The etiology of colorectal cancer (CRC) is multifactorial with genetic molecular

The etiology of colorectal cancer (CRC) is multifactorial with genetic molecular inflammatory and environmental risk factors. for such contamination? In the above example the answer would be antibiotic-induced dysbiosis. Moreover the state of microbiota has been associated with conditions such as diabetes skin disease obesity inflammatory bowel disease GSK1059615 and even cancer all of which are commonly regarded as noninfectious processes. Although inflammatory infectious and neoplastic diseases are often considered categorically unique processes evidence has shown significant overlap between them. In fact it is estimated that 15% of worldwide cancer is usually of infectious nature with human papillomavirus hepatitis B computer virus hepatitis C computer virus human herpesvirus-8 and recognized as the definitive cause of cervical malignancy liver malignancy Kaposi’s GSK1059615 sarcoma and belly malignancy/lymphoma respectively. Furthermore direct GSK1059615 causation of malignancy by chronic inflammatory conditions is very well documented. The association of inflammatory bowel disease (IBD) with increased risk of colon cancer is usually a case in point. Thus it should come as no surprise that alterations of the microbiome may lead to infectious inflammatory and ultimately cancerous disease. It is the focus of this review to detail the interrelationship between colorectal malignancy (CRC) and the gut microbiome. Background CRC is the DLEU7 second leading type of malignancy in females and the third in males worldwide with over 1.2 million new cases and over 600 0 estimated deaths in 2008 [1]. In the United States an estimate of 142 820 new cases of CRC with over 50 0 deaths occur annually [2]. However both incidence and mortality rates of CRC in the United States have steadily declined and this decrease may be attributed to prevention early screening detection and treatment of CRC [3]. Major risk factors of CRC have also been established. In sporadic CRC age is a risk factor with increased incidence between the ages of 40-50 with 90% of cases occurring after the age of 50 [4]. In the United States men have a 25% higher incidence of CRC than women and African Americans have a 20% higher incidence than Caucasians. Genetic risk factors are obvious in hereditary CRC syndromes such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal malignancy (HNPCC). In FAP the adenomatous polyposis coli (APC) gene located on chromosome 5 is usually mutated and accounts for less than 1% of CRCs [5]. HNPCC accounts for 3-5% of CRCs and has a germline mutation in one allele of a mismatch repair gene including hMLH1 hMSH2 hMSH6 or PMS2 with inactivation of the second allele by loss of heterozygosity somatic mutation or promoter hypermethylation [5 6 HNPCC-related CRCs present with KRAS mutations and do not have BRAF mutations [7]. Additional risk factors include personal or family history of CRC or adenomatous colon polyps [8 9 (Physique 1) Physique 1 Overview of factors leading to colorectal carcinogenesis. The microbiome interacts with inflammatory mechanisms as well as dietary factors in progression of tumorigenesis. The majority of CRCs are sporadic with tumorigenesis that involves mutations in APC (5q) DNA hypomethylation and acquisition of multiple additional alterations especially in KRAS2 (12p) DCC (18q) and p53 (17p) [10 11 BRAF mutations are especially prevalent in sporadic CRC of smokers [12]. At least three molecular pathways have been layed out in colorectal tumorigenesis. The chromosomal instability (CIN) pathway is seen in FAP as well as in sporadic CRC and is characterized by chromosomal abnormalities including deletions insertions and loss of heterozygosity [13]. The mutator GSK1059615 phenotype/mismatch repair pathway is usually represented by HNPCC as layed out above. The third hypermethylation phenotype GSK1059615 hyperplastic/serrated polyp pathway includes epigenetic changes including hypermethylation of some CpG islands. This alteration may result in hypermethylation of the promoter region of mismatch repair enzymes such as MLH1 [14]. IBD including ulcerative colitis (UC) and Crohn disease also predispose to CRC. Although the pathogenesis of CRC in the establishing of IBD is usually poorly understood studies suggest.