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Published on: April 11, 2016
Rapid, ultra low coverage copy number profiling of cell-free DNA as a precision oncology screening strategy
Daniel H Hovelson1,2, Chia-Jen Liu1,3, Yugang Wang4
1Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Abstract:
Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization.
Insights
A new whole genome sequencing method for cell-free DNA (cfDNA) called PRINCe enables rapid, inexpensive cancer screening. This approach detects copy number alterations (CNAs) in advanced cancers, improving precision oncology strategies and treatment outcome predictions.
Area of Science:
- Genomics
- Oncology
- Molecular Diagnostics
Background:
- Current cell-free DNA (cfDNA) next-generation sequencing (NGS) in precision oncology is often limited to targeted or disease-specific panels.
- Advanced cancers present opportunities for precision oncology due to elevated tumor burden and cfDNA content.
- There is a need for broadly applicable, cost-effective cfDNA screening methods for advanced cancers.
Purpose of the Study:
- To demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome cfDNA NGS approach (PRINCe) for precision oncology screening.
- To determine cfDNA tumor content and profile genome-wide copy number alterations (CNAs) using ultra-low coverage sequencing.
- To assess the concordance of cfDNA and tissue-based NGS profiles and the association of cfDNA alterations with treatment outcomes in metastatic castration-resistant prostate cancer (mCRPC).
Main Methods:
- Applied the PRINCe method (whole genome cfDNA NGS at ~0.01x coverage) to 124 cfDNA samples from 100 patients with advanced cancers, including 76 with mCRPC.
- Analyzed cfDNA tumor content, focal CNAs, and performed concordance analyses with tissue-based NGS.
- Assessed associations between cfDNA alterations and mCRPC treatment outcomes.
Main Results:
- Therapeutically relevant focal CNAs were detected in 34% of cfDNA samples, including AR amplification in 39% of mCRPC samples.
- PRINCe identified pre-treatment cfDNA CNA profiles useful for disease monitoring.
- High concordance (median Pearson correlation = 0.87) was observed between genome-wide PRINCe cfDNA and matched tissue CNA profiles in mCRPC. PRINCe-detectable AR amplifications predicted reduced time on therapy (p < 0.0001).
Conclusions:
- The PRINCe approach enables robust, broadly applicable cfDNA-based precision oncology for advanced cancer patients.
- PRINCe facilitates scalable identification of therapeutically relevant CNAs and genomic profiles for pre- and post-treatment assessment.
- This screening strategy optimizes cfDNA- or tissue-based precision oncology workflows.
