PBRM1 presents a potential ctDNA marker to monitor response to neoadjuvant chemotherapy in cervical cancer

Area of Science:

• Oncology
• Genetics
• Biomarker Discovery

Background:

• Neoadjuvant chemotherapy (NACT) is a standard treatment for locally advanced cervical cancer (LACC).
• Monitoring treatment response in LACC patients is crucial for optimizing outcomes.
• Liquid biopsy using circulating tumor DNA (ctDNA) offers a minimally invasive approach to track treatment dynamics.

Purpose of the Study:

• To identify novel liquid biopsy biomarkers for monitoring NACT response in LACC patients.
• To investigate the role of specific gene mutations in predicting treatment outcomes and resistance.
• To explore the therapeutic implications of identified biomarkers, particularly in relation to targeted therapies.

Main Methods:

• Targeted next-generation sequencing (NGS) of ctDNA and tumor tissue DNA (ttDNA) from LACC patients undergoing platinum-based NACT.
• Comparative analysis of mutation profiles between NACT responders and non-responders.
• In vitro experiments using cervical cancer cell lines to assess the functional impact of PBRM1 mutations on drug sensitivity.

Main Results:

• Sixty-four gene mutations were identified in non-responders but not in responders during NACT.
• PBRM1, SETD2, and ROS1 mutations were frequently detected in ctDNA and ttDNA of non-responders.
• Mutant PBRM1 was significantly associated with poorer patient survival and conferred resistance to cisplatin in vitro, while increasing sensitivity to olaparib.

Conclusions:

• Mutant PBRM1 in ctDNA can serve as a potential biomarker for emerging resistance to NACT in LACC.
• PBRM1 mutations may predict increased sensitivity to poly-ADP-ribose-polymerase (PARP) inhibitors like olaparib.
• Further clinical validation is warranted to establish mutant PBRM1 as a predictive biomarker for LACC treatment strategies.