NRAS Biomarker

The NRAS gene is a proto-oncogene responsible for the production of the NRAS protein. Proto-oncogenes typically play a role in regulating normal cellular processes and when mutated (now called an oncogene), have the potential to cause cancer.   

NRAS mutations have a very similar effect on cancer cells as KRAS mutations. However, they are much less common.  A wild-type NRAS (or normal) protein acts as an “on-and-off switch” involved in controlling cell growth, division, and survival. Mutated NRAS protein acts as an “on switch” resulting in uncontrollable cell growth and division, which can lead to cancer.  

The most common NRAS mutations are G12D, G12V, G12C, G12S, G12A, G12R, Q61K, and Q61R.  

These mutations are written to represent the location and types of amino acid being mutated within the protein. The letters represent the amino acids, building blocks of protein, that are produced from a gene that has been mutated. The number refers to the location of the mutation. The location can be thought of as the codon or the amino acid location – as codons are three nucleotide sequences in messenger RNA (mRNA) transcripts that “call” for a specific amino acid. 

Using G12D as an example, G and C represent the amino acids and 12 represents the location of the amino acid. In this case, glycine (G) got replaced by aspartic acid (D), while 12 refers to the 12^th codon in a mRNA transcript or amino acid in the protein sequence. 

NRAS mutations are rare, occurring in 3-5% of colorectal cancer cases. 

Patients with stage IV colorectal cancer should have their tumors tested for NRAS mutations. Patients with recurrent colorectal cancer at any stage should also have their tumors tested for NRAS mutations. NRAS mutation tumor testing is also useful in patients being considered for EGFR inhibitor treatment. 

The most common method for testing NRAS is using a tumor biopsy sample from the primary or metastatic tumor. Alternatively, a blood sample using circulating tumor DNA (ctDNA), also called a liquid biopsy may be used. NRAS may be tested individually or as part of a multi-gene panel. 

The best way to ensure you have been tested for NRAS mutations is to ask your medical care provider.   

A report for your tumor’s NRAS biomarker may be reported as “NRAS wild-type” or “NRAS WT” if there is no NRAS mutation present. If there is a NRAS mutation present, it may be listed as “NRAS mutant” or with the specific mutation, such as “NRAS Q61K” mutation, “NRAS codon 12 mutation,” or “NRAS exon 3 mutation.” 

NRAS mutations are much less common than KRAS mutations. NRAS mutations are found in only 5% of colorectal cancers. This means that approximately 95% of colorectal cancers are NRAS wild-type (WT). NRAS mutations involved in colorectal cancer are not hereditary. 

If your tumor has wild-type NRAS, you do not have a mutation within its NRAS gene.  

• Patients with wild-type NRAS tumors often benefit from targeted treatment with EGFR inhibitors (or anti-EGFR therapies). 
• Patients with wild-type NRAS tumors typically have a more favorably prognosis than those with NRAS mutations. 

If you have a tumor with mutant NRAS, it has a mutation within its NRAS gene.  

• Patients with mutant NRAS tumors often do NOT respond to targeted EGFR inhibitors and they are not recommended. Why not? EGFR inhibitors block the epidermal growth factor receptor (EGFR). Typically, wild-type RAS proteins are turned “on” or activated by EGFR. However, mutant RAS proteins are often always turned “on” or constitutively active. So, even if EGFR is inhibited by targeted therapies, mutant RAS proteins will still be “on” or active.   
• Treatment options for patients with mutant NRAS tumors often include traditional chemotherapy combinations. If indicated by other biomarker testing, other targeted treatments may be recommended for use in patients with NRAS mutant colorectal cancer. 
• Colorectal cancers with NRAS mutations are often more aggressive with a higher risk of occurrence. You should talk to your medical team about how you will be checked for recurrence during your follow-up care. 

There are currently no approved treatments directly targeting NRAS mutations in colorectal cancer. 

A NRAS-mutant colorectal cancer is often treated with traditional chemotherapy (FOLFOX, FOLFIRI, CAPOX) with or without bevacizumab. 

If indicated by other biomarker testing, other targeted treatments may be recommended for use in patients with NRAS mutant colorectal cancer. 

The most effective treatment varies by individual. It is best to speak with your medical team to learn more about the best treatment options for you. 

EGFR inhibitors, such as cetuximab or panitumumab, may be used as a stand-alone treatment or in combination with other traditional therapies (FOLFOX or FOLFIRI).  

The most effective treatment varies by individual. It is best to speak with your medical team to learn more about the best treatment options for you. 

Drugs targeting NRAS mutations are being tested in clinical trials. Talk to your medical team to determine if you may benefit from a clinical trial.  

Check out Fight CRC’s Clinical Trial Finder to search for trials for NRAS patients and read our Clinical Trials Conversations for important trials to consider.