title: Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs.
abstract: BACKGROUND
  Ovarian and triple-negative breast cancers with BRCA1 or BRCA2 loss are highly sensitive to treatment with PARP inhibitors and platinum-based cytotoxic agents and show an accumulation of genomic scars in the form of gross DNA copy number aberrations. Cancers without BRCA1 or BRCA2 loss but with accumulation of similar genomic scars also show increased sensitivity to platinum-based chemotherapy. Therefore, reliable biomarkers to identify DNA repair-deficient cancers prior to treatment may be useful for directing patients to platinum chemotherapy and possibly PARP inhibitors. Recently, three SNP array-based signatures of chromosomal instability were published that each quantitate a distinct type of genomic scar considered likely to be caused by improper DNA repair. They measure telomeric allelic imbalance (named NtAI), large scale transition (named LST), and loss of heterozygosity (named HRD-LOH), and it is suggested that these signatures may act as biomarkers for the state of DNA repair deficiency in a given cancer.
  
  
  RESULTS
  We explored the pan-cancer distribution of scores of the three signatures utilizing a panel of 5371 tumors representing 15 cancer types from The Cancer Genome Atlas, and found a good correlation between scores of the three signatures (Spearman's ρ 0.73-0.87). In addition we found that cancer types ordinarily receiving platinum as standard of care have higher median scores of all three signatures. Interestingly, we also found that smaller subpopulations of high-scoring tumors exist in most cancer types, including those for which platinum chemotherapy is not standard therapy.
  
  
  CONCLUSIONS
  Within several cancer types that are not ordinarily treated with platinum chemotherapy, we identified tumors with high levels of the three genomic biomarkers. These tumors represent identifiable subtypes of patients which may be strong candidates for clinical trials with PARP inhibitors or platinum-based chemotherapeutic regimens.
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 8, 2800 Lyngby, Denmark.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Marquard
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 8, 2800 Lyngby, Denmark.
authors.forename: Aron C
authors.initials: AC
authors.lastname: Eklund
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 8, 2800 Lyngby, Denmark.
authors.forename: Tejal
authors.initials: T
authors.lastname: Joshi
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 8, 2800 Lyngby, Denmark.
authors.forename: Marcin
authors.initials: M
authors.lastname: Krzystanek
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 8, 2800 Lyngby, Denmark.
authors.forename: Francesco
authors.initials: F
authors.lastname: Favero
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, 02215 Boston, Massachusetts USA.|Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, 02115 Boston, Massachusetts USA.
authors.forename: Zhigang C
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, 02115 Boston, Massachusetts USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, 02215 Boston, Massachusetts USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, 02215 Boston, Massachusetts USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Silver
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 8, 2800 Lyngby, Denmark.|Harvard Medical School, Children's Hospital Informatics Program at the Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology (CHIP@HST), 320 Longwood Avenue, Boston, Massachusetts USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 8, 2800 Lyngby, Denmark.
authors.forename: Nicolai J
authors.initials: NJ
authors.lastname: Birkbak
keywords: Cancer; Genomic scars; Homologous recombination deficiency