The Landscape of Alterations in DNA Damage Response Pathways in Colorectal Cancer

Area of Science:

• Oncology
• Genomics
• Cancer Biology

Background:

• Defective DNA damage response (DDR) is a key feature of cancer, contributing to genomic instability and influencing treatment response.
• While mismatch repair alterations in colorectal cancer are well-studied, the clinical impact of other DDR pathway defects remains less understood.

Purpose of the Study:

• To investigate alterations in DNA damage response (DDR) pathways in colorectal cancer.
• To explore the association between DDR gene mutations and clinical features in colorectal cancer patients.

Main Methods:

• Utilized next-generation sequencing and whole-transcriptome sequencing on patient samples.
• Classified tumors as DDR-mutant (DDR-MT) or DDR-wild type (DDR-WT) based on mutations in 29 DDR genes.

Main Results:

• 13.8% of 9,321 colorectal cancer patients were DDR-MT, with higher prevalence in microsatellite instability-high (MSI-H) tumors.
• DDR-MT tumors exhibited higher mutational burden and immune-related gene expression, independent of MSI status.
• Associations with clinical features like tumor location and specific mutations were often linked to MSI status.

Conclusions:

• Identified a distinct colorectal cancer subgroup with DDR gene mutations, frequently associated with MSI-H.
• DDR-mutant tumors display an activated immune signature irrespective of MSI status.
• These findings highlight the need for personalized treatment strategies for this patient subgroup.