Gene Copy Number Estimation from Targeted Next-Generation Sequencing of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification.
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Authors
Seed, G
Yuan, W
Mateo, J
Carreira, S
Bertan, C
Lambros, M
Boysen, G
Ferraldeschi, R
Miranda, S
Figueiredo, I
Riisnaes, R
Crespo, M
Rodrigues, DN
Talevich, E
Robinson, DR
Kunju, LP
Wu, Y-M
Lonigro, R
Sandhu, S
Chinnaiyan, AM
de Bono, JS
Yuan, W
Mateo, J
Carreira, S
Bertan, C
Lambros, M
Boysen, G
Ferraldeschi, R
Miranda, S
Figueiredo, I
Riisnaes, R
Crespo, M
Rodrigues, DN
Talevich, E
Robinson, DR
Kunju, LP
Wu, Y-M
Lonigro, R
Sandhu, S
Chinnaiyan, AM
de Bono, JS
Document Type
Journal Article
Date
2017-10-15
Date Accepted
2017-07-19
Abstract
Purpose: Precise detection of copy number aberrations (CNA) from tumor biopsies is critically important to the treatment of metastatic prostate cancer. The use of targeted panel next-generation sequencing (NGS) is inexpensive, high throughput, and easily feasible, allowing single-nucleotide variant calls, but CNA estimation from this remains challenging.Experimental Design: We evaluated CNVkit for CNA identification from amplicon-based targeted NGS in a cohort of 110 fresh castration-resistant prostate cancer biopsies and used capture-based whole-exome sequencing (WES), array comparative genomic hybridization (aCGH), and FISH to explore the viability of this approach.Results: We showed that this method produced highly reproducible CNA results (r = 0.92), with the use of pooled germline DNA as a coverage reference supporting precise CNA estimation. CNA estimates from targeted NGS were comparable with WES (r = 0.86) and aCGH (r = 0.7); for key selected genes (BRCA2, MYC, PIK3CA, PTEN, and RB1), CNA estimation correlated well with WES (r = 0.91) and aCGH (r = 0.84) results. The frequency of CNAs in our population was comparable with that previously described (i.e., deep deletions: BRCA2 4.5%; RB1 8.2%; PTEN 15.5%; amplification: AR 45.5%; gain: MYC 31.8%). We also showed, utilizing FISH, that CNA estimation can be impacted by intratumor heterogeneity and demonstrated that tumor microdissection allows NGS to provide more precise CNA estimates.Conclusions: Targeted NGS and CNVkit-based analyses provide a robust, precise, high-throughput, and cost-effective method for CNA estimation for the delivery of more precise patient care. Clin Cancer Res; 23(20); 6070-7. ©2017 AACR.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (20), pp. 6070 - 6077
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Prostate Cancer Targeted Therapy Group