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  • Writer's pictureDr Edin Hamzić

🧬 The KRAS Gene & KRAS G12C Mutation

Updated: Jan 13

🧬 What Is the KRAS Gene?

  • The KRAS in the name of the KRAS gene stands for Kirsten rat sarcoma virus (KRAS).

🗺️ Who Discovered KRAS?

  • The gene got its name from the Rat sarcoma virus (Ras) that was discovered by Werner H. Kirsten, a cancer researcher, and consequently, Mr. Kirsten discovered the KRAS gene as well, which was an oncogene.

  • The KRAS gene is located on chromosome 12, and it is roughly 40000 bp long.

🕴️What Does the KRAS Gene Do?

  • As a majority of genes, the KRAS gene also encodes a protein, and in the case of the KRAS gene, it is the K-Ras protein.

❓ Is the KRAS Gene or Protein?

  • The abbreviation KRAS stands for Kirsten rat sarcoma virus based on which KRAS gene got its name, the KRAS gene encodes the K-Ras protein, and Ras in the protein’s name is an abbreviation of Rat sarcoma virus.

  • So, there is the KRAS gene and K-Ras protein that is encoded by the KRAS gene.

🧮How Many Amino Acids Are in KRAS? Is KRAS a Monomer?

  • K-Ras protein or KRAS protein is a monomeric protein that is roughly 21kDa long.

  • Monomeric means that KRAS protein is a monomer and can react together with other monomer molecules to form larger molecules called polymers which is just a chemical property of a given molecule.

  • There are two major isoforms of K-Ras protein and one is composed of 188 amino acids while the other is composed of 189 amino acids.

What Is the Function of the KRAS Protein?

  • The KRAS protein, like all Ras protein family members, belongs to a class of protein known as small GTPase and K-Ras is part of the RAS/MAPK signaling pathway.

  • GTPases are proteins, more specifically enzymes, that convert guanosine triphosphate (GTP) into guanosine diphosphate (GDP). This does not mean much to an average reader, but in this way, the K-Ras protein acts like a switch that is turned on and off by the GTP and GDP molecules and this is how K-Ras protein is actually involved in transmitting signals within cells.

  • To explain all of this in layman's terms, the KRAS protein behaves like a molecular switch. This conversion of GTP to GDP at the cellular level can be considered analogous to the computer transistor that can be used as a switch.

  • Above we mentioned that the KRAS protein is part of the RAS/MAPK pathway. This pathway is involved in relaying signals from outside the cell to the cell’s nucleus. These signals are very important as they instruct the cell to grow and multiply or to mature and specialize for a specific function.

🕴️What Happens if the KRAS Gene Is Mutated?

  • As it goes with genes they can mutate which means that some part of the gene sequence gets changed.

  • In the case of the KRAS gene, the MyCancerGenome database reports 65 biomarker mutations in the KRAS gene that are associated with different types of cancers.

  • Moreover, the KRAS gene is mutated in 15.95% of all cancers as reported by The AACR Project GENIE Consortium, and among those most common cancers are:

    • lung adenocarcinoma

    • pancreatic adenocarcinoma

    • colon adenocarcinoma

    • colorectal adenocarcinoma, and

    • rectal adenocarcinoma have the greatest prevalence.

🧬 What Are the Most Common Mutations in the KRAS Gene?

  • Within the RAS family, the KRAS gene is the most commonly mutated and is considered to be the most common oncogenic gene driver in human cancers. KRAS mutations are most common in pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer and here I refer to somatic mutations. To learn more about somatic mutations check my other blog post on this topic here.

  • The profile of KRAS mutations differs significantly depending on the type of cancer where they occur.

  • Generally, KRAS mutations are dominated by single-base missense mutations, 98% of which are found at codon 12 (G12), codon 13 (G13), or codon 61 (Q61) [reference].

  • Notably, KRAS mutations occur in many cancers with different mutation frequencies, but there is also a large variation in mutation subtypes

  • For example, in NSCLC, KRAS mutations account for 20.4% of KRAS, and the dominant substitution is G12C (glycine (GGT) to cysteine (TGT)).

  • In comparison, KRAS mutation accounts for up to 67.6% of KRAS in pancreatic adenocarcinoma, and KRAS (G12D) is the dominant mutant subtype.

  • It is important to note that the mutation rate of KRAS in the pancreas was 67.6% based on this acquired data analysis, which is lower than the commonly cited 90%.

  • The incidence of KRAS mutations between 25 and 35% in smokers and 5% in nonsmokers has been reported, and smoking is usually considered a relevant factor [reference].

  • Furthermore, the profiles of KRAS mutations are distinct in smokers and nonsmokers, and not all mutations in KRAS are driver mutations.

🧪 The KRAS G12C Genetic Testing

  • For instance, KRAS (G12C) is usually found in heavily smoking patients, while KRAS (G12D) is more usually identified in tumors from nonsmoking patients.

  • If the KRAS G12C mutation if present in adult patients locally advanced or metastatic non-small cell lung cancer (NSCLC) it is indicated to use sotorasib (brand name LUMAKRAS)

  • LUMAKRAS is a RAS GTPase family inhibitor, for adult patients with KRAS G12C mutated locally advanced or metastatic non-small cell lung cancer, as determined by an FDA approved test, who have received at least one prior systemic therapy.

  • The KRAS G12C genetic testing can be performed using FDA approved companion diagnostics for Lumakras:

    • QIAGEN therascreen® K-RAS RGQ PCR kit for use in tissue, and

    • the Guardant360® CDx for use in plasma

  • If no KRAS G12C mutation is detected in a plasma specimen, the tumor tissue should be tested.


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