Replication stress defines distinct molecular subtypes across cancers

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Replication stress drives genomic instability and cancer development.
• Current methods for assessing replication stress are low-throughput and not widely applicable across diverse tumor types.

Purpose of the Study:

• To develop and validate a transcriptional profile for assessing replication stress.
• To define a gene signature (repstress) that characterizes tumors with replication stress.
• To explore the clinical implications of this repstress signature in cancer.

Main Methods:

• Leveraged established cellular characteristics associated with replication stress.
• Developed a gene signature (repstress) based on transcriptional profiles.
• Validated the signature across various tumor lineages and assessed its correlation with clinical outcomes and treatment response.

Main Results:

• The repstress gene signature identified a subset of tumors with specific molecular features: activated oncogenes, aneuploidy, extrachromosomal DNA amplification, immune evasion, high genomic instability, and poor survival.
• The repstress score demonstrated superior prediction of response to replication stress-targeting agents compared to existing transcriptomic measures.
• The signature revealed distinct molecular subtypes of cancer associated with replication stress, suggesting potential therapeutic vulnerabilities.

Conclusions:

• The repstress gene signature provides a robust molecular profile of replication stress in tumors.
• This signature offers novel biological insights into the replication stress phenotype and its role in tumorigenesis and cancer progression.
• The repstress score has significant clinical implications, potentially guiding treatment strategies for cancers dependent on replication stress pathways.