Genetic pathways, prevention, and treatment of sporadic colorectal cancer

Abstract

Epithelial cancer of the colon and rectum, also known as colorectal cancer (CRC), results from a progressive accumulation of genetic and epigenetic alterations that lead to uncontrolled growth of colonocytes, the cells lining the colon and rectum. CRC is the second leading cause of cancer-related deaths and the third most common cancer in men and in women in the U.S. Of all the patients diagnosed with CRC every year, it is estimated that the vast majority of CRCs are non-hereditary "sporadic cancers" with no apparent evidence of an inherited component. Sporadic CRC results from the cumulative effects of multiple genetic and epigenetic alterations caused by somatic mutations, which may themselves be the indirect result of several environmental factors. This review examines our current understanding of the major genetic alterations leading to colon cancer, options for prevention and early detection of CRC, and the currently available treatment approaches that may target these different genetic alterations.

Keywords: colon cancer; genetic pathway; sporadic.

Figure 1. Multiple genetic pathways in colorectal cancer pathogenesis

Three distinct parallel pathways are implicated in CRC pathogenesis: Chromosomal Instability (CIN), Microsomal Instability (MSI), and Serrated Pathway. The sequential genetic and epigenetic changes occurring in each pathway are simplified. (A) The CIN pathway is driven by inactivating mutations in tumor suppressor genes, such as the adenomatous polyposis coli (APC) gene and activating mutations in proto-oncogenes, such as KRAS etc. which lead to increased clonal expansion of the cells. Subsequent loss of heterozygosity (LOH) for the long arm of chromosome 18 (18q) and loss of tumor suppressor TP53 confer these expanding cells with additional growth advantages which ultimately leads to invasive cancers. (B) The MSI pathway is driven by the loss of APC gene, and is characterized by inactivation of the mismatch repair (MMR) genes, such as MutL homolog 1 (MLH1) etc. The inactivation of MMR genes mostly is caused by epigenetic silencing via promoter hypermethylation. The failure of MMR genes subsequently leads to mutations in specific target genes involved in proliferation and cellular differentiation such as transforming growth factor β receptor II (TGFβRII); proteins involved in apoptosis regulation such as BAX and others, ultimately leading to microsatellite unstable invasive tumors. (C) The Serrated Pathway is driven by hypermethylation of genes and is characterized by presence of proto-oncogene BRAF mutation which causes increased MAPKs/ERKs signaling, leading to increased cell proliferation. Subsequent methylation of other genes and loss of tumor suppressor genes such as TP53, p16 etc. will lead to CRC.