Colorectal Cancer _ ___________________________________________________________________________
Chronic colorectal inflammatory disease is a risk factor for colorectal cancer, and such tumors may result from longstanding, continuous damage, inflammation, and repair (LOCDIR). LOCDIR changes cellular features of the epithelium, causing loss of cellular differentiation (loss of cellular mucus) and development of cellular atypia and mutations at multiple sites. DNA damage, with MSI and genomic instability, may arise within one year [183]. LOCDIR may play a role in the commonly observed inactivation of Kruppel-like factor 6 (KLF-6), a tumor-suppressor gene [184]. As cellular atypia increase, there may be progression from low- to high-grade dysplasia. After 10 or more years, carcinomas may develop without an exophytic feature. After 10 years of ulcerative colitis, the risk of colorectal cancer is 20 to 30 times that for a matched population. As an effective preventive measure, most patients with ulcerative colitis undergo total colectomy with ileostomy. A more controversial but also effective procedure is proctocolectomy with distal rectal mucosectomy. Although Crohn disease had long been thought to lack association with the development of colorectal cancers, it is now known that there is an 8% risk of developing colorectal cancer over a 20-year period. The problem of chronic inflammation with healing and epithelial changes at the cellular and molecular levels may be involved, as most of these cancers occur in strictured areas of the large bowel [179; 183]. SIGNALING PATHWAY DEREGULATION Important contributions to the pathogenesis of colorectal cancer come from accumulated mutations in specific genes and resultant deregulation in signaling pathways that mediate cell proliferation, differentiation, apoptosis, immortalization, angiogenesis, and invasion [169]. Transforming Growth Factor-Beta Pathway Transforming growth factor-beta signaling is a tumor-suppressor pathway in the colon. Deregulation in this pathway occurs by inactivating mutations in receptor genes, post-receptor signaling pathway genes, and transforming growth factor-beta superfamily members [169; 181]. Functionally significant mutations in TGFBR2 , a signaling receptor gene, are detected in up to 30% of all colorectal cancers. They are most common in MSI tumors but also occur in 15% of CIN tumors and are associated with transformation of late adenomas to malignancy. Mediators of Epidermal Growth Factor Receptor Signaling Mutations of PI3K pathway genes occur in up to 40% of colorectal cancer cases and may promote the transition from adenoma to carcinoma. PTEN , a tumor suppressor gene that negatively regulates PI3K signaling, is mutated in up to 30% of MSI tumors and 9% of CIN tumors. The PI3K pathway is modulated by epidermal growth factor receptor (EGFR) signaling in part via KRAS activation [169; 181].
The most clinically important oncogene in colorectal cancer, KRAS is a downstream effector of EGFR that signals (through BRAF) the activation of mitogen activated kinase (MAPK) pathways and promotion of cell growth and survival. KRAS mutations occur in roughly 40% of colorectal cancers, primarily in CIN tumors secondary to inactivating APC mutations [169; 181]. Mutated in roughly 10% to 15% of colorectal cancers, BRAF encodes a protein kinase that acts as the downstream effector of KRAS in the RAS/RAF/ MAPK signaling pathway. KRAS and BRAF mutations are mutually exclusive; activating mutation in either gene is sufficient to promote tumorigenesis via increased MAPK signaling. BRAF mutations are more frequent in MSI tumors (35%) than CIN tumors (5%) [169; 181]. PATIENT AND TUMOR CHARACTERISTICS ASSOCIATED WITH KRAS AND BRAF V600E MUTATIONS IN COLON CANCER KRAS and BRAF V600E mutations are important predictive and prognostic markers, respectively, in colon cancer, but until recently little has been known about the associated patient and clinical characteristics. Analysis of 2,326 patients with stage III colon cancer found that 35% showed KRAS mutations and 14% BRAF mutations, which were near-100% mutually exclusive [185]. KRAS mutations were more frequent in patients with negative family history of colon cancer and never smokers. Tumors with KRAS mutations were significantly less likely to have defective MMR (dMMR) and high-grade histology and were more often right-sided [185]. Tumors with BRAF V600E mutations were more frequent in patients 70 years of age or older and current or former smokers, and less frequent in non-Whites and men. Tumors with BRAF V600E mutations were more frequently right-sided, with four or more positive lymph nodes, high-grade histology, and dMMR [185]. PROGNOSTIC/PREDICTIVE RELATIONSHIP TO GENETIC/MOLECULAR PATHOLOGY Advances in the understanding of genetic and molecular alterations in the pathogenesis of colorectal cancer have been used to link specific gene mutations in colorectal cancer with treatment response and prognosis in colorectal cancer [169; 181; 186]: • MSI vs. CIN: Numerous studies have established a better prognosis, independent of colorectal cancer stage, in patients with MSI tumors and unfavorable prognosis with CIN tumor. • KRAS codon 12/13 mutations: Present in roughly 40% of colorectal cancers, strong evidence demonstrates this mutation predicts resistance to anti-EGFR therapy. • BRAF V600E mutations: Occurring in 10% of colorectal cancers, moderate evidence suggests this mutation is likely to predict resistance to anti-EGFR therapy.
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