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.
