Exome sequencing of contralateral breast cancer identifies metastatic disease
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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.
KeywordsBreast 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.
- 1.Globocan 2008 [http://globocan.iarc.fr]
- 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
- 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.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.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
- 11.Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, Adejola N, GÃ¼rel 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.SeqPrep [https://github.com/jstjohn/SeqPrep]. Accessed 10 March 2014
- 15.Picard [http://picard.sourceforge.net]. version 1.85. Accessed 10 Feb 2013
- 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.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.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