Molecular alterations and biomarkers in colorectal cancer

Abstract

The promise of precision medicine is now a clinical reality. Advances in our understanding of the molecular genetics of colorectal cancer (CRC) are leading to the development of a variety of biomarkers that are being used as early detection markers, prognostic markers, and markers for predicting treatment responses. This is no more evident than in the recent advances in testing CRCs for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor. In this review, we update a prior review published in 2010 and describe our current understanding of the molecular pathogenesis of CRC and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers), and the prediction of treatment responses (predictive markers).

Keywords: BRAF; EGFR; KRAS; MSI; biomarkers; cetuximab; chromosome instability; colon cancer; microsatellite instability; panitumumab..

Figure 1. The polyp-to-carcinoma progression sequence

Colorectal carcinogenesis progresses by at least two well-recognized pathways. The chromosome instability (CIN) pathway is characterized by classic tubular adenoma histology and the early acquisition of APC mutations that lead to deregulated WNT signaling, frequent activating mutations of the KRAS oncogene at the early adenoma stage, loss of heterozygosity at chromosome 18q (18qLOH) in late adenomas, and TP53 mutations that facilitate the transition to frank malignancy. By contrast, tumors that harbor microsatellite instability (MSI) frequently acquire BRAF mutations and are not associated with 18qLOH or TP53 mutations. Sporadic MSI cancers appear to commonly arise via the serrated neoplasia pathway, in which sessile serrated adenomas are the most frequently observed pre-cancerous lesions. (Modified from Pritchard and Grady(Pritchard and Grady))

Figure 2. Mediators of EGFR signaling and anti-EGFR antibodies

EGFR forms a homodimer after ligand activation, which results in phosphorylation/activation of the intra-cellular kinase domain and a cascade of downstream signaling including activation of the Ras/Raf/MAPK and phosphoinositol-3-kinase (PI3K) pathways that are associated with cell growth, differentiation, survival, and invasion. Monoclonal antibodies used to treat patients with metastatic colorectal cancer including cetuximab and panitumumab bind to the extracellular portion of EGFR and inhibit signaling in some patients. Activating mutations in KRAS occur in ∼40% of colorectal cancers and are thought to confer resistance to these drugs by bypassing the need for upstream EGFR signals. Activating mutations in BRAF – the direct downstream effector of KRAS – occur in ∼10% of colorectal cancers and also probably confer resistance to anti-EGFR monoclonal antibodies. Emerging evidence supports an additional role of oncogenic aberrations in the PI3K pathway in cetuximab and panitumumab resistance. Modified from Pritchard and Grady(Pritchard and Grady)