Four decades ago a “war” was declared on cancer with the passing of the National Cancer Act of 1971, but only recently has the overall cancer-related death rate begun to slowly decline as the death rate for other diseases has plummeted.1,2
For the most part, this relatively minor decline in mortality has been attributed to increased disease prevention efforts, improved treatments for advanced malignancy, and early detection and treatment of localized cancers.3
Notwithstanding, cancer remains a major cause of mortality in the United States (U.S.); in fact, it was the second leading cause of death for all ages, genders, and races in 2009 and is expected to top the list this year.2
Advances are urgently needed from the key stakeholders in translational cancer research, which will impact cancer-related mortality in the near-term. It is felt that these advances will most likely come from studies focusing on early detection of cancer rather than the prevention or treatment of cancer, as the latter require a fundamental understanding of the underlying causes and complex mechanisms of cancer.3
Numerous recent trials have already demonstrated an improvement in survival for patients with breast, colon, prostate and lung cancer when the disease is identified and treated early.4-7
Colorectal cancer (CRC) is the third most common cause of cancer-related death in the US.1
The colorectal adenoma-carcinoma sequence is well established. For CRC, the identification and treatment of early stage, pre-malignant lesions are highly effective interventions that substantially reduce CRC-specific mortality. Due to its excellent diagnostic accuracy, coupled with its ability to remove pre-cancerous lesions, colonoscopy continues to be the primary screening tool. However, the nature of the procedure limits its effectiveness as a screening method.8
A significant advance in the screening and care of these patients could be realized by blood-based biomarkers, which could accurately identify patients at-risk for CRC development whom might benefit from early and/or more frequent surveillance for disease. Extensive cancer research over the last decade has uncovered numerous genomic alterations in CRC - epidermal growth factor receptor (EGFR), BRAF, tumor MSI-H expression (defects in DNA mismatch repair, MSI phenotype), 18q AI expression, p53 expression and KRAS mutation. But, these are poor targets for early detection biomarkers for CRC due to their lack of global expression across all CRC molecular subtypes. Alongside these advances in the detection and understanding of genomic modifications in CRC over the past decade, an appreciation for the importance of epigenetic modifications has emerged.
Epigenetic modifications refer to changes in gene expression and cellular phenotype without corresponding changes in the DNA sequence i.e. DNA methylation and histone modification. An important epigenetic mechanism for silencing tumor suppressor genes during carcinogenesis is the hyper-methlyation of CpG islands. This methylation of the base cytosine in CpG islands is under intense investigation and it has been reported, that in certain cancers such as colorectal, small bowel, and endometrial cancers, loss of function of the DNA mismatch repair gene hMLH1 by hyper-methylation of its promoter can be observed.9
DNA methylation studies have demonstrated that dense methylation of promoter regions is associated with transcriptional silencing and that this silencing, especially of tumor suppressor genes, is important in tumorigenesis. Furthermore, DNA methylation profiles are reportedly distinct between diseased and benign tissues and may be useful in cancer screening. The aim of our review is to discuss the potential for serum-based DNA methylation biomarkers for screening and early detection of CRC.