KRAS Mutation G12V

[DCook54]

I am trying to understand KRAS mutations. I know I can count on you all to tell me the truth about what it means! Mine is G12V.

[catstaff]

K-RAS (Kirsten Rat Sarcoma, the "Kirsten" was the last name of the discoverer) is a protein that basically tells cells to divide. It switches between "off" and "on." KRAS is the corresponding gene with the instructions for this protein. When it is mutated, the "divide" signal stays on, resulting in uncontrolled growth. There are other RAS proteins but KRAS is very frequently mutated in human cancers. G12V means that at codon 12 of the gene, the DNA code that represents the amino acid glycine that is supposed to be there, is replaced by the code for valine. Similarly for G12D, which is more common but has similar consequences, the glycine is replaced by aspartic acid.

It's a mutation that is acquired over the course of the development of the cancer; it's not inborn.

The protein has a smooth structure so there aren't really any places for potential drugs to grab on to it. There is a new drug for the G13C mutation, which is rare in colorectal but fairly common in lung cancer. New drugs for G12D and V (and others) focus on other proteins that cells use for dividing.

The "always on" signal means that KRAS mutant cancers may grow and spread more rapidly than those with "wild type" KRAS.

[DCook54]

Thank you so much for this information. I appreciate you putting it in terms I can better understand. I find myself looking for any clue as to what my prognosis might be! I'm glad to know there are new developments on the horizon!

[Rock_Robster]

A very good summary above. The other clinical point worth noting is that the presence of a KRAS mutation all but guarantees that a particular tumour won’t respond to treatment with EGFR inhibitors (such as Erbitux and Vectibix), so these should not be used. Because of this, KRAS (and NRAS) mutated tumours have one fewer “line” of treatment available, which can explain a significant amount of the difference in average prognosis.

As KRAS vaccines start to be become available however it is very likely we’ll see this outcome gap start to narrow (and possibly even reverse).

[GrouseMan]

You particular KRAS mutation is not one of the common ones that have a known resistance to KRAS pathway inhibitors. KRAS mutations are usually activating ones that result in turning pathways on that promote the release of growth factors that promote tumor growth. Sometime EGFr Inhibitors can be used with colon cancer patients having Wild type KRAS. But seeing as most colon cancers have KRAS mutations most don't get long term benefit from EGFr inhibition because the tumors become resistant to these agents. My wife was on Erbitux for a while but she was KRAS wild and had some benefit from it. However since she had mets in per peritoneal cavity and this is hard to treat systemically it only slowed the growth most likely. Also those Mets might have had a different set of mutations that that of the primary used for the genetic testing.

The nomenclature here is the first letter is the normal amino acid found at that location in Wild type protein (12) followed by the one that replaces it. So in you case The mutation is that the Glycine (G) is replaced by Valine (V) in location 12.

Over all 44% of people with CRC have a KRAS mutation. There are other mutation in codons 13, 18, 61 and 117 as well. KRAS G13D is the most prominent of the codon 13 ones in CRC. Kras G12C (~3 to 4% in CRC) Kras G12D (~ 13% in CRC), and G12V (~9% in CRC).

Have a look at
https://en.wikipedia.org/wiki/KRAS
https://clincancerres.aacrjournals.org/ ... 0.full.pdf
https://www.nature.com/articles/srep08535

A Lot to digest here. One should note that even people without mutations in KRAS may have abnormally high levels of this gene that drives their cancer. The original thinking was tat if you had a mutation in Kras, EGFr Inhibitors would not work. That is changing as its been found that these mutations may be in fact vulnerable to new irreversible inhibitors.

Good Luck
GrouseMan