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A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations
Yiqun Zhang1, Patrick Kwok-Shing Ng2, Melanie Kucherlapati3
1Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
Molecular alterations involving the PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11,219 human cancers representing 32 major types. Within specific mutated genes, frequency, mutation hotspot residues, in silico predictions, and functional assays were all informative in distinguishing the subset of genetic variants more likely to have functional relevance. Multiple oncogenic pathways including PI3K/AKT/mTOR converged on similar sets of downstream transcriptional targets. In addition to mutation, structural variations and partial copy losses involving PTEN and STK11 showed evidence for having functional relevance. A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation.
Insights
This study analyzed molecular changes in the PI3K/AKT/mTOR pathway across 11,219 human cancers. It identified key genetic variants and alternative mechanisms driving pathway activation in various cancer types.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- The PI3K/AKT/mTOR pathway is frequently dysregulated in cancer.
- Understanding molecular alterations is crucial for targeted therapies.
Purpose of the Study:
- To comprehensively analyze molecular alterations within the PI3K/AKT/mTOR pathway across a large cohort of human cancers.
- To identify functionally relevant genetic variants and alternative mechanisms of pathway activation.
Main Methods:
- Analysis of mutation, copy number, protein, and RNA data from 11,219 human cancers across 32 types.
- In silico predictions and functional assays to assess variant relevance.
- Investigation of structural variations and copy losses in key genes (PTEN, STK11).
Main Results:
- Identified specific genetic variants with functional relevance in the PI3K/AKT/mTOR pathway.
- Demonstrated convergence of multiple oncogenic pathways on shared downstream targets.
- Revealed that a significant fraction of cancers exhibit high mTOR activity without canonical genetic alterations, including those with IDH1 or VHL mutations.
Conclusions:
- Molecular alterations in the PI3K/AKT/mTOR pathway are diverse and context-dependent.
- Multiple mechanisms contribute to pathway activation, highlighting the complexity of cancer signaling.
- Findings provide insights into potential therapeutic strategies targeting this critical pathway.
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