Profound Tissue Specificity in Proliferation Control Underlies Cancer Drivers and Aneuploidy Patterns

Area of Science:

• Genomics
• Cancer Biology
• Molecular Genetics

Background:

• Cancer is characterized by uncontrolled cell proliferation.
• Identifying oncogenic drivers, especially those acting via gene dosage, remains a challenge.
• Genomics has detailed cancer genome structures, but functional driver identification needs refinement.

Purpose of the Study:

• To identify genes regulating cancer cell proliferation across different human cell types.
• To investigate the relationship between proliferation regulators and somatic copy number alterations (SCNAs) in tumors.
• To understand the genetic network architecture underlying SCNA and driver selection in cancer.

Main Methods:

• Construction of modular, barcoded libraries of human open reading frames (ORFs).
• High-throughput screening of ORF libraries to identify proliferation regulators in multiple cell types.
• Analysis of gene enrichment in SCNA data from corresponding tumors.
• In vivo screening to validate findings.

Main Results:

• Approximately 10% of genes were identified as proliferation regulators.
• Most identified proliferation regulators exhibited high tissue specificity.
• Proliferation drivers showed significant enrichment in SCNAs within cognate tumors.
• SCNA-associated drivers helped predict aneuploidy patterns in tumors.
• 147 amplified and 107 deleted genes were identified as potential SCNA-associated drivers.

Conclusions:

• Tissue-specific genetic networks influence SCNA and driver selection in different cancer types.
• SCNAs are linked to specific proliferation drivers in a context-dependent manner.
• This study significantly expands the catalog of SCNA-associated cancer drivers and provides insights into tumor aneuploidy architecture.