Alterations in DNA Damage Repair Genes in Primary Liver Cancer

Area of Science:

• Genomics
• Oncology
• Molecular Biology

Background:

• Alterations in DNA damage repair (DDR) genes are established therapeutic biomarkers.
• The specific characteristics and clinical significance of DDR alterations in primary liver cancer (PLC) are not well-defined.

Purpose of the Study:

• To investigate the landscape of DDR gene alterations in primary liver cancer (PLC).
• To determine the association of DDR alterations with genetic and clinicopathologic features.
• To evaluate the potential of DDR alterations as biomarkers for precision oncology in PLC.

Main Methods:

• A cohort of 357 PLC patients (including hepatocellular carcinoma, ICC, and mixed types) was enrolled.
• Targeted next-generation sequencing of 450 cancer-related genes, including 31 DDR genes, was performed on tumor and blood samples.
• The OncoKB knowledge database was used to identify actionable alterations, and treatment decisions were made by a multidisciplinary tumor board.

Main Results:

• 25.8% of PLC patients (92/357) harbored at least one DDR gene mutation, with 15 having germline mutations.
• ATM (5%) and BRCA1/2 (4.8%) were the most frequently altered DDR genes.
• DDR mutations correlated with higher tumor mutation burden. Actionable alterations were identified in 26.1% of DDR-mutated PLC cases. Patients with BRCA mutations treated with olaparib showed objective responses.

Conclusions:

• The study identified a significant prevalence of DDR gene mutations in primary liver cancer.
• These DDR alterations are associated with higher tumor mutational burden and actionable targets.
• Patients with DDR-altered PLC are potential candidates for precision oncology treatments.