This progress in the molecular pathogenesis of colorectal cancer has allowed the definition of two pathways of cellular/molecular development of colorectal cancer, starting from two different precursor lesions: adenoma-carcinoma pathway and the serrated pathway, characterized by different genetic lesions. The development of colorectal cancer is dictated by a mixture of genetic and environmental factors. The development of sophisticated molecular techniques for the analysis of the genome has enabled the identification of several genetic alterations involved in the pathogenesis of colorectal cancer. The recent innovations in molecular biology and cancer genetics have improved the understanding of the pathogenesis of sporadic and hereditary colorectal cancer syndromes. The present review paper offers a comprehensive description of the progress made in the last three decades in the understanding of the molecular basis of colorectal cancers. In this context, the available evidence suggests that medullary colon cancer is associated with microsatellite instability (MSI) and seems to be associated with a better prognosis, while signet-ring cell carcinomas have a poor prognosis. There is no simple link between the histotype and tumor prognosis. Rarer histological subtypes are represented by mucinous adenocarcinoma, adenosquamous carcinoma, signet-cell carcinoma and medullary carcinoma. Most colon cancers are classified as adenocarcinomas, subdivided according to the grade of the tumor into low-grade and high-grade. Rectal cancers show higher rates of loco-regional relapse and lung metastases, whereas colon cancers have a higher tropism for liver spread and usually have a moderately better prognosis. Finally, colon cancers are classified as rectal cancers when they arise within 15 cm of the anal sphincter. Based on the data observed in the period 2007–2013, it was estimated that about 65% of patients survive five years or more after being diagnosed with colorectal cancer.įrom a clinical point of view, colon cancers are usually subdivided as proximal or right-sided when they originate from colon sections proximal to the splenic flexure (cecum, ascending colon and transverse colon), whereas distal or left-sided colon tumors arise distally with respect to this site (descending colon and sigmoid colon). From 1992 to 2014 there was a consistent decrease in the incidence of new cases of colorectal cancer. Based on the 2012–2014 data, it was estimated that 4.3% of men and women will be diagnosed with colorectal cancer at some point during their lifetime. The National Cancer Institute estimated 135,430 new cases of colorectal cancer in USA in 2017, corresponding to 8% of all new cancer cases the estimated number of deaths in 2017 in the USA was 50,260, corresponding to 8.4% of all cancer deaths. It was estimated that more than one million individuals develop worldwide colorectal cancer each year and the disease-related mortality corresponds to about 33% in the developed world. Colorectal cancer is the second most common cause of cancer death in Europe. Colon cancer stem cells seem to be involved in tumor chemoresistance, radioresistance and relapse.Ĭolorectal cancer is one of the most frequent malignancies worldwide, being second in males and third in females for its frequency and ranking fourth and third for cancer-related deaths among males and females, respectively. Various experimental evidence suggests that colorectal cancers may derive from the malignant transformation of intestinal stem cells or of intestinal cells that acquire stem cell properties following malignant transformation. The homeostasis of the rapidly renewing intestinal epithelium is ensured by few stem cells present at the level of the base of intestinal crypts. The ensemble of molecular studies, including gene expression studies, has led to two proposed classifications of colorectal cancers, with the identification of four/five non-overlapping groups. Studies carried out in the last years have characterized the main molecular alterations occurring in colorectal cancers, showing that the tumor of each patient displays from two to eight driver mutations. In many patients, the development of a colorectal cancer is preceded by a benign neoplastic lesion: either an adenomatous polyp or a serrated polyp. Most colorectal cancer occurrences are sporadic, not related to genetic predisposition or family history however, 20–30% of patients with colorectal cancer have a family history of colorectal cancer and 5% of these tumors arise in the setting of a Mendelian inheritance syndrome. Colon cancer is the third most common cancer worldwide.
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