Pan-Cancer Genomic Scars of Alternative End Joining and Single-Strand Annealing

Area of Science:

• Genomics
• Molecular Biology
• Cancer Research

Background:

• DNA double-strand breaks (DSBs) are critical DNA lesions that can lead to genome instability and cancer.
• Homologous recombination (HR) is the primary high-fidelity repair pathway for DSBs.
• Error-prone pathways, single-strand annealing (SSA) and alternative end joining (Alt-EJ), act as backups, particularly in HR-deficient cells.

Purpose of the Study:

• To systematically analyze the genomic scars left by SSA and Alt-EJ across various cancer types.
• To investigate the relationship between these backup repair pathways and HR deficiency.
• To understand the influence of local genomic and transcriptional context on DSB repair pathway engagement.

Main Methods:

• Whole-genome sequencing of 2,157 tumors across 17 cancer types.
• Identification and characterization of SSA-like and Alt-EJ-like deletion signatures.
• Correlation analysis between deletion burdens, HR deficiency scores, and genomic features.

Main Results:

• Identified 832 SSA-like and 37,359 Alt-EJ-like deletions.
• Alt-EJ is the dominant backup pathway in HR-deficient tumors.
• Elevated SSA-like deletions were observed in prostate adenocarcinoma and hepatocellular carcinoma, irrespective of HR deficiency.
• SSA-like deletions show enrichment in SINE-rich regions and near transcription start sites in specific tumor types.

Conclusions:

• SSA and Alt-EJ repair pathways are active beyond HR-deficient contexts.
• The engagement of these backup pathways is significantly influenced by local genomic and transcriptional environments.
• Genomic scars provide insights into DSB repair mechanisms beyond HR deficiency, revealing distinct repair activities.