the predictive value of MSI or CIMP on 5-FU drug response due to the high degree of overlap between CIMP and MSI and the fact that 5-FU is the most widely used chemotherapy, administered to almost all eligible CRC patients.[21,22]. Recently, Ebert et al. published a specific association of a particular promotor methylation status with therapy response. Hypermethylation of TFAP2E in primary as well as metastatic CRCs was shown to be associated with decreased expression of this gene and nonresponsiveness to 5-FU. The fact that hypermethylation of TFAP2E was observed in 51% of the patients in this cohort indicates the possible impact this knowledge could have on future CRC treatment. In addition, if this gene was not methylated, it resulted in a six-times higher response rate then the total CRC population [23].The clinical application of DNA methylation biomarkers in CRC is rapidly developing into a competitive scientific field and has been noticed by the commercial industry as a marketable product. We expect DNA methylation biomarkers to take a definitive place in CRC diagnostics in the near future.Financial & competing interests disclosurePW Laird is inventor of the MethyLight technology, which has been licensed exclusively to Epigenomics AG, for use by Epigenomics in colorectal cancer DNA methylation biomarker assays, including SEPT9. PW Laird receives royalties in this context, but he is neither a shareholder nor consultant for Epigenomics AG, and receives no other financial support from Epigenomics AG. Epigenomics AG did not contribute to this manuscript in any way. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J. Clin.61(2),69–90 (2011).Crossref, Medline, Google Scholar2 Draht MX, Riedl RR, Niessen H et al. Promoter CpG island methylation markers in colorectal cancer: the road ahead. Epigenomics4(2),179–194 (2012).Link, CAS, Google Scholar3 Hitchins MP, Rapkins RW, Kwok CT et al. Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5´UTR. Cancer Cell20(2),200–213 (2011).Crossref, Medline, CAS, Google Scholar4 Mrkonjic M, Roslin NM, Greenwood CM et al. Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer. PLoS ONE5(10),e13314 (2010).Crossref, Medline, Google Scholar5 Cui H, Cruz-Correa M, Giardiello FM et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science299,1753–1755 (2003).Crossref, Medline, CAS, Google Scholar6 Febbo PG, Ladanyi M, Aldape KD et al. NCCN Task Force report: evaluating the clinical utility of tumor markers in oncology. J. Natl Compr. Canc. Netw.9(Suppl. 5),S1–32; quiz S33 (2011).Crossref, Medline, CAS, Google Scholar7 Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat. Rev. 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Med.366(1),44–53 (2012).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByEpigenetics and its therapeutic potential in colorectal cancerMahsa Akbari Oryani, Afsaneh Tavasoli, Mohammad Amin Ghalavand, Rahele Zokaei Ashtiani, Alisam Rezaee, Rasadokht Mahmoudi, Hossein Golvari, Soroor Owrangi & Mehdi Soleymani-Goloujeh27 April 2022 | Epigenomics, Vol. 14, No. 11A novel DNA methylation biosensor by combination of isothermal amplification and lateral flow deviceSensors and Actuators B: Chemical, Vol. 333Advances in CpG Island Methylator Phenotype Colorectal Cancer Therapies26 February 2021 | Frontiers in Oncology, Vol. 11Cell free circulating tumor nucleic acids, a revolution in personalized cancer medicineCritical Reviews in Oncology/Hematology, Vol. 144DNA methylation and chromatin modifiers in colorectal cancerMolecular Aspects of Medicine, Vol. 69BMP3 promoter hypermethylation in plasma-derived cell-free DNA in colorectal cancer patients10 January 2018 | Genes & Genomics, Vol. 40, No. 4Active BRAF-V600E is the key player in generation of a sessile serrated polyp-specific DNA methylation profile28 March 2018 | PLOS ONE, Vol. 13, No. 3Future Challenges and Prospects for the Role of Epigenetic Mechanisms in Cancer ManagementDevelopment of an electrochemical detection system for measuring DNA methylation levels using methyl CpG-binding protein and glucose dehydrogenase-fused zinc finger proteinBiosensors and Bioelectronics, Vol. 93Assessment of Bone Morphogenetic Protein 3 Methylation in Iranian Patients with Colorectal Cancer25 June 2017 | Middle East Journal of Digestive Diseases, Vol. 9, No. 3CpG island methylator phenotype is associated with the efficacy of sequential oxaliplatin- and irinotecan-based chemotherapy and EGFR-related gene mutation in Japanese patients with metastatic colorectal cancer19 July 2016 | International Journal of Clinical Oncology, Vol. 21, No. 6Evaluation of Methylation Biomarkers for Detection of Circulating Tumor DNA and Application to Colorectal Cancer15 December 2016 | Genes, Vol. 7, No. 12Meta-analysis of DNA methylation biomarkers in hepatocellular carcinoma8 November 2016 | Oncotarget, Vol. 7, No. 49Clinical stage and risk of recurrence and mortality: interaction of DNA methylation factors in patients with colorectal cancer13 June 2016 | Journal of Investigative Medicine, Vol. 64, No. 7The Extraordinary Progress in Very Early Cancer Diagnosis and Personalized Therapy: The Role of Oncomarkers and NanotechnologyJournal of Nanotechnology, Vol. 2016Accessing Genetic Information with Liquid BiopsiesTrends in Genetics, Vol. 31, No. 10Potential of DNA methylation in rectal cancer as diagnostic and prognostic biomarkers3 September 2015 | British Journal of Cancer, Vol. 113, No. 7Chronic Inflammation Induces a Novel Epigenetic Program That Is Conserved in Intestinal Adenomas and in Colorectal Cancer13 May 2015 | Cancer Research, Vol. 75, No. 10Detection strategies for methylated and hypermethylated DNATrAC Trends in Analytical Chemistry, Vol. 66Quantitative detection of methylated NDRG4 gene as a candidate biomarker for diagnosis of colorectal cancer19 December 2014 | Oncology Letters, Vol. 9, No. 3WITHDRAWN: SEPT9 DNA methylation as an early diagnostic marker in colorectal cancerCancer GeneticsThe Epigenetics in Intestinal Tumorigenesis20 September 2015Comparison of CpG Island Methylator Phenotype (CIMP) Frequency in Colon Cancer Using Different Probe- and Gene-Specific Scoring Alternatives on Recommended Multi-Gene Panels21 January 2014 | PLoS ONE, Vol. 9, No. 1 Vol. 5, No. 2 Follow us on social media for the latest updates Metrics History Published online 8 April 2013 Published in print April 2013 Information© Future Medicine LtdKeywordsbiomarkerscolorectal cancerDNA methylationepigeneticsepigenomicsFinancial & competing interests disclosurePW Laird is inventor of the MethyLight technology, which has been licensed exclusively to Epigenomics AG, for use by Epigenomics in colorectal cancer DNA methylation biomarker assays, including SEPT9. PW Laird receives royalties in this context, but he is neither a shareholder nor consultant for Epigenomics AG, and receives no other financial support from Epigenomics AG. Epigenomics AG did not contribute to this manuscript in any way. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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