Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide and in the USA it represents the second reason for cancer-associated deaths. The incidence and mortality rates of CRC vary widely according to race and ethnicity (1). It is tagged as a “silent” disease and takes years or even decades to develop. Increasing age is also a risk factor for CRC, which raises the importance of the issue of screening and surveillance. Colonic polyps are precursors to the development of colorectal cancer. Generally, clinical manifestations such as intestinal bleeding or abdominal pain do not develop until the cancer is metastasized. Usually, 7-10 years required for transformation of adenoma to carcinoma, and this gap provides a chance for early detection of CRC. MARCH, is the National Colorectal Cancer Awareness Month. Communities, organizations, families, and individuals get involved and spread the awareness about colorectal cancer and its prevention. The goal is to challenge assumptions and misconceptions about colorectal cancer by dispelling myths, raising awareness, and connecting people across the country with information and support.
Several screening recommendations from the U.S. Preventative Services Task Force, American Cancer Society, U.S. Multi-Society Taskforce with the American College of Radiology, American College of Gastroenterology, and the National Comprehensive Cancer Network have been laid. Screening tests available and recommended include examining stool for occult blood or newer tests examining DNA mutations/alterations radiologic or endoscopic methods. At present standard tool for CRC evaluation is colonoscopy, which is an invasive process along with high cost. Colonic puncture sometimes also leads to intraperitoneal bleeding and some possible infection. At certain ages (especially older patients) and under some circumstances the harm of screening for CRC outweighs the benefits. There is a critical requirement for the development of noninvasive and more reliable diagnostics for CRC. The epigenetic markers have been proposed to provide noninvasive, cost-effective, highly specific and sensitive tools for the early investigation of premalignant stages in cancer progression. New molecular detection methods are being evaluated and they need to be approved in large randomized trials before its implementation.
The survival rate for most of the cancerous diseases relies on the stage of the tumor at the time of diagnosis. Hence, there is a requirement for early diagnostic markers. CRC is a polygenic disease and the three major molecular pathways resulting in carcinogenesis by genetic alterations are chromosomal instability (CIN), microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP). Microsatellites are short repeats of 1-6 base pairs and the human genome contains about half a million microsatellites. Microsatellites are mostly subjected to duplication errors which get fixed by the Mismatches repair (MMR) systems (2). MMR systems role is to identify and fix any mistakes happen in microsatellites during DNA synthesis. The defect of MMR system genes results in the collection of DNA mistakes and subsequently microsatellite instability which drive the progression of CRC. Approximately, 15%-20% of CRC patients have been shown to demonstrate MSI. Adenomatous Polyposis Coli (APC) encodes a multifunctional protein with an important role in Wnt signaling pathway, cell cycle regulation, cytoskeleton stabilization, intracellular adhesion, as well as apoptosis. APC contributes to many essential functions connecting several pathways regulating significant cellular activities such as cell division, differentiation, apoptosis, and genetic instability. That apparently justifies why any defect in APC may become carcinogenic.
Detection of CRC specific RNA marker in the stool is also proposed to be a useful marker for CRC. Approximately, 10¹º colonocytes are found to peel off from crypts daily easily appear in the stool. Yamao et al, and Matsushita et al suggested the survival of cancer cells in stool in comparison to normal cells (3). Fecal occult blood test (FOBTs) represents one of the oldest tools for early screening of CRC with less sensitivity and specificity. miRNA is non-coding molecule contains between 18-25 nucleotides controlling the role of particular mRNA. miRNA role is associated with inhibition the expression of several genes via either destruction of their mRNA or interfering with their translation.
It contributes to the regulation of about 30% of human protein-coding genes. More critical functions are either in normal growth or tumor cell proliferation, differentiation. Fecal miRNA is reported since 1990s, and in 1998 the defective expression of CD44 in CRC stool was evaluated. A meta-analysis study has been performed to estimate the diagnostic importance of miRNA in CRC investigation. Several miRNA tests reported better diagnostic value than single miRNA tests. The epigenetic alterations include DNA methylation, histone modification, and posttranscriptional gene regulation. DNA methylation process is critical for normal growth and several factors contribute to aberrant DNA methylation in colorectal mucosa. Abnormal DNA methylation patterns of CRC cells have been detected in the DNA derived from blood or feces of CRC patients. These genes can be employed as diagnostic, predictive and prognostic biomarkers.
Colorectal cancer screening, which detects both precancerous polyps and colorectal cancer, can reduce both colorectal cancer incidence and mortality.30–40 Through screening, the incidence of colorectal cancer can be reduced by 17% to 33% with a mortality reduction of 11% to 53% depending on the modality employed.30–34,36,37 While no one screening method is advocated a number of consensus documents offer. Early prognosis is important for CRC which will contribute to the reduction and prevention of mortality. However, there is no reliable prognostic biomarker that provides a clear clue about CRC cases. The new prognostic indicator is also critical for the development of better treatment options (4). In context with that, several novel prognostic biomarkers for CRC have been studied. KRAS and BRAF are the two currently approved biomarkers. The KRAS encodes for a protein involved in the G-protein signal transduction pathway affecting cellular proliferation and differentiation. Mutation of KRAS has been reported in 35-40% of mCRC individuals Patient with mutations in these genes have shorter overall survival and poor prognosis. BRAF belongs to the family of serine-threonine kinase and is a downstream effector of KRAS in RS/RAF/MAPK signaling pathway. Mutation in BRAF helps to differentiate between familial and sporadic CRC. The impact of BRAF mutation on survival rate and drug efficiency in stage III colon cancer was studied and results showed extremely bad survival rate among mutated BRAF cases. The potential biomarkers which are under development include miR-21, miR-92a, miR-200 and miR320E, and THBS2
Till date, CRC lacks a novel molecular biomarker or biomarker panel applicable for wide-spectrum screening purposes. There is a requirement of effective laboratory-based molecular CRC screening method to detect early-stage colorectal malignancy. Decisions regarding screening, surveillance, and treatment for colorectal cancer require a multidisciplinary approach. Clinically relevant cost-effective biomarkers which can be easily assayed in a clinical setting is the need of the hour.
- VERMA, M. & KUMAR, V. 2016. Epigenetic Biomarkers in Colorectal Cancer. Molecular Diagnosis & Therapy, 1-13.
- LOSSO, G. M., MORAES, R. D. S., GENTILI, A. C. & MESSIAS-REASON, I. T. 2012. Microsatellite instability-MSI markers (BAT26, BAT25, D2S123, D5S346, D17S250) in rectal cancer. ABCD. Arquivos Brasileiros de Cirurgia Digestiva (São Paulo), 25, 240- 244.
- MATSUSHITA, H., MATSUMURA, Y., MORIYA, Y., AKASU, T., FUJITA, S., YAMAMOTO, S., ONOUCHI, S., SAITO, N., SUGITO, M. & ITO, M. 2005. A new method for isolating colonocytes from naturally evacuated feces and its clinical application to colorectal cancer diagnosis. Gastroenterology, 129, 1918-1927.
- WANG, X., ZHANG, L., LI, H., SUN, W., ZHANG, H. & LAI, M. 2016. THBS2 is a Potential Prognostic Biomarker in Colorectal Cancer. Scientific Reports, 6.