title: BreaKmer: detection of structural variation in targeted massively parallel sequencing data using kmers.
abstract: Genomic structural variation (SV), a common hallmark of cancer, has important predictive and therapeutic implications. However, accurately detecting SV using high-throughput sequencing data remains challenging, especially for 'targeted' resequencing efforts. This is critically important in the clinical setting where targeted resequencing is frequently being applied to rapidly assess clinically actionable mutations in tumor biopsies in a cost-effective manner. We present BreaKmer, a novel approach that uses a 'kmer' strategy to assemble misaligned sequence reads for predicting insertions, deletions, inversions, tandem duplications and translocations at base-pair resolution in targeted resequencing data. Variants are predicted by realigning an assembled consensus sequence created from sequence reads that were abnormally aligned to the reference genome. Using targeted resequencing data from tumor specimens with orthogonally validated SV, non-tumor samples and whole-genome sequencing data, BreaKmer had a 97.4% overall sensitivity for known events and predicted 17 positively validated, novel variants. Relative to four publically available algorithms, BreaKmer detected SV with increased sensitivity and limited calls in non-tumor samples, key features for variant analysis of tumor specimens in both the clinical and research settings.
authors.affiliation: Center for Cancer Genome Discovery and Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Abo
authors.affiliation: Center for Cancer Genome Discovery and Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ducar
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Garcia
authors.affiliation: Center for Cancer Genome Discovery and Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Thorner
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Rojas-Rudilla
authors.affiliation: Center for Cancer Genome Discovery and Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Center for Cancer Genome Discovery and Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: Center for Cancer Genome Discovery and Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors.forename: Neal I
authors.initials: NI
authors.lastname: Lindeman
authors.affiliation: Center for Cancer Genome Discovery and Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Van Hummelen
authors.affiliation: Center for Cancer Genome Discovery and Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA laura_macconaill@dfci.harvard.edu.
authors.forename: Laura E
authors.initials: LE
authors.lastname: MacConaill
mesh_terms: D001706:Biopsy; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D009696:Nucleic Acids / Q000737:chemistry / Q000235:genetics*; D017421:Sequence Analysis
chemical_list: D009696:Nucleic Acids