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Variation in cancer-causing KRAS mutations greater than thought

Variation in cancer-causing KRAS mutations greater than thought

A mutation at the amino acid glycine 12 (orange) of the KRAS protein (purple) has an effect on KRAS dynamics. Credit: Tatu Pantsar

The effects of KRAS mutations underlying many different types of cancer are more diverse than previously thought, according to a new study led by the University of Eastern Finland. Different mutations in the same amino acid of the KRAS protein have so varied effects on protein function that they may require different approaches when it comes to treatment and drug development.

The findings were published in PLOS Computational Biology.

Mutations occurring in the proteins of the human body often constitute a critical factor that predisposes to cancer development. In this sense, one of the most important proteins is KRAS, whose mutations play a role in the development of pancreatic cancer, among others. Point mutation of the glycine 12 amino acid of the KRAS protein can – depending on the mutation – cause glycine to mutate into any of the six possible different amino acids, all of which make the protein overactive. This causes uncontrolled cell growth and, consequently, the development of cancerous tissue.

Previously, all of the six different mutations occurring in the same location of the KRAS protein were regarded equal in their function. However, this may not be the case, as the newly published study now shows that these mutations are not fully random: different mutations occur more or less frequently in different tissue types. This suggests that different mutations may have a different effect on protein function.

The researchers conducted a thorough analysis of the effects of different mutations on protein function with the help of computer-simulated molecular dynamics. The simulation showed that different mutations have different effects on protein dynamics and, consequently, on protein function. These observed differences may partially explain why different mutations occur more or less frequently in different tissue types.

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