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Oncotarget. 2017 Apr 4;8(14):23588-23602. doi: 10.18632/oncotarget.15802.

Next generation mapping reveals novel large genomic rearrangements in prostate cancer.

Author information

1
Laboratory for Human Comparative and Prostate Cancer Genomics, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
2
St Vincent's Clinical School, University of New South Wales, Randwick, Australia.
3
Bionano Genomics Inc., San Diego, California, USA.
4
Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
5
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Randwick, Australia.
6
School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa.
7
Central Clinical School, University of Sydney, Camperdown, Australia.

Abstract

Complex genomic rearrangements are common molecular events driving prostate carcinogenesis. Clinical significance, however, has yet to be fully elucidated. Detecting the full range and subtypes of large structural variants (SVs), greater than one kilobase in length, is challenging using clinically feasible next generation sequencing (NGS) technologies. Next generation mapping (NGM) is a new technology that allows for the interrogation of megabase length DNA molecules outside the detection range of single-base resolution NGS. In this study, we sought to determine the feasibility of using the Irys (Bionano Genomics Inc.) nanochannel NGM technology to generate whole genome maps of a primary prostate tumor and matched blood from a Gleason score 7 (4 + 3), ETS-fusion negative prostate cancer patient. With an effective mapped coverage of 35X and sequence coverage of 60X, and an estimated 43% tumor purity, we identified 85 large somatic structural rearrangements and 6,172 smaller somatic variants, respectively. The vast majority of the large SVs (89%), of which 73% are insertions, were not detectable ab initio using high-coverage short-read NGS. However, guided manual inspection of single NGS reads and de novo assembled scaffolds of NGM-derived candidate regions allowed for confirmation of 94% of these large SVs, with over a third impacting genes with oncogenic potential. From this single-patient study, the first cancer study to integrate NGS and NGM data, we hypothesise that there exists a novel spectrum of large genomic rearrangements in prostate cancer, that these large genomic rearrangements are likely early events in tumorigenesis, and they have potential to enhance taxonomy.

KEYWORDS:

next generation mapping; next generation sequencing; prostate cancer; structural genomic rearrangements

PMID:
28423598
PMCID:
PMC5410329
DOI:
10.18632/oncotarget.15802
[Indexed for MEDLINE]
Free PMC Article

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