CNV Radar: An improved method for somatic copy number alteration characterization in oncology

David Soong, Jeran Stratford, Herve Avet-Loiseau, Nizar Bahlis, Faith Davies, Angela Dispenzieri, A. Kate Sasser, Jordan M. Schecter, Ming Qi, Chad Brown, Wendell Jones, Jonathan J. Keats, Daniel Auclair, Christopher Chiu, Jason Powers, Michael Schaffer

Research output: Contribution to journalArticle

Abstract

Background: Cancer associated copy number variation (CNV) events provide important information for identifying patient subgroups and suggesting treatment strategies. Technical and logistical issues, however, make it challenging to accurately detect abnormal copy number events in a cost-effective manner in clinical studies. Results: Here we present CNV Radar, a software tool that utilizes next-generation sequencing read depth information and variant allele frequency patterns, to infer the true copy number status of genes and genomic regions from whole exome sequencing data. Evaluation of CNV Radar in a public multiple myeloma dataset demonstrated that CNV Radar was able to detect a variety of CNVs associated with risk of progression, and we observed > 70% concordance with fluorescence in situ hybridization (FISH) results. Compared to other CNV callers, CNV Radar showed high sensitivity and specificity. Similar results were observed when comparing CNV Radar calls to single nucleotide polymorphism array results from acute myeloid leukemia and prostate cancer datasets available on TCGA. More importantly, CNV Radar demonstrated its utility in the clinical trial setting: in POLLUX and CASTOR, two phase 3 studies in patients with relapsed or refractory multiple myeloma, we observed a high concordance rate with FISH for del17p, a risk defining CNV event (88% in POLLUX and 90% in CASTOR), therefore allowing for efficacy assessments in clinically relevant disease subgroups. Our case studies also showed that CNV Radar is capable of detecting abnormalities such as copy-neutral loss of heterozygosity that elude other approaches. Conclusions: We demonstrated that CNV Radar is more sensitive than other CNV detection methods, accurately detects clinically important cytogenetic events, and allows for further interrogation of novel disease biology. Overall, CNV Radar exhibited high concordance with standard methods such as FISH, and its success in the POLLUX and CASTOR clinical trials demonstrated its potential utility for informing clinical and therapeutic decisions.

Original languageEnglish (US)
Article number98
JournalBMC bioinformatics
Volume21
Issue number1
DOIs
StatePublished - Mar 6 2020

Keywords

  • Acute myeloid leukemia
  • Copy number variation
  • Multiple myeloma
  • Next generation sequencing
  • Prostate cancer

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics

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    Soong, D., Stratford, J., Avet-Loiseau, H., Bahlis, N., Davies, F., Dispenzieri, A., Sasser, A. K., Schecter, J. M., Qi, M., Brown, C., Jones, W., Keats, J. J., Auclair, D., Chiu, C., Powers, J., & Schaffer, M. (2020). CNV Radar: An improved method for somatic copy number alteration characterization in oncology. BMC bioinformatics, 21(1), [98]. https://doi.org/10.1186/s12859-020-3397-x