Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes

Area of Science:

• Genomics
• Cancer Biology
• Translational Oncology

Background:

• Advanced and metastatic cancers with complex treatment histories are a major cause of cancer mortality.
• Understanding the genomic impact of therapies is crucial for improving outcomes in these patients.

Purpose of the Study:

• To describe the POG570 cohort, a comprehensive dataset integrating whole-genome, transcriptome, and clinical data.
• To explore the relationship between therapeutic exposures and genomic alterations in advanced cancers.

Main Methods:

• Whole-genome sequencing
• Transcriptome sequencing
• Clinical data analysis
• Identification of mutational signatures and genomic events

Main Results:

• DNA-damaging chemotherapies and mutations in DNA repair genes (e.g., POLQ, Polζ) correlate with genome-wide mutagenesis.
• Platinum therapies and DNA synthesis inhibitors are associated with specific mutational signatures (SBS31, DSB5, SBS17b).
• Gene alterations (ESR1, EGFR, CTNNB1, FGFR1, VEGFA, DPYD) reflect drug sensitivity/resistance; recurrent noncoding events identified in regulatory hotspots.
• Mutation burden and immune signatures correlate with overall survival and immunotherapy response.

Conclusions:

• The POG570 cohort provides a rich resource for studying advanced cancers.
• Genomic landscape analysis aids in interpreting sequencing data within a clinical context.
• Findings illuminate therapy-induced mutagenesis and its clinical implications for advanced cancer patients.