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Nucleic Acids Res. 2017 Nov 2;45(19):e162. doi: 10.1093/nar/gkx712.

Chromosome-scale mega-haplotypes enable digital karyotyping of cancer aneuploidy.

Author information

1
Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA.
2
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Department of Neurosurgery, Stanford University Hospital and Clinics, Stanford, CA 94305, USA.

Abstract

Genomic instability is a frequently occurring feature of cancer that involves large-scale structural alterations. These somatic changes in chromosome structure include duplication of entire chromosome arms and aneuploidy where chromosomes are duplicated beyond normal diploid content. However, the accurate determination of aneuploidy events in cancer genomes is a challenge. Recent advances in sequencing technology allow the characterization of haplotypes that extend megabases along the human genome using high molecular weight (HMW) DNA. For this study, we employed a library preparation method in which sequence reads have barcodes linked to single HMW DNA molecules. Barcode-linked reads are used to generate extended haplotypes on the order of megabases. We developed a method that leverages haplotypes to identify chromosomal segmental alterations in cancer and uses this information to join haplotypes together, thus extending the range of phased variants. With this approach, we identified mega-haplotypes that encompass entire chromosome arms. We characterized the chromosomal arm changes and aneuploidy events in a manner that offers similar information as a traditional karyotype but with the benefit of DNA sequence resolution. We applied this approach to characterize aneuploidy and chromosomal alterations from a series of primary colorectal cancers.

PMID:
28977555
PMCID:
PMC5737808
DOI:
10.1093/nar/gkx712
[Indexed for MEDLINE]
Free PMC Article

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