The Kirsten rat sarcoma virus gene (KRAS) is a focus in oncology due to its involvement in cellular signaling. This gene provides instructions for making a protein that acts as a molecular switch, controlling how cells grow, divide, and survive. Understanding the KRAS status in a patient’s tumor is mandatory for guiding treatment decisions. The term “Wild Type” (WT) refers to the natural, unmutated version of the gene, which functions normally. This article explores the biological significance of KRAS WT status and its implications for cancer therapy.
The Biological Role of KRAS
The KRAS protein is a member of the RAS family of small proteins that function as guanosine triphosphatases (GTPases). Positioned inside the cell membrane, it acts as a relay point for external signals. KRAS operates as a biological switch, cycling between an active state (bound to guanosine triphosphate, or GTP) and an inactive state (bound to guanosine diphosphate, or GDP).
In its active, GTP-bound form, KRAS initiates a cascade of signals, primarily through the RAS/MAPK (mitogen-activated protein kinase) pathway, promoting cell proliferation. When signaling is complete, KRAS hydrolyzes GTP back to GDP, turning the switch “off” and halting the growth signal. This precise regulation is essential for maintaining normal cell division.
Defining Wild Type Versus Mutant Status
The designation of KRAS Wild Type indicates that the gene sequence is structurally normal, meaning it has not acquired a cancer-driving mutation. A WT protein retains its intrinsic GTPase activity and remains fully responsive to regulatory mechanisms, correctly cycling between the active “on” and inactive “off” states.
In contrast, KRAS Mutant status means the gene contains a change in its DNA sequence, most frequently occurring at specific codons like G12 or G13. This mutation results in a structural defect that impairs the protein’s ability to hydrolyze GTP back to GDP. Consequently, the mutant protein gets perpetually stuck in the active, GTP-bound conformation.
This constant “on” state bypasses normal regulatory controls, leading to growth signals that drive tumor development. The WT protein is correctly regulated by upstream signals, whereas the mutant protein is constitutively active and independent of those controls. This fundamental difference dictates the selection of targeted therapies.
Diagnostic Testing for KRAS Status
Determining a patient’s KRAS status is typically performed on a biopsy sample of the tumor tissue to identify whether the DNA contains a KRAS mutation or the WT version. The primary assessment method is Next-Generation Sequencing (NGS), which rapidly and accurately analyzes multiple genes, including KRAS, for mutations across several key exons.
Older techniques, such as Sanger sequencing, are less sensitive in detecting low-frequency mutations compared to modern methods like NGS or Pyrosequencing. Pyrosequencing, a sequencing-by-synthesis method, offers higher sensitivity and can quantify the proportion of mutant alleles present in a tumor sample.
In cases where a tissue biopsy is not possible, a liquid biopsy may be used to analyze circulating tumor DNA (ctDNA) shed by the tumor into the bloodstream. Highly sensitive methods like droplet digital PCR (ddPCR) or NGS on ctDNA are employed in this context. Obtaining an accurate WT result confirms the absence of a known KRAS mutation, which is important for subsequent treatment planning.
Treatment Implications of KRAS Wild Type Status
The presence of KRAS Wild Type status is a positive prognostic indicator in several cancers, most notably metastatic colorectal cancer (mCRC). The WT result qualifies patients for targeted therapies that specifically block the Epidermal Growth Factor Receptor (EGFR) on the cell surface. These anti-EGFR monoclonal antibodies, such as cetuximab and panitumumab, interfere with the external signal that normally activates the KRAS pathway.
In a WT tumor, the KRAS protein remains dependent on the upstream EGFR signal to become active. Blocking the EGFR effectively shuts down the entire downstream growth pathway, which can lead to tumor shrinkage.
Conversely, anti-EGFR drugs are ineffective in patients with KRAS mutant tumors. This is because the mutant KRAS protein is already locked in the “on” position, making it impervious to blocking the upstream EGFR signal. The WT status confirms the tumor’s growth remains linked to the EGFR pathway, making it a viable therapeutic target for a precision medicine approach.