Colorectal Tumor Prognostic & Predictive Markers

Tissue-based markers are now available that can provide the GI oncologist with tools to help assess the clinical outcome in patients with colorectal adenocarcinoma and to help select appropriate therapies.

Microsatellite Instability, Mismatch Repair Genes, and Colonic Neoplasia

Microsatellite instability (MSI) due to defective mismatch repair genes has been reported in a subset of sporadic colorectal carcinomas and in the majority of tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Several studies have demonstrated that colorectal adenocarcinomas demonstrating microsatellite instability appear to be directly related to the altered expression of mismatch repair enzymes hMLH1, hMSH2, hMSH6, and hPMS2, which can be assessed by immunohistochemistry. Furthermore, studies have validated the high sensitivity and specificity of IHC for the detection of tumors with the MSI genotype. IHC is a highly accurate and cost effective method for identifying patients with microsatellite unstable tumors who should be investigated for HNPCC, offered long-term follow up, who may not respond to standard chemotherapy regimens, and appear to have more favorable clinical outcomes.


H&E	hMLH1	hMSH2
Right-sided colonic adenocarcinoma from a 45-year-old male showing ‘MSI’ phenotype of loss of expression of hMLH1 mismatch repair enzyme. Note retention of hMLH1 in nuclei of adjacent non-neoplastic cells. No loss of expression was found of hMSH2 (directly above) or of hMSH6 (not shown).

Thymidylate Synthase

Colorectal adenocarcinoma showing high levels of expression of thymidylate synthase, located predominantly in the nucleus.

Thymidylate synthase (TS) is both a prognostic and predictive marker for colorectal adenocarcinoma. As a prognostic marker, high levels of TS expression are a marker of adverse outcome in this tumor. TS plays an important role in pyrimidine nucleotide synthesis and represents a key target for 5-fluorouracil (5-FU) chemotherapy in colorectal adenocarcinoma. As a prognostic marker, high levels of TS, as demonstrated by immunohistochemistry, have been demonstrated to predict lack of response to 5-FU, both in the primary and metastatic setting.

DCC

Colorectal adenocarcinoma showing retention of the cytoplasmic DCC protein.

The deleted in colon cancer (DCC) gene is a putative tumor suppressor gene that encodes for a transmembrane protein that can be detected by immunohistochemistry. It is commonly expressed in most normal tissues, including normal colonic epithelium. Loss of expression of DCC protein has been shown to convey a poor prognosis in patients with primary colorectal adenocarcinoma and is also a strong predictor of survival in patients with unresectable, metastatic colorectal adenocarcinomas who are undergoing palliative FU-based chemotherapy.

Epidermal Growth Factor Receptor

The positive signal for EGFR is membranous, much like HER2 in breast cancers. However, unlike HER2, EGFR expression is generally heterogeneous, as shown in this image.

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that contains an extracellular ligand binding domain that binds to EGF and TGF-alpha, as well as an intracellular tyrosine kinase domain. EGFR expression has been shown to be a prognostic marker of adverse outcome in colorectal adenocarcinoma, but more recently, the expression of EGFR has been used to screen patients for eligibility for EGFR targeted therapies, e.g., Erbitux™ (cetuximab).

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