Colon tumor
Molecular pathways of colorectal carcinoma

Author: Charanjeet Singh, M.D. (see Authors page)

Revised: 8 August 2018, last major update September 2011

Copyright: (c) 2003-2018,, Inc.

PubMed Search: Molecular pathways AND colorectal carcinoma [title]
Cite this page: Singh, C. Molecular pathways of colorectal carcinoma. website. Accessed December 11th, 2018.
Chromosome instability pathway
  • 80% of carcinomas
  • Mutations in oncogenes and tumor suppressor genes, including: APC, beta catenin, Kras, BRAF, SMAD4, PTEN, p53 and bax (Arch Pathol Lab Med 2011;135:578)
  • Have altered total DNA content, cytogenetic aneuploidy and numerous allelic gains and losses
  • Important in familial adenomatous polyposis and variants (APC gene) and juvenile polyposis (DPC4, PTEN genes)
  • 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 70% + of colorectal carcinomas (Neoplasia 2008;10:680)
  • 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)
  • 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 (news item)
Microsatellite instability pathway
  • 15% of carcinomas
  • Have high (MSI-H) or low levels of instability (MSI-L)
  • Includes alterations in mismatch repair genes MSH2, MSH6, MLH1, PMS2 and genes whose alterations cause gross chromosomal abnormalities (BUB1, BUBR1, CDC4, Cancer Metastasis Rev 2004;23:11)
  • Inactivation of both alleles of nucleotide mismatch repair, usually hMSH2 or hMLH1, promotes tumorigenesis
  • Tumors have numerous nucleotide substitutions and insertion / deletion mutations in repeated nucleotide sequences (microsatellites), normal total DNA content and relatively normal cytogenetics with only infrequent allelic gains / losses
  • Either germline mutations (Lynch syndrome and variants) or sporadic due to promotion methylation - differentiate by BRAF - mutations present in about 40 - 50% of sporadic MSI-H tumors but absent in Lynch syndrome; this has implications in follow up (Arch Pathol Lab Med 2011;135:578)
  • Includes medullary, mucinous and signet ring cell carcinoma subtypes
  • Often present at earlier stage than other colon carcinomas (Am J Surg Pathol 2003;27:1393)
  • Frequent present in colon / stomach double primaries (Mod Pathol 2001;14:543)
  • Gross: usually right sided, expansive growth
  • Micro: tumor infiltrating lymphocytes, peritumoral lymphocytes, no "dirty" necrosis; may be associated with serrated adenomas
MYH pathway
  • Mutations in both copies of MUTYH / MYH repair gene; not well understood
  • Biallelic patients (mutations in both genes) have multiple adenomas (Hum Mutat 2006;27:1064)
  • 93× excess risk of colorectal carcinoma compared to normal controls, but account for < 1% of all cases (Am J Hum Genet 2005;77:112)
CpG island methylation pathway
  • 30% of carcinomas
  • Important mechanism of inactivating tumor suppressor genes in chromosomal instability pathway above (Curr Mol Med 2006;6:401, Cancer Metastasis Rev 2004;23:29)
  • CpG islands are 500 to 2000 base regions rich in cytosine-guanosine dinucleotide repeats present at 5' region in 50% of human genes
  • Methylation of cytosine residues in promoter regions and proximal exons of these islands represses transcription
  • May also have methylation of MLH1