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Review: Pathways of Colorectal Carcinogenesis

Key findings

  • Although colorectal tumors are heterogenous at a genetic level, they appear to develop via one of several distinct pathways: chromosome instability, microsatellite instability or serrated neoplasia
  • Chromosome instability is observed in 65% to 70% of sporadic colorectal tumors, which tend to develop slowly over decades
  • Microsatellite instability is observed in nearly 15% of sporadic colorectal tumors and nearly all colorectal tumors in Lynch syndrome; these tumors are hypermutated and colorectal cancer develops within one to three years
  • Serrated polyps give rise to an estimated 15% of colorectal cancers; some of these tumors are characterized by microsatellite instability and progress rapidly
  • A group of colorectal tumors has been identified that are hypermutated in the absence of aneuploidy or microsatellite instability, suggestive of a new pathway of colorectal tumorigenesis

Colorectal cancer (CRC) is no longer considered a single disease entity. A wide variety of genetic and molecular changes mediate colorectal carcinogenesis, with dozens of somatic mutations identified to date. Still, all colorectal tumors appear to develop through one of several distinct pathways, notably chromosome instability, microsatellite instability or serrated neoplasia.

In GastroenterologyLong H. Nguyen, MD, MS, gastroenterology fellow in the Division of Gastroenterology at Massachusetts General Hospital, Daniel C. Chung, MD, gastroenterologist, medical co-director of the Center for Cancer Risk Assessment at the Mass General Cancer Center, and colleagues review these pathways and their implications for patient care.

Chromosome Instability Pathway

The chromosome instability (CIN) pathway is observed in 65% to 70% of sporadic colorectal tumors. CIN pathway tumors develop slowly, typically over decades. Its main feature is a high number of somatic copy number alterations caused by aneuploidy, deletions, insertions, amplifications or loss of heterozygosity.

These chromosomal abnormalities are coupled with:

  • Mutation of the adenomatous polyposis coli gene (APC), considered the earliest genetic event in colorectal tumorigenesis, in approximately 80% of CIN tumors
  • Activation of the Wnt pathway—an important regulator of intestinal epithelial cell proliferation—in nearly all CIN tumors
  • Inactivating mutations in the TP53 gene, which regulates DNA repair and cell responses to oxidative stress, in about 60% of CIN tumors
  • Activating mutations in KRAS, a component of several growth factor signaling pathways, including the epidermal growth factor receptor pathway
  • Activating mutations in PIK3CA, which helps regulate cell proliferation and survival

Microsatellite Instability Pathway

Cells in tumors with the microsatellite instability (MSI) phenotype do not properly detect and repair mismatched DNA, so they maintain and replicate their mutations and acquire additional mutations. This hypermutation phenotype is observed in nearly 15% of sporadic colorectal tumors and nearly all colorectal tumors that develop in patients with Lynch syndrome, the most common hereditary colon cancer syndrome.

APC mutations are found in 35% to 50% of MSI tumors, so the event that initiates adenoma formation might be shared by MSI and CIN tumors. However, a subset of MSI tumors develop because of an initiating BRAF mutation, and such tumors share traits of the MSI and serrated pathways. Because of hypermutation, CRC develops within one to three years in tumors with high levels of MSI.

The determination of MSI status is now routinely recommended as part of staging newly diagnosed CRC. There's growing consensus that adjuvant, single-agent, fluoropyrimidine-based chemotherapy is not effective and might even be harmful to patients with MSI-high CRC. On the other hand, MSI-high tumors are susceptible to treatment with PD-1 checkpoint inhibitors.

Serrated Neoplasia Pathway

Serrated polyps, as opposed to tubular adenomas, give rise to an estimated 15% of CRCs via the serrated neoplasia pathway. Serrated polyps are a heterogeneous group of lesions that includes benign hyperplastic polyps, precancerous sessile serrated adenomas or polyps and traditional serrated adenomas.

The initial event in the serrated pathway is the activating V600E mutation in BRAF. Afterward, serrated tumors develop via two different routes:

  • One route converges with the MSI pathway: Mutations in a DNA mismatch repair gene result in an MSI-high tumor. These tumors typically develop from sessile serrated adenomas
  • Alternatively, tumors can acquire TP53 mutations and activate several oncogenic pathways, including Wnt signaling, TGF-beta signaling and the epithelial-to-mesenchymal transition. Such tumors are microsatellite stable and typically develop through the traditional serrated adenoma as an intermediate lesion

The first subset of serrated tumors, those that become MSI-high, progress relatively rapidly from a precancerous lesion to carcinoma. A large proportion of interval CRCs (those that develop within recommended surveillance periods, typically three to five years) probably arise via the serrated pathway.

New Pathways

As published in Nature, through comprehensive molecular analysis, the Cancer Genome Atlas Network was the first to detect frequent mutations in polymerase epsilon (POLE), which helps regulate DNA synthesis, in colorectal tumors. Subsequent research has demonstrated that POLE mutations generate a hypermutated CRC phenotype with a high frequency of single-nucleotide variants in the absence of aneuploidy or MSI. APC mutations appear to be the initiating event in this pathway. Although these tumors do not have MSI, their hypermutated status makes them promising candidates for immunotherapy.

As researchers continue to genotype large panels of colorectal tumors, it can be expected that additional new pathways of CRC carcinogenesis will be recognized.

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Patients who had colorectal cancer diagnosed through screening or surveillance had a significantly better prognosis than patients who underwent colonoscopy because of symptoms.


According to prospective follow-up of more than 120,000 individuals, those with non-advanced adenoma or small sessile polyps did not have an increased risk of colorectal cancer.