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Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors.

Publication ,  Journal Article
Hovelson, DH; McDaniel, AS; Cani, AK; Johnson, B; Rhodes, K; Williams, PD; Bandla, S; Bien, G; Choppa, P; Hyland, F; Gottimukkala, R; Liu, G ...
Published in: Neoplasia
April 2015

Next-generation sequencing (NGS) has enabled genome-wide personalized oncology efforts at centers and companies with the specialty expertise and infrastructure required to identify and prioritize actionable variants. Such approaches are not scalable, preventing widespread adoption. Likewise, most targeted NGS approaches fail to assess key relevant genomic alteration classes. To address these challenges, we predefined the catalog of relevant solid tumor somatic genome variants (gain-of-function or loss-of-function mutations, high-level copy number alterations, and gene fusions) through comprehensive bioinformatics analysis of >700,000 samples. To detect these variants, we developed the Oncomine Comprehensive Panel (OCP), an integrative NGS-based assay [compatible with <20 ng of DNA/RNA from formalin-fixed paraffin-embedded (FFPE) tissues], coupled with an informatics pipeline to specifically identify relevant predefined variants and created a knowledge base of related potential treatments, current practice guidelines, and open clinical trials. We validated OCP using molecular standards and more than 300 FFPE tumor samples, achieving >95% accuracy for KRAS, epidermal growth factor receptor, and BRAF mutation detection as well as for ALK and TMPRSS2:ERG gene fusions. Associating positive variants with potential targeted treatments demonstrated that 6% to 42% of profiled samples (depending on cancer type) harbored alterations beyond routine molecular testing that were associated with approved or guideline-referenced therapies. As a translational research tool, OCP identified adaptive CTNNB1 amplifications/mutations in treated prostate cancers. Through predefining somatic variants in solid tumors and compiling associated potential treatment strategies, OCP represents a simplified, broadly applicable targeted NGS system with the potential to advance precision oncology efforts.

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Published In

Neoplasia

DOI

EISSN

1476-5586

Publication Date

April 2015

Volume

17

Issue

4

Start / End Page

385 / 399

Location

United States

Related Subject Headings

  • ras Proteins
  • beta Catenin
  • Transcriptional Regulator ERG
  • Trans-Activators
  • Serine Endopeptidases
  • Retrospective Studies
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins p21(ras)
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins
 

Citation

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Hovelson, D. H., McDaniel, A. S., Cani, A. K., Johnson, B., Rhodes, K., Williams, P. D., … Tomlins, S. A. (2015). Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors. Neoplasia, 17(4), 385–399. https://doi.org/10.1016/j.neo.2015.03.004
Hovelson, Daniel H., Andrew S. McDaniel, Andi K. Cani, Bryan Johnson, Kate Rhodes, Paul D. Williams, Santhoshi Bandla, et al. “Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors.Neoplasia 17, no. 4 (April 2015): 385–99. https://doi.org/10.1016/j.neo.2015.03.004.
Hovelson DH, McDaniel AS, Cani AK, Johnson B, Rhodes K, Williams PD, et al. Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors. Neoplasia. 2015 Apr;17(4):385–99.
Hovelson, Daniel H., et al. “Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors.Neoplasia, vol. 17, no. 4, Apr. 2015, pp. 385–99. Pubmed, doi:10.1016/j.neo.2015.03.004.
Hovelson DH, McDaniel AS, Cani AK, Johnson B, Rhodes K, Williams PD, Bandla S, Bien G, Choppa P, Hyland F, Gottimukkala R, Liu G, Manivannan M, Schageman J, Ballesteros-Villagrana E, Grasso CS, Quist MJ, Yadati V, Amin A, Siddiqui J, Betz BL, Knudsen KE, Cooney KA, Feng FY, Roh MH, Nelson PS, Liu C-J, Beer DG, Wyngaard P, Chinnaiyan AM, Sadis S, Rhodes DR, Tomlins SA. Development and validation of a scalable next-generation sequencing system for assessing relevant somatic variants in solid tumors. Neoplasia. 2015 Apr;17(4):385–399.
Journal cover image

Published In

Neoplasia

DOI

EISSN

1476-5586

Publication Date

April 2015

Volume

17

Issue

4

Start / End Page

385 / 399

Location

United States

Related Subject Headings

  • ras Proteins
  • beta Catenin
  • Transcriptional Regulator ERG
  • Trans-Activators
  • Serine Endopeptidases
  • Retrospective Studies
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins p21(ras)
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins