Integrated digital error suppression for improved detection of circulating tumor DNA

Area of Science:

• Genomics and Molecular Biology
• Cancer Research
• Biotechnology

Background:

• Personalized cancer therapy relies on analyzing circulating tumor DNA (ctDNA).
• Low cell-free DNA (cfDNA) quantities and sequencing artifacts limit current ctDNA analysis sensitivity.
• Existing methods struggle with accurate noninvasive cancer detection and monitoring.

Purpose of the Study:

• To develop an advanced method for enhancing the analytical sensitivity of ctDNA sequencing.
• To overcome limitations posed by low cfDNA concentrations and sequencing errors in cancer profiling.
• To enable more accurate and sensitive noninvasive cancer detection and monitoring.

Main Methods:

• Introduction of an integrated digital error suppression (iDES) approach.
• Combination of in silico artifact elimination with molecular barcoding for cfDNA recovery.
• Application of iDES-enhanced Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq).

Main Results:

• The iDES method synergistically improved CAPP-Seq sensitivity by approximately 15-fold.
• Enabled noninvasive variant detection across hundreds of kilobases with high accuracy.
• Achieved 90% sensitivity and 96% specificity for patient-level non-small cell lung cancer (NSCLC) profiling.
• Demonstrated ctDNA monitoring down to 4 in 10^5 cfDNA molecules in NSCLC patients.

Conclusions:

• iDES significantly enhances the sensitivity and specificity of ctDNA analysis for personalized cancer therapy.
• The approach facilitates biopsy-free profiling and sensitive monitoring of NSCLC.
• iDES is poised to advance noninvasive genotyping and ctDNA detection in research and clinical settings.