Colorectal cancer (CRC), is the third most common form of cancer and the second leading cause of death among cancers worldwide, with approximately 1, 000, 000 new cases of CRC and 50, 000 deaths related to CRC each year [1
]. Sporadic colon cancer represents the 70% of newly diagnosed cases, and it is believed to slowly develop via a progressive accumulation of multiple mutations that affect tumour suppressor genes, as well as oncogenes or mismatch repair genes (MMR) [3
Statistics concerning colon cancer survival show differences between countries. In US, the overall five-year survival rate is 62% while in Europe is 43%. The reasons for this different behaviour are not very clear, although quality of care and screening programs could play a central role in the survival of CRC, since it is well established that the stage of the disease at diagnosis greatly impacts colon cancer survival rates. In this way, the US Centres for Disease and Control Prevention (CDC) state that the 5-year survival rate for persons who received a diagnosis of localized colorectal cancer is 91% compared with 70% for regional-state cancer and 11% for distant -stage cancer [4
]. Also, a study registered at the National Cancer Institute's SEER database, conducted with more than 28, 000 people diagnosed with colon cancer between 1998 and 2000, found that the observed 5-year survival rates related to the stage of the disease at diagnosis were the following: I-74%, IIA-67%, IIB-59%, IIC-37%, IIIA-73%, IIIB-46% and IIIC-28% (source: American Cancer Society).
This and other evidences have convinced the scientific and medical community of the great importance of screening for CRC to reduce incidence and mortality, through detection of premalignant polyps as well as diagnosis of early -stage cancer [4
]. As a result, data from the CDC show that CRC incidence and mortality have experienced a decline in recent years due to the screening campaigns [6
]. In spite of this, the same studies indicate that CRC remains the second most common cause of cancer deaths after lung cancer in the US and the leading cause of cancer deaths among non-smokers. In this context, there is a global awareness for the implementation of CRC screening programmes [8
]. Not only the US, but also France put into action a screening programme in 2003, Finland in 2004, UK in 2006, etc. However, there is no international consensus on the preferred strategy to carry on the screening, mainly due to the limitations of the available screening techniques at present.
The currently used methods for the early detection of CRC are the Faecal Occult Blood Test (FOBT) and the endoscopy. FOBT is simple, inexpensive and the least invasive method of screening available. Also, it has been shown through prospective randomized trials that FOBT reduces CRC mortality, and consequently the evidence for its use is robust. However, FOBT presents relatively high false negative and false positive rates, and it has particularly poor sensitivity for the detection of early-stage lesions [9
]. In an attempt to improve on the false positive rates of FOBT, a new Faecal Immunochemical testing (FIT) has been developed. It has slightly superior performance characteristics but at a greatly increased financial cost, and its implementation has not been effective as yet [12
On the other hand, colonoscopy offers significant improvements in detection rates for CRC but it also has important disadvantages associated, as inconvenience, high economic burden and potential major complications (bleeding, perforation) [13
All this emphasizes the urgent necessity of new diagnostic approaches in order to improve the outcome of CRC screening programs. In particular. there is a clinical need for identifying specific biomarkers for early detection of CRC [2
]. Moreover, there is at the present time a widespread awareness, not only between scientists and practicing clinicians but also among regulatory organizations and healthcare systems, that the development of biomarkers will offer the major advances in CRC detection [15
]. The scientific world even holds an expectation that a new generation of molecular markers should improve compliance with CRC screening in the same way other markers do in other illnesses screening programs (lipid monitoring, PSA,...).
The recent advances in genomics and proteomics have contributed to our molecular understanding of CRC by evaluating the expression profiles of genes and proteins, in cancerous and non-cancerous surrounding tissues and body fluids. The identification of genes and/or proteins that are characteristic of the development of CRC can render potential biomarkers that will facilitate the early detection of CRC. There is quite a number of recently discovered potential molecular biomarkers, such as CEA, CA 19-9, K-ras
, L-DNA, APC, TIMP-1, NNMT, MIF, PSME3, Septin 9, MMP-9, MMP-7, Spondin-2, DcR3, Trail-R2, MICI, CCSA-2, CCSA-3, CCSA-4, etcetera [16
]. Some of them have been questioned because of insufficient sensitivity or specificity (CEA, CA 19-9,...), others because of poor performance in early stages of CRC (TIMP-1,...), and some others remain promising but there is insufficient evidence for their routine implementation (CCSA-3, CCSA-4, MIF, DcR3, Spondin-2,...) [17
]. Many authors agree that a panel of biomarkers will be likely necessary to reach appropriate sensitivity for clinical use as a screening biomarker, due to the genetic heterogeneity of CRC [12
]. Furthermore, a limited number of markers have been identified to date in CRC, but their individual use has led to conflicting results [1
]. In this context, genomic techniques, such as DNA microarrays, allow high-throughput analysis of genes, rendering big volumes of data which increases the possibilities for uncovering potential biomarkers. Namely, DNA microarray-based gene expression profiling technology provides a strategy to search systematically with a combinatorial manner for molecular markers of colon cancer.
Our aim in the present study was to develop a model or biomarker for the objective diagnosis of CRC based on gene expression patterns. For this purpose, we used the microarray technology in combination with advanced statistics analysis techniques. The identification of a robust panel of CRC-specific biomarkers through genomics would be the cornerstone for their posterior development into non invasive samples-based diagnosis markers.