title: Contralateral breast cancer can represent a metastatic spread of the first primary tumor: determination of clonal relationship between contralateral breast cancers using next-generation whole genome sequencing.
abstract: BACKGROUND
  By convention, a contralateral breast cancer (CBC) is treated as a new primary tumor, independent of the first cancer (BC1). Although there have been indications that the second tumor (BC2) sometimes may represent a metastatic spread of BC1, this has never been conclusively shown. We sought to apply next-generation sequencing to determine a "genetic barcode" for each tumor and reveal the clonal relationship of CBCs.
  
  
  METHODS
  Ten CBC patients with detailed clinical information and available fresh frozen tumor tissue were studied. Using low-coverage whole genome DNA-sequencing data for each tumor, chromosomal rearrangements were enumerated and copy number profiles were generated. Comparisons between tumors provided an estimate of clonal relatedness for tumor pairs within individual patients.
  
  
  RESULTS
  Between 15-256 rearrangements were detected in each tumor (median 87). For one patient, 76 % (68 out of 90) of the rearrangements were shared between BC1 and BC2, highly consistent with what has been seen for true primary-metastasis pairs (>50 %) and thus confirming a common clonal origin of the two tumors. For most of the remaining cases, BC1 and BC2 had similarly low overlap as unmatched randomized pairs of tumors from different individuals, suggesting the CBC to represent a new independent primary tumor.
  
  
  CONCLUSIONS
  Using rearrangement fingerprinting, we show for the first time with certainty that a contralateral BC2 can represent a metastatic spread of BC1. Given the poor prognosis of a generalized disease compared to a new primary tumor, these women need to be identified at diagnosis of CBC for appropriate determination of treatment. Our approach generates a promising new method to assess clonal relationship between tumors. Additional studies are required to confirm the frequency of CBCs representing metastatic events.
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. Sara.Alkner@med.lu.se.|Skåne Clinic of Oncology, Skåne University Hospital Lund, Lund, SE-22241, Sweden. Sara.Alkner@med.lu.se.
authors.forename: Sara
authors.initials: S
authors.lastname: Alkner
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. Man-Hung_Eric.Tang@med.lu.se.
authors.forename: Man-Hung Eric
authors.initials: MH
authors.lastname: Tang
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. christian.brueffer@med.lu.se.
authors.forename: Christian
authors.initials: C
authors.lastname: Brueffer
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. Malin.Dahlgren@med.lu.se.
authors.forename: Malin
authors.initials: M
authors.lastname: Dahlgren
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. Yilun.Chen@med.lu.se.
authors.forename: Yilun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. Eleonor.Olsson@med.lu.se.
authors.forename: Eleonor
authors.initials: E
authors.lastname: Olsson
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. christof.winter@med.lu.se.
authors.forename: Christof
authors.initials: C
authors.lastname: Winter
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. Sara.Baker@med.lu.se.
authors.forename: Sara
authors.initials: S
authors.lastname: Baker
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. anna.ehinger@med.lu.se.|Department of Pathology and Cytology, Blekinge County Hospital, Karlskrona, SE-37185, Sweden. anna.ehinger@med.lu.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Ehinger
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. Lisa.Ryden@med.lu.se.|Clinic of Surgery, Skåne University Hospital Lund, Lund, SE-22241, Sweden. Lisa.Ryden@med.lu.se.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rydén
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. Lao.Saal@med.lu.se.
authors.forename: Lao H
authors.initials: LH
authors.lastname: Saal
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. Marten.Ferno@med.lu.se.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fernö
authors.affiliation: Division of Oncology and Pathology, Clinical Sciences Lund, Lund University, MV 404-B2, Lund, SE-22381, Sweden. Sofia.Gruvberger@med.lu.se.
authors.forename: Sofia K
authors.initials: SK
authors.lastname: Gruvberger-Saal
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000473:pathology*