High resolution copy number inference in cancer using short-molecule nanopore sequencing

Area of Science:

• Genomics
• Molecular Biology
• Bioinformatics

Background:

• Genome copy number variations are crucial in health and disease, particularly in cancer.
• Short-read sequencing is standard for inferring Copy Number Alterations (CNAs) in precision oncology.
• Nanopore sequencing offers portability and lower cost but faces limitations in read yield for accurate CNA inference.

Purpose of the Study:

• To enhance the accuracy of CNA inference using Nanopore sequencing.
• To optimize Nanopore sequencing for increased read yield from short DNA molecules.
• To demonstrate the clinical utility of this improved Nanopore approach.

Main Methods:

• Targeted sequencing of short-length DNA molecules at optimized concentrations.
• Utilizing Nanopore sequencing technology to increase read/molecule yield per run.
• Applying the method to infer CNAs in acute myeloid leukemia samples.

Main Results:

• Short-molecule Nanopore sequencing reproducibly achieved high read counts.
• High-quality CNA inference was enabled by the optimized sequencing approach.
• Accurate CNA profiling was demonstrated in acute myeloid leukemia samples, outperforming traditional methods.

Conclusions:

• Short-molecule Nanopore sequencing provides a sensitive, accurate, cost-effective, and rapid method for CNA detection.
• This approach offers a viable framework for genomic analysis in research and clinical settings, including multiplex testing.
• The technology has broad applications beyond CNA inference, enhancing the utility of Nanopore sequencing.