A sequence context-based approach for classifying tumor structural variants without paired normal samples.
Wolu Chukwu, Siyun Lee, Alexander Crane, Shu Zhang, Sophie Webster, Oumayma Dakhama, Ipsa Mittra, Carlos Rauert, Marcin Imielinski, Rameen Beroukhim, Frank Dubois, Simona Dalin
Author Information
Wolu Chukwu: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Siyun Lee: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Alexander Crane: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Shu Zhang: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Sophie Webster: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Oumayma Dakhama: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Ipsa Mittra: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Carlos Rauert: Charit��-Universit��tsmedizin Berlin, Corporate Member of Freie Universit��t Berlin, Humboldt-Universit��t zu Berlin, Institute of Pathology, Berlin, Germany.
Marcin Imielinski: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA; New York Genome Center, New York, NY, USA; Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA; Department of Pathology and Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA.
Rameen Beroukhim: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Frank Dubois: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Charit��-Universit��tsmedizin Berlin, Corporate Member of Freie Universit��t Berlin, Humboldt-Universit��t zu Berlin, Institute of Pathology, Berlin, Germany. Electronic address: frank.dubois@charite.de.
Simona Dalin: Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: sdalin@broadinstitute.org.
Although several recent studies have characterized structural variants (SVs) in germline and cancer genomes independently, the genomic contexts of these SVs have not been comprehensively compared. We examined similarities and differences between 2 million germline and 115 thousand tumor SVs from a cohort of 963 patients from The Cancer Genome Atlas. We found significant differences in features related to their genomic sequences and localization that suggest differences between SV-generating processes and selective pressures. For example, our results show that features linked to transposon-mediated processes are associated with germline SVs, while somatic SVs more frequently show features characteristic of chromoanagenesis. These genomic differences enabled us to develop a classifier-the Germline and Tumor Structural Variant or "the great GaTSV" -that accurately distinguishes between germline and cancer SVs in tumor samples that lack a matched normal sample.
