Breast Cancer Research and Treatment

, Volume 151, Issue 2, pp 319–324 | Cite as

Exome sequencing of contralateral breast cancer identifies metastatic disease

  • Daniel KlevebringEmail author
  • Johan Lindberg
  • Julia Rockberg
  • Camilla Hilliges
  • Per Hall
  • Maria Sandberg
  • Kamila Czene
Preclinical study


Women with contralateral breast cancer (CBC) have significantly worse prognosis compared to women with unilateral cancer. A possible explanation of the poor prognosis of patients with CBC is that in a subset of patients, the second cancer is not a new primary tumor but a metastasis of the first cancer that has potentially obtained aggressive characteristics through selection of treatment. Exome and whole-genome sequencing of solid tumors has previously been used to investigate the clonal relationship between primary tumors and metastases in several diseases. In order to assess the relationship between the first and the second cancer, we performed exome sequencing to identify somatic mutations in both first and second cancers, and compared paired normal tissue of 25 patients with metachronous CBC. For three patients, we identified shared somatic mutations indicating a common clonal origin thereby demonstrating that the second tumor is a metastasis of the first cancer, rather than a new primary cancer. Accordingly, these patients all developed distant metastasis within 3 years of the second diagnosis, compared with 7 out of 22 patients with non-shared somatic profiles. Genomic profiling of both tumors help the clinicians distinguish between true CBCs and subsequent metastases.


Breast cancer Contralateral Bilateral Recurrence Metastasis 



The authors would like to thank the Science for Life Laboratory Stockholm Application lab for sequencing and Gabriela Prochazka, Anna Westring, Simon Sundling, and Heidi Talvitie for help with library preparation of the samples.

Conflict of interest

The authors have no conflicts of interest.

Supplementary material

10549_2015_3403_MOESM1_ESM.pdf (44 kb)
(PDF 45 kb)


  1. 1.
    Globocan 2008 []
  2. 2.
    Brenner H, Engelsmann B, Stegmaier C, Ziegler H (1993) Clinical epidemiology of bilateral breast cancer. Cancer 72:3629–3635CrossRefPubMedGoogle Scholar
  3. 3.
    Hartman M, Czene K, Reilly M, Adolfsson J, Bergh J, Adami H-O, Dickman PW, Hall P (2007) Incidence and prognosis of synchronous and metachronous bilateral breast cancer. J Clin Oncol 25:4210–4216CrossRefPubMedGoogle Scholar
  4. 4.
    Janschek E, Kandioler-Eckersberger D, Ludwig C, Kappel S, Wolf B, Taucher S, Rudas M, Gnant M, Jakesz R (2001) Contralateral breast cancer: molecular differentiation between metastasis and second primary cancer. Breast Cancer Res Treat 67:1–8CrossRefPubMedGoogle Scholar
  5. 5.
    Imyanitov EN, Suspitsin EN, Grigoriev MY, Togo AV, Kuligina ES, Belogubova EV, Pozharisski KM, Turkevich EA, Rodriquez C, Cornelisse CJ, Hanson KP, Theillet C (2002) Concordance of allelic imbalance profiles in synchronous and metachronous bilateral breast carcinomas. Int J Cancer 100:557–564CrossRefPubMedGoogle Scholar
  6. 6.
    Brommesson S, Jönsson G, Strand C, Grabau D, Malmström P, Ringnér M, Fernö M, Hedenfalk I (2008) Tiling array-CGH for the assessment of genomic similarities among synchronous unilateral and bilateral invasive breast cancer tumor pairs. BMC Clin Pathol 8:6CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Teixeira MR, Ribeiro FR, Torres L, Pandis N, Andersen JA, Lothe RA, Heim S (2004) Assessment of clonal relationships in ipsilateral and bilateral multiple breast carcinomas by comparative genomic hybridisation and hierarchical clustering analysis. Br J Cancer 91(4):775–782PubMedCentralPubMedGoogle Scholar
  8. 8.
    Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, Ritchey JK, Young MA, Lamprecht T, Mclellan MD, Mcmichael JF, Wallis JW, Lu C, Shen D, Harris CC, Dooling DJ, Fulton RS, Fulton LL, Chen K, Schmidt H, Kalicki-Veizer J, Magrini VJ, Cook L, Mcgrath SD, Vickery TL, Wendl MC, Heath S, Watson MA, Link DC, Tomasson MH et al (2012) Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481:506–509CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Ding L, Ellis MJ, Li S, Larson DE, Chen K, Wallis JW, Harris CC, Mclellan MD, Fulton RS, Fulton LL, Abbott RM, Hoog J, Dooling DJ, Koboldt DC, Schmidt H, Kalicki J, Zhang Q, Chen L, Lin L, Wendl MC, Mcmichael JF, Magrini VJ, Cook L, Mcgrath SD, Vickery TL, Appelbaum E, Deschryver K, Davies S, Guintoli T, Lin L et al (2010) Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464:999–1005CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Van Allen EM, Foye A, Wagle N, Kim W, Carter SL, McKenna A, Simko JP, Garraway LA, Febbo PG (2013) Successful whole-exome sequencing from a prostate cancer bone metastasis biopsy. Prostate Cancer Prostatic Dis 17:23–27CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, Adejola N, Gürel M, Hicks J, Meeker AK, Halushka MK, Simons JW, Isaacs WB, De Marzo AM, Nelson WG, Yegnasubramanian S (2013) Tracking the clonal origin of lethal prostate cancer. J Clin Invest 123:4918–4922CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    SeqPrep []. Accessed 10 March 2014
  13. 13.
    Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R (2009) 1000 genome project data processing subgroup: the sequence alignment/map format and SAMtools. Bioinformatics 25:2078–2079CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Picard []. version 1.85. Accessed 10 Feb 2013
  16. 16.
    McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, Gabriel SB, Meyerson M, Lander ES, Getz G (2013) Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol 31:213–219CrossRefPubMedGoogle Scholar
  18. 18.
    Network Cancer Genome Atlas (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70CrossRefGoogle Scholar
  19. 19.
    Banelli B, Casciano I, Di Vinci A, Gatteschi B, Levaggi A, Carli F, Bighin C, Salvi S, Allemanni G, Ghiorzo P, Pronzato P, Venturini M, Romani M, Del Mastro L (2010) Pathological and molecular characteristics distinguishing contralateral metastatic from new primary breast cancer. Ann Oncol 21:1237–1242CrossRefPubMedGoogle Scholar
  20. 20.
    Bastien RR, guez-Lescure LR, Ebbert MT, Prat A, Rriz BM, Rowe L, Miller P, Ruiz-Borrego M, Anderson D, Lyons B, lvarez I, Dowell T, Wall D, Segu MN, Barley L, Boucher KM, Alba E, Pappas L, Davis CA, Aranda I, Fauron C, Stijleman IJ, Palacios J, Antón A, Carrasco E, Caballero RA, Ellis MJ, Nielsen TO, Perou CM, Astill M et al (2012) PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers. BMC Med Genomics 5(1):44CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Ivshina AV, George J, Senko O, Mow B, Putti TC, Smeds J, Lindahl T, Pawitan Y, Hall P, Nordgren H, Wong JEL, Liu ET, Bergh J, Kuznetsov VA, Miller LD (2006) Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Cancer Res 66:10292–10301CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
  2. 2.Science for Life LaboratoryStockholmSweden
  3. 3.Department of Oncology-PathologyKarolinska InstitutetStockholmSweden
  4. 4.Department of Clinical PathologyKarolinska University HospitalStockholmSweden
  5. 5.Institute of Environmental MedicineKarolinska InstitutetStockholmSweden

Personalised recommendations