DNA Damage Response and Repair Pathway Alteration and Its Association With Tumor Mutation Burden and Platinum-Based...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• DNA damage response (DDR) and repair pathway alterations are known biomarkers for platinum sensitivity.
• DDR alterations are increasingly recognized as predictive biomarkers for immune checkpoint inhibitors due to their correlation with tumor mutation burden (TMB).

Purpose of the Study:

• To investigate the correlation between DDR pathway alterations and TMB in small cell lung cancer (SCLC).
• To evaluate the predictive and prognostic value of DDR alterations and TMB in SCLC patients with extensive disease (ED) and limited disease (LD).

Main Methods:

• Target gene sequencing of 381 genes was performed on 100 ED and 66 LD SCLC patients.
• Mutations were classified into double-strand break (DSB) and single-strand break (SSB) repair pathways.
• Tumor mutation burden (TMB) was assessed, and correlations with DDR alterations and survival outcomes were analyzed.

Main Results:

• Patients with DDR alterations (homologous recombination, non-homologous end joining, mismatch repair, DSB, SSB) exhibited significantly higher TMB compared to those with intact DDR.
• In LD patients, higher TMB correlated with prolonged progression-free survival and overall survival following chemoradiotherapy.
• No significant survival benefit was observed for DDR alterations in ED patients receiving platinum chemotherapy, while Fanconi anemia gene mutations in LD patients were associated with shorter progression-free survival.

Conclusions:

• DDR pathway alterations in SCLC are positively correlated with high TMB, suggesting potential implications for immunotherapy.
• The predictive value of DDR alterations for platinum-based chemotherapy efficacy in SCLC appears limited.
• TMB may have prognostic value in LD SCLC patients treated with chemoradiotherapy.