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Oncology- Multistep Carcinogenesis
I. The Driver Mutation Concept:
II. Progression from Benign to Malignant:
I. The Driver Mutation Concept:
- Origin: The idea of "driver mutations" emerged from sequencing studies, but the observation of frequent specific mutations in certain cancers predates this by over 20 years. These mutations are not random; they play a crucial role in initiating and driving cancer development.
- Initiating Events: Certain mutations are highly prevalent in specific cancers, suggesting they are initiating events. Examples include:
- APC: Frequently mutated in colorectal cancer (78-80%). Leads to benign polyps.
- KRAS: Frequently mutated in pancreatic ductal adenocarcinomas (up to 95%). Leads to pre-malignant PanINs.
- BRAF: Frequently mutated in benign nevi (skin moles), precursors to melanoma.
II. Progression from Benign to Malignant:
- Second Hits and Beyond: Progression from benign lesions to malignant tumors requires the acquisition of additional mutations ("second hits" and subsequent hits). These are not random; they often act in response to the effects of the initiating oncogene.
- Example: Overcoming Senescence: KRAS and BRAF mutations often induce cellular senescence (growth arrest), preventing further progression. However, mutations in genes that counteract senescence, such as p16, PTEN, and p53, allow the tumor to bypass this growth arrest and progress to malignancy.
- Multistep Progression: The multistep model is best exemplified in colon cancer. Following the initiating APC mutation, further mutations frequently occur in:
- KRAS
- TP53
- Genes in the TGFβ pathway
- Genes in the PI3 kinase pathway
- Pathway Involvement: Most colon cancers show mutations in at least three of these five pathways. While other mutations exist outside these pathways, their roles in tumor progression are less well understood and require further research.
- Driver vs. Passenger Mutations: Driver mutations are functionally important for tumor initiation and progression. Passenger mutations have no significant effect.
- Multistep Nature of Carcinogenesis: Cancer development is a multi-step process requiring accumulation of multiple mutations over time.
- Context-Specific Mutations: The importance of a specific mutation depends on the context of other mutations present within the cell.
- Therapeutic Implications: Understanding the specific driver mutations in a cancer helps to select targeted therapies.
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