A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations

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.