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Tissue-Specific Oncogenic Activity of KRASA146T
Emily J Poulin1,2, Asim K Bera3, Jia Lu3
1Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Cancer Discovery
|April 7, 2019
Summary
Specific KRAS mutations have distinct biological properties that influence their prevalence in different cancers. This study reveals how KRASA146T and KRASG12D mutations impact tissue homeostasis differently, explaining their varied occurrence in human cancers.
Area of Science:
- Oncology
- Molecular Biology
- Structural Biology
Background:
- KRAS is the most frequently mutated oncogene in cancer.
- The varying incidence of specific KRAS alleles across different cancer types suggests potential biological selection, but experimental evidence is limited.
Purpose of the Study:
- To investigate the biological differences between common KRASG12D and rare KRASA146T mutations.
- To determine if allele-specific signaling properties explain the tissue-specific mutational patterns of KRAS in human cancers.
Main Methods:
- Cross-disciplinary approach combining biochemical and structural studies.
- Analysis of KRASA146T structure and nucleotide binding.
- Use of genetically engineered mouse models expressing KRASG12D or KRASA146T.
Main Results:
- KRASA146T exhibits an extended switch 1 region, enhancing KRAS activation.
- KRASG12D and KRASA146T displayed distinct tissue-specific effects on homeostasis in mouse models.
- These tissue-specific effects correlated with the mutational frequencies of these alleles in human cancers.
Conclusions:
- The distinct signaling properties of KRAS mutants, such as KRASA146T and KRASG12D, drive their allele-specific selection in human cancers.
- Context-dependent signaling variations downstream of different KRAS mutants explain the observed mutational patterns in various cancer types.
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