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Cancer Discov DOI:10.1158/2159-8290.CD-11-0184

High-throughput detection of actionable genomic alterations in clinical tumor samples by targeted, massively parallel sequencing.

Publication TypeJournal Article
Year of Publication2012
AuthorsWagle, N, Berger, MF, Davis, MJ, Blumenstiel, B, DeFelice, M, Pochanard, P, Ducar, M, Van Hummelen, P, MacConaill, LE, Hahn, WC, Meyerson, M, Gabriel, SB, Garraway, LA
JournalCancer Discov
Volume2
Issue1
Pages82-93
Date Published2012 Jan
ISSN2159-8290
KeywordsCell Line, Tumor, DNA Mutational Analysis, Gene Dosage, High-Throughput Nucleotide Sequencing, Humans, Neoplasms
Abstract

UNLABELLED: Knowledge of "actionable" somatic genomic alterations present in each tumor (e.g., point mutations, small insertions/deletions, and copy-number alterations that direct therapeutic options) should facilitate individualized approaches to cancer treatment. However, clinical implementation of systematic genomic profiling has rarely been achieved beyond limited numbers of oncogene point mutations. To address this challenge, we utilized a targeted, massively parallel sequencing approach to detect tumor genomic alterations in formalin-fixed, paraffin-embedded (FFPE) tumor samples. Nearly 400-fold mean sequence coverage was achieved, and single-nucleotide sequence variants, small insertions/deletions, and chromosomal copynumber alterations were detected simultaneously with high accuracy compared with other methods in clinical use. Putatively actionable genomic alterations, including those that predict sensitivity or resistance to established and experimental therapies, were detected in each tumor sample tested. Thus, targeted deep sequencing of clinical tumor material may enable mutation-driven clinical trials and, ultimately, "personalized" cancer treatment.

SIGNIFICANCE: Despite the rapid proliferation of targeted therapeutic agents, systematic methods to profile clinically relevant tumor genomic alterations remain underdeveloped. We describe a sequencingbased approach to identifying genomic alterations in FFPE tumor samples. These studies affirm the feasibility and clinical utility of targeted sequencing in the oncology arena and provide a foundation for genomics-based stratification of cancer patients.

URLhttp://cancerdiscovery.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22585170
DOI10.1158/2159-8290.CD-11-0184
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22585170?dopt=Abstract

Alternate JournalCancer Discov
PubMed ID22585170
PubMed Central IDPMC3353152
Grant ListR33 CA155554-01 / CA / NCI NIH HHS / United States
P01 CA142536 / CA / NCI NIH HHS / United States
R33 CA155554-02 / CA / NCI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
R33 CA126674-04 / CA / NCI NIH HHS / United States
DP2OD002750 / OD / NIH HHS / United States
DP2 OD002750 / OD / NIH HHS / United States
U24CA143867 / CA / NCI NIH HHS / United States
R33 CA126674 / CA / NCI NIH HHS / United States
R33 CA155554 / CA / NCI NIH HHS / United States
R33CA126674 / CA / NCI NIH HHS / United States
U24 CA143867 / CA / NCI NIH HHS / United States