| Although great progresses have been made in earlier treatnent and entending survival time of patients, colorectal cancer, which is the third most commonly diagnosed cancer in males and the second in females, with over1.2million new cancer cases and33%mortality rates per year, is still a global burden of human health. No one could neglect these circumstances. Colorectal cancer incidence rates are rapidly increasing in several areas historically at low risk, including a number of countries within Eastern Asia. While colorectal cancer death rates have been decreasing in Western countries, due to increased awareness and earlier screening, the incidence rates continue to increase in many developing countries with limited resources and health infrastructure, particularly in China.In China, which is an area historically at low incidence rates and death rates of colorectal cancer, the situation is not optimistic. With t the improvement of people’s living standard and increasingly westernized lifestyle, the incidence rates and death rates of colorectal cancer is increasing every year, and the situation is very similar to Japan. In2008, new cases colorectal cancer reached about22.1million (7.9%of overall cancer incidence) and the number of deaths was approximately11million (5.6%of overall cancer mortality). The Age-standardized incidence rate (World-wide)(ASR incidence W) is14.2(per100thousand), while the Age-standardized mortality rate (World-wide)(ASR mortality W) is6.9(per100thousand).5-year prevalence is47.6(per100thousand),(Table1-1). Furthermore, the incidence, the number of deaths and the5-year prevalence of colorectal cancer in China are higher than that in the US, and the incidence and deaths in China account for more than half of the Asia-Pacific region (incidence:22.1:39.4, Deaths:11:18.2).Colorectal cancer incidence in China shows regional distribution due to the difference in economic levels. The southeast coast of the more developed regions compared to the inner mainland demonstrate higher colorectal cancer incidence, such as Zhejiang, Shanghai, Jiangsu and Fujian. According to the statistics of2010, the first commonly cancer in Shenzhen is lung cancer and the second is colorectal cancer accounting for10.35%of all cancer patients. In the whole country, colorectal cancer has become the fifth largest cancer killer in Chinese people. To this end, scientists from all over the world have put a lot of effort and great deal of money to study colorectal cancer.Colorectal cancer can be divided into colon cancer and rectal cancer in anatomical location, which were distinguished to be treated in some of studies. In contrast with colon cancer, rectal cancer has a high incidence of local recurrence, and patients with rectal cancer have a higher incidence requiring the addition of pelvic radiation therapy. Thus, in this study, we only investigate molecular characteristics and clinical features of patients with colon cancer.It is well known that different individuals with the same cancer behave different symptoms, and patients who have the same symptoms need different therapy regimens. Although there are pathologic staging system and clinical staging system for determining prognosis and treatment options, due to changes in molecular level in the individuals makes the different outcomes of the patients who have the same pathologic stage and were given the same treatment. The fundamental reason of this phenomenon is that the molecular mechanisms of the specific cancer occurrence, development and metastasis were not known clearly by scientists and clinical doctors. One approach to deal with this problem is that it is preferable to utilize the bioinformatics methods on numerous clinical samples to investigate the alterations in molecular level of the specific cancer.So far the most studies on colon cancer focus on the specific stages in colon cancer to discover molecular mechanisms and potential therapy targets, such as recurrence of Dukes’B colon cancer and Stage II colon cancer prognosis prediction using gene expression profiling generated from microarrays. The subtypes of colon cancer in different molecular levels including gene expression level, MicroRNA expression level and DNA methylation expression level were found. However, colon cancer patients show heterogeneity in subtypes, the work in colon cancer subtype classification has yet to be further explored, and to date we are still far from having a complete atlas of molecular subtypes of colon cancer.In this study, several bioinformatics approaches such as clustering analysis and discriminant analysis are utilized to discover the subtypes in two different molecular levels which are gene expression level and DNA methylation level on153colon cancer samples from TCGA data portal. Consensus clustering is one of the unsupervised clustering methods for detect the number of classification using resampling strategy on samples, and Prediction analysis of microarrays (PAM) is a widely used discriminant analysis method to select significant genes that have most contribution to samples classification. We further explored the functions of these significant genes using gene set enrichment analysis, pathway enrichment analysis as well co-expression analysis. Database for annotation, visualization and integrated discovery (DAVID) and GENEMANIA can get the work done well.At gene expression level, we identified two major subgroups, ECL1and ECL2, which have distinct biological characteristics and clinical features and a list of genes that best reflect the biological and clinical characteristics of the two subgroups. In addition, samples in subgroup ECL1shows more heterogeneity than in subgroup ECL2, thus, the re-classification in subgroup ECL1was discussed. HOTAIR is one of the significant differential expression genes in sub-clusters, and it may be a potential biomarker to target bad prognosis.At DNA methylation level, we uncovered three major subgroups, MCL1, MCL2and MCL3, which have distinct biological characteristics and reflect different clinical features. Compared with earlier studies, especially Hinoue’s paper and TCGA’s paper, some differences were found that subtypes of CIMP in colon cancer are three but not four. The authors also investigate re-classification on the subgroup MCL2, and there is no powerful evidence to explain the distinction of two sub-clusters generated from MCL2.At last, classification analysis was performed at both gene expression level and DNA methylation level, and a classifier was constructed at each level.As a paradigm of cancer research, analysis strategy used in this study could be applied to other cancers research. The future study should focus on integrating more levels of genomic data to provide more significant knowledge and insight for molecular subtype underly colorectal cancer. |
PDF Full Text Request