___________________________________________________________________________ Colorectal Cancer
The CIN Pathway CIN is the most common form of genomic instability and is found in as many as 85% of colorectal cancers. The hallmark of the CIN phenotype is mutations that inactivate the APC gene, found in up to 70% of sporadic colorectal cancers, and that cause FAP. APC mutations occur during the earliest stages of neoplasia and are predominantly associated with the classic tubular adenoma pathway and CIN tumor [169]. Increasing size, increasing number, and worsening histology of polyps reflect the linear process of carcinogenesis along the CIN pathway [179]. As discussed, the APC gene is a tumor-suppressor gene that indirectly regulates the transcription of several critical cell proliferation genes by encoding transcription factor beta-catenin, a protein involved in cell adhesion, signal transduction, transcription regulation, cell cycle control, apoptosis, and maintenance of chromosomal segregation fidelity. APC inactivation produces loss of beta-catenin function, allowing unchecked cellular replication at the crypt surface, and activation of oncogenes c-myc and cyclin D1 that drive the progression to malignant phenotype [103; 171; 180]. The MSI Pathway MSI tumors are characterized by MMR system defects. DNA MMR genes correct nucleotide base miss-pairs and small insertions or deletions that occur during DNA replication. The MMR defect promotes adenoma development and accelerates the progression from adenoma to carcinoma. These colorectal malignancies are distinguished at the molecular level by alterations in repeating units of DNA that occur normally throughout the genome, termed DNA microsatellites. Microsatellite unstable tumors are generally considered mutually exclusive of CIN tumors [169; 181]. The mechanisms that underlie MSI involve MMR gene inactivation by aberrant methylation or somatic mutation. Roughly 20% to 30% of colorectal cancers display a characteristic pattern of gene hypermethylation, termed the CpG island methylator phenotype (CIMP). Some CIMPs display MSI, and these account for roughly 90% of Lynch syndrome cases and 15% to 20% of sporadic colon and rectal cancers [106; 171; 182].
Adenomas are the primary precursor lesion of colorectal cancer. These polyps are benign tumors that may transform into malignancy. Of all patients with adenomatous polyps discovered by screening colonoscopy, one-year follow-up colonoscopy reveals additional polyps in 29%. The risk of colorectal malignancy in patients with history of polyp removal is 2.7 to 7.7 times that of the general population [174; 175]. Epithelial-derived adenoma or adenocarcinoma tumors represent the predominant colorectal cancer tumor type. More than 95% of colorectal cancers are carcinomas, and more than 95% of these adenocarcinomas. Other histologic types account for the remaining 2% to 5%. Adenomas are histologically classified, by order of increasing malignant potential, as tubular, tubulovillous, or villous adenomas. Characteristics of adenomas that highly predict malignant transformation
include [1; 176]: • Larger size • Villous pathology • Degree of dysplasia within the adenoma
Adenomas may reflect an innate or acquired tendency of the colon to form tumors. Benign and malignant tissue occurs within colorectal tumors, and 20-year follow-up of patients with adenomas has found a 25% malignancy rate in adenoma sites. Removal of adenomatous polyps is linked with reduced colorectal cancer incidence and represents the foundation of primary colorectal cancer prevention [170]. The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events. The mucosa in the large intestine regenerates roughly every six days. Crypt cells migrate from the base of the crypt to the surface, where they undergo differentiation and maturation and ultimately lose the ability to replicate. As noted, most colorectal carcinomas are adenocarcinomas. Adenomas precede adenocarcinomas, with roughly 10% of adenomas eventually developing into adenocarcinomas during a process that occurs over up to 8 to 10 years with sporadic colorectal cancers. Dysplastic adenomas progress to colorectal malignancies through a multistep process involving inactivation of a variety of tumor-suppressor and DNA-repair genes and simultaneous activation of oncogenes. Colonic epithelial cells are selectively vulnerable to the transformation from normal colonic epithelium to adenomatous polyp to invasive carcinoma [171; 177; 178].
THE INFLAMMATORY BOWEL DISEASE DYSPLASIA PATHWAY
A separate carcinogenic pathway is described for inflammatory bowel syndrome that does not involve an adenoma-carcinoma sequence. Chronic inflammation, such as ulcerative colitis, can result in genetic alterations that promote dysplasia and carcinoma formation [179]. The elevated risk of colorectal cancer in ulcerative colitis and Crohn disease is mediated through an intermediate step of intraepithelial dysplasia [171].
POLYP-TO-CARCINOMA PATHWAYS OF COLORECTAL CARCINOGENESIS
The accumulation of acquired genetic and epigenetic changes transform normal epithelial cells into benign neoplasms (adenomas and sessile serrated polyps), invasive adenocarcinomas, and ultimately, metastatic colorectal cancer. The polyp-to-carcinoma progression sequence of colorectal carcinogenesis occurs through at least two well-recognized pathways: the CIN pathway and the MSI pathway [169].
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