Colorectal Cancer and Novel Biomarkers

Traditionally, predicting survival of patients newly diagnosed with colorectal cancer relies primarily on cancer stage and/or anatomic extent of colorectal cancer. The common system for cancer staging is the American Joint Committee on Cancer (AJCC) staging system based on tumor invasiveness, number of lymph nodes, and metastasis. However, such a system does not provide a very accurate prediction at the individual level. Recently, several molecular markers have been proposed to be used together with the AJCC staging system to improve accuracy of prognosis for colorectal cancer patients, and to facilitate the choice of optimal treatment modality.

About 15-20% of colorectal cancers have high frequency of microsatellite instability (MSI). Microsatellite instability is characterized by inactivation of mismatch repair (MMR) genes. This occurs in both sporadic colorectal cancer and in hereditary non-polyposis colorectal cancer (HNPCC). Colorectal cancers with microsatellite instability are more likely to locate in the proximal colon and are often poorly differentiated (Malesci et al., 2007). They also have considerable lymphocytic infiltration, are of mucinous histological type and more likely to metastasize (Alexander et al., 2001).

Colorectal cancers with microsatellite instability are more resistant to 5-FU therapy. Interestingly, Popat et al. (2005) conducted a meta-analysis (including more than 7000 patients) and showed that colorectal cancers with microsatellite instability have better overall survival in comparison to colorectal cancers with chromosomal instability.

Other important genomic identification includes LOH18q and p53. Loss of 18q is observed in 60-70% of colorectal cancer cases. Aschele et al. (2004) showed that patients with advanced stage II or stage III colorectal cancer have poorer prognosis with loss of 18q. Mutation of p53 is observed in half of colorectal cancer cases. However, it is unclear whether mutation of p53 has any effect on clinical outcome.

The use of gene expression profiling offers a method to identify patients with aggressive and treatment-resistant colorectal cancers. Eschrich et al (2005) used a cDNA microarray (with more than 30000 gene transcripts) and were able to predict 3-year survival with great accuracy. Eschrich et al (2005) also showed that use of molecular staging provides more accurate prognosis than Dukes staging.

In summary, molecular and genomic prognostic factors have great promises. However, the most reliable prognostic system at this moment is still tumor stage.

Alexander J, Watanabe T, Wu TT, et al. Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 2001;158:527–35.

Gafa R, Maestri I, Matteuzzi M, et al. Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer 2000;89:2025–37.

Malesci A, Laghi L, Bianchi P, et al. Reduced likelihood of metastases in patients with microsatellite-unstable colorectal cancer. Clin Cancer Res 2007;13:3831–9.

Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol 2005;23:609–18

Aschele C, Debernardis D, Lonardi S, et al. Deleted in colon cancer protein expression in colorectal cancer metastases: a major predictor of survival in patients with unresectable metastatic disease receiving palliative fluorouracil-based chemotherapy. J Clin Oncol 2004;22:3758–65.

Eschrich S, Yang I, Bloom G, et al. Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol 2005;23:3526–35.