Chromosome instability pathway
Reviewers: Shilpa Jain, M.D, New York University (see Reviewers page)
Revised: 31 October 2010, last major update September 2010
Copyright: (c) 2003-2010, PathologyOutlines.com, Inc.
● Common pathway in colorectal carcinoma
● Mutations in oncogenes and tumor suppressor genes, including APC, beta catenin, KRAS, BRAF, SMAD4, PTEN, p53 and bax
● Have altered total DNA content, cytogenetics, aneuploidy and numerous allelic gains and losses and translocations
● 70%+ of colorectal carcinomas (Neoplasia 2008;10:680)
● Alterations in beta catenin pathway appear to be important in ulcerative colitis related and sporadic colon carcinomas (Mod Pathol 2001;14:29)
● RAS signaling pathway (Kras, BRAF, NF1 and RASSF1A) shows dysregulation in at least one gene in 80%
● Activating Kras mutations found in 30-40%, associated with poor response to anti-EGFR therapies in primary (Virchows Arch 2008;453:417, N Engl J Med 2008;359:1757) or metastatic disease (J Clin Oncol 2008;26:1626, J Clin Oncol 2008;26:374)
● Important in familial adenomatous polyposis and variants (APC gene) and juvenile polyposis (DPC4, PTEN genes)
● High rate of concordance for Kras status between primaries and metastases (Oncologist 2008;13:1270)
● Patterns of Kras mutation vary based on germline mismatch repair defects and hMLH1 methylation status (Hum Mol Genet 2004;13:2303)
● Updated National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Colon Cancer now recommend that tumors from all patients with stage IV disease be tested for the Kras gene
● Only patients whose tumors have normal (wild-type) Kras should receive cetuximab and panitumumab
End of Colon tumor > Molecular pathways > Chromosome instability pathway
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