Colorectal Cancer Mutation Detection Panel

Available Products

*Includes all controls.  

KRAS, NRAS, BRAF, PIK3CA and AKT1 mutations and cancer

Colorectal cancer (CRC) develops through a progressive accumulation of genetic alterations that code for proteins involved in pathways downstream of the epidermal growth factor receptor (EGFR).  KRAS, NRAS, BRAF, PIK3CA and AKT1 somatic mutations are commonly found in CRC with prevalence of 36-40%, 1-6%, 8-10%, 10-30% and 1-6%, respectively.

The KRAS gene encodes a small GTPase that plays a key role in transducing signals from the epidermal growth factor receptor (EGFR) to downstream effectors. KRAS mutations have been commonly found in several types of human malignancies, such as metastatic colorectal cancer (mCRC), lung adenocarcinoma and thyroid cancer. The most common mutations are found in codons 12 and 13 of KRAS. Several studies have demonstrated that tumors carrying any of these mutant forms of the KRAS gene are less likely to respond to anti-EGFR antibody therapy (Van Cutsem et al. 2011). The American Society of Clinical Oncology (ASCO) recently released its first Provisional Clinical Opinion (PCO) suggesting that all patients to be administered anti-EGFR monoclonal antibody therapy (e.g. cetuximab, panitumumab and erlotnib) should be screened for KRAS mutations.  Recent studies have also shown that not all mCRC patients with wild-type KRAS tumors respond to anti-EGFR therapy (Shaib et al. 2013). This suggests that additional genes and/or pathways may be involved in the mechanism of resistance to these drugs. Mutations in BRAF, another downstream effector of the EGF-activated pathway, have been identified in up to 8-10% of mCRC tumors. Studies with mCRC patients have shown resistance to anti-EGFR therapy in patients with tumors expressing mutated BRAF (Di Nicolantonio et al. 2008). Those same individuals also had decreased progression-free (PFS) and overall (OS) survival when treated with EGFR antagonists.

In colon cancers without KRAS or BRAF mutation, the presence of an NRAS mutation is also linked to resistance to anti-EGFR therapy. NRAS is a member of the RAS family of GTPases and plays a central role in the MAPK signaling pathway.  Activating mutations in exon 2 (codon 12/13), exon 3 (codon 61), and exon 4 (codon 146) have been found in various cancers and are found in 1-6% of colorectal cancers. These findings strongly suggest that screening for KRAS, BRAF and NRAS mutations is necessary to more accurately identify tumor cells that will not respond to anti-EGFR drugs.

Additional biomarkers such as PIK3CA have been associated with a lack of response to anti-EGFR therapy (Mao et al. 2012), although their prognostic role is still a matter for debate. Nevertheless PIK3CA represents one of the most frequently mutated genes in CRC, with approximately 10%–30% of CRCs harboring PIK3CA activating mutations. These somatic mutations commonly occur in exon 9, which encodes the helical domain and exon 20, which encodes the kinase domain. The PIK3CA gene encodes the p110a subunit of phosphatidyl 3-kinase, a lipid involved in the PI3K-AKT-mTOR pathway that regulates cell growth, survival and proliferation. Another key protein that functions as a component of the PI3K signaling pathway is AKT1, a serine-threonine kinase. AKT1 is a downstream mediator of PI3 kinase. A somatic mutation that substitutes glutamic acid (E) with lysine (K) at amino acid position 17 results in a constitutively active form of the enzyme that is no longer dependent on activation of upstream components of the pathway. The AKT1 E17K mutation has been found in various cancers, including colon, lung and breast. Studies have shown that tumors harboring the AKT1 E17K mutation are less sensitive to AKT inhibitors (Carpten et al. 2007). Furthermore, tumors with the AKT1 E17K mutation are generally found to be negative for EGFR, KRAS and ALK driver mutations.

The table below lists the frequency of 5 common oncogenic mutations detected in CRC.

Kit Features

The Colorectal Cancer Mutation Detection Panel detects somatic mutations found in KRAS, NRAS, BRAF, PIK3CA and AKT1 genes. Below is a list of mutations detected by this kit.

Testing Procedure and Analysis

Equipment and Materials