Dr. Vanessa Hayes, one of the world’s leading researchers in prostate cancer, shares her experience with Bionano genome mapping in her work. Prostate cancer is the second most prevalent cancer among men, and understanding the structure of prostate cancer genomes, namely large structural variations, is vital to unlocking new information about the disease.
Dr. Vanessa Hayes is the Lab Head of Human Comparative and Prostate Cancer Genomics at the Garvan Institute of Medical Research in Sydney, Australia, and holds the Petre Chair of Prostate Cancer Research Medicine at the University of Sydney. The Garvan Institute is one of Australia’s leading medical research institutes. Research at Garvan is focused on understanding the role of molecular and cellular processes in health and disease as the basis for developing future preventions, treatments, and cures.
Q: What are the goals of your research in prostate cancer genomics?
A: The objective of our research is to identify genomic signatures that can be used for the clinical management of prostate cancer, from determining risk to outcomes to treatment. We must determine which men will die with, rather than from, prostate cancer, not only to avoid mortality, but also to prevent over-treatment of non-lethal disease. As there are generally no early warning signs for prostate cancer, and no cure once the disease is metastatic disease, it is critical that we identify lethal prostate cancer early.
Q: Can you discuss the importance of revealing true genome structure in prostate cancer?
A: One in every four men will develop prostate cancer in their lifetime. Of these men, at least 10% will die as a direct result of prostate cancer. Prostate cancer is a genetic disease. It not only has the highest heritability rates of any adult cancer, but its disease course is driven by acquired genomic events. Prostate cancer also has a high degree of tumor genomic heterogeneity, which increases with mutagenesis and allows for clonal reseeding.
Q: In your work, what have you discovered regarding large structural variations in prostate cancer?
A: Unlike other adult cancers, prostate cancer has an overabundance of large complex structural variations over small single nucleotide variations (SNVs) and indels. These large structural variations appear to be early events in tumorigenesis and may persist or drive metastasis.
Q: How did you study structural variations prior to Bionano genome mapping?
A: Prior to mapping, we inferred structural variations using informatics tools for whole genome, paired-end, short-read sequencing data. As two-thirds of the human genome is made of repetitive sequences, detecting the full range of large structural variations is problematic, even using a combination of these inference tools.
Q: Can you provide examples where Bionano genome mapping revealed information other tools failed to provide?
A: Using Bionano next-generation mapping (NGM) technology, we identified a novel spectrum of large potentially oncogenic structural variations in prostate cancer that were largely not detectable using short-read next-generation sequencing (NGS) alone. Our data suggest that these genomic rearrangements are not only common, but are early events in tumor development.
We also found the total impact of these structural variations on the tumor genome far outweighs the impact of small somatic variants detectable using NGS. Additionally, we noted an abundance of large insertion (or duplication) events; the latter notably difficult to detect using NGS alone. Importantly, we identified much-needed potential actionable targets within patients with lethal metastatic prostate cancer.
With Bionano data, we can also interrogate NGS data further. Now, we can identify what were previously hidden signatures. The Bionano data therefore give NGS data an extra layer of information for interrogation.
Q: Are there additional areas where you plan to apply Bionano genome mapping and Bionano data?
A: Genomic rearrangements are common to many types of cancer. Detecting the full range and complement of these complex structural variations using NGS is problematic, as discussed. We plan to use the Bionano technology to interrogate additional cancer types, including those with chained, often inter-chromosomal fusion events resulting from a genome shattering and re-ligation event. Bionano technology provides a tool for the observation of these complex rearrangements in human cancers that goes beyond the signatures observed for prostate cancer.
Q: Where do you see Bionano in the future of cancer research?
A: As we move into the era of precision medicine, it is critical that we have the power to detect the large structural variations driving cancers. As the human genome is rife with hard-to-sequence repetitive elements, Bionano NGM is an optical, non-sequencing-based method that is not impacted by the limitations of NGS. In this case, we use Bionano NGM as a complementary technology to NGS to detect large structural variations and guide NGS analysis.
Bionano data gives NGS data orientation and location. Although the overlap between structural variations detected using NGM and NGS approaches are minimal, once armed with NGM localities, we see evidence in the NGS reads for a large number of these genomic rearrangements that are not detectable using NGS alone. This is of particular relevance for tumor genomes where low tumor purity and genomic heterogeneity mask somatic structural variation detection.
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