An mRNA expression-based signature for oncogene-induced replication-stress

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Oncogene-induced replication stress is a hallmark of aggressive cancers, yet identifying affected tumors is challenging.
• Targeting replication stress is a promising therapeutic strategy, necessitating reliable biomarkers.

Purpose of the Study:

• To develop and validate a gene expression signature for identifying oncogene-induced replication stress.
• To assess the prevalence of this stress signature across diverse cancer subtypes.

Main Methods:

• Engineered cancer cell lines to induce replication stress via oncogene overexpression (CDC25A, CCNE1, MYC).
• Performed RNA sequencing to identify differentially expressed genes.
• Analyzed large-scale patient tumor datasets (TCGA, GEO) for gene expression and oncogene amplification.
• Validated the signature using immunohistochemistry for NAT10 and DNA damage markers (phospho-RPA, γH2AX).

Main Results:

• Identified a 52-gene signature of oncogene-induced replication stress in cell lines.
• Developed a refined six-gene signature (NAT10, DDX27, ZNF48, C8ORF33, MOCS3, MPP6) by integrating cell line and patient data.
• NAT10 expression strongly correlated with DNA damage markers in breast cancer.
• Applied the signature to over 22,000 patient samples, revealing high replication stress in diffuse large B cell lymphoma, ovarian cancer, triple-negative breast cancer, and colorectal carcinoma.

Conclusions:

• The six-gene signature effectively identifies oncogene-induced replication stress.
• This signature can stratify patients and guide the development of replication stress-targeting therapies.
• Specific cancer subtypes exhibit a high burden of oncogene-induced replication stress, representing potential candidates for targeted treatments.