Ras protein abundance correlates with Ras isoform mutation patterns in cancer.
Fiona E HoodYasmina M SahraouiRosalind E JenkinsIan A PriorPublished in: Oncogene (2023)
Activating mutations of Ras genes are often observed in cancer. The protein products of the three Ras genes are almost identical. However, for reasons that remain unclear, KRAS is far more frequently mutated than the other Ras isoforms in cancer and RASopathies. We have quantified HRAS, NRAS, KRAS4A and KRAS4B protein abundance across a large panel of cell lines and healthy tissues. We observe consistent patterns of KRAS > NRAS»HRAS protein expression in cells that correlate with the rank order of Ras mutation frequencies in cancer. Our data provide support for the model of a sweet-spot of Ras dosage mediating isoform-specific contributions to cancer and development. We suggest that in most cases, being the most abundant Ras isoform correlates with occupying the sweet-spot and that HRAS and NRAS expression is usually insufficient to promote oncogenesis when mutated. However, our results challenge the notion that rare codons mechanistically underpin the predominance of KRAS mutant cancers. Finally, direct measurement of mutant versus wildtype KRAS protein abundance revealed a frequent imbalance that may suggest additional non-gene duplication mechanisms for optimizing oncogenic Ras dosage.
Keyphrases
- wild type
- papillary thyroid
- squamous cell
- genome wide
- gene expression
- childhood cancer
- binding protein
- lymph node metastasis
- squamous cell carcinoma
- amino acid
- signaling pathway
- protein protein
- young adults
- dna methylation
- poor prognosis
- small molecule
- transcription factor
- antibiotic resistance genes
- genome wide identification
- copy number
- single cell
- genome wide analysis
- wastewater treatment
- data analysis