Genetic and epigenetic biomarkers for diagnosis, prognosis and treatment of colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most common cancer worldwide and results from the accumulation of mutations and epimutations in colonic mucosa cells ultimately leading to cell proliferation and metastasis. Unfortunately, CRC prognosis is still poor and the search of novel diagnostic and prognostic biomarkers is highly desired to prevent CRC-related deaths. The present article aims to summarize the most recent findings concerning the use of either genetic or epigenetic (mainly related to DNA methylation) biomarkers for CRC diagnosis, prognosis, and response to treatment. Recent large-scale DNA methylation studies suggest that CRC can be divided into several subtypes according to the frequency of DNA methylation and those of mutations in key CRC genes, and that this is reflected by different prognostic outcomes. Increasing evidence suggests that the analysis of DNA methylation in blood or fecal specimens could represent a valuable non-invasive diagnostic tool for CRC. Moreover, a broad spectrum of studies indicates that the inter-individual response to chemotherapeutic treatments depends on both epigenetic modifications and genetic mutations occurring in colorectal cancer cells, thereby opening the way for a personalized medicine. Overall, combining genetic and epigenetic data might represent the most promising tool for a proper diagnostic, prognostic and therapeutic approach.

Keywords: APC; Colorectal cancer; DNA methylation; Diagnostic biomarkers; Epigenetic biomarkers; Genetic biomarkers; KRAS; MGMT.

Figure 1

Representation of epidermal growth factor receptor pathway in response to therapy with anti-epidermal growth factor receptor inhibitors in wild-type and mutant patients. A: The binding of monoclonal antibodies (mAb) to EGFR normally causes the blockage (indicated with a red cross) of downstream RAS/RAF/MAPK and PI3K/AKT/mTOR signalling pathways and so the blockage of gene expression and cell cycle progression; B: Mutations in any gene of this pathway (indicated with a red star) cause a constitutive activation of the pathway leading to gene expression, upregulated proliferation, impaired differentiation and no response to monoclonal inhibitors. EGFR: Epidermal growth factor receptor; KRAS: v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog gene; BRAF: V-raf murine sarcoma viral oncogenes homolog B1; MEK: MAPK/ERK kinase; ERK: Extracellular signal-regulated kinases; PTEN: Phosphatase and tensin homolog; PI3K: Phosphatidylinositide-3-kinases; AKT: Protein Kinase B (PKB); mTOR: Mammalian target of rapamycin.

Figure 2

Sources of epigenetic biomarkers of colorectal cancer. Blood and fecal DNA samples represent available non-invasive sources of epigenetic diagnostic biomarkers of colorectal cancer, such as the analysis of methylation of septin 9 (SEPT9) and vimentin (VIM) genes, respectively. In addition, the analysis of DNA samples from bioptic tumor tissues could be of relevance for the best choice of therapeutic intervention.