Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis

// Anne Bruun Krøigård 1, 2 , Martin Jakob Larsen 1, 2 , Anne-Vibeke Lænkholm 3 , Ann S. Knoop 4 , Jeanette D. Jensen 5 , Martin Bak 6 , Jan Mollenhauer 7, 8 , Torben A. Kruse 1, 2, 7 , Mads Thomassen 1, 2, 7 1 Department of Clinical Genetics, Odense University Hospital, 5000 Odense C, Denmark 2 Human Genetics, Institute of Clinical Research, University of Southern Denmark, 5000 Odense C, Denmark 3 Department of Pathology, Slagelse Hospital, 4200 Slagelse, Denmark 4 Department of Oncology, Rigshospitalet, 2100 Copenhagen, Denmark 5 Department of Oncology, Odense University Hospital, 5000 Odense C, Denmark 6 Department of Pathology, Odense University Hospital, 5000 Odense C, Denmark 7 Lundbeckfonden Center of Excellence NanoCAN, 5000 Odense C, Denmark 8 Molecular Oncology Group, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense C, Denmark Correspondence to: Anne Bruun Krøigård, e-mail: anne.kroeigaard@rsyd.dk Keywords: Breast cancer, Metastasis models, Copy number aberrations, Linear progression model Received: November 27, 2014      Accepted: January 08, 2015      Published: January 29, 2015 ABSTRACT Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer necessitates knowledge of the degree of genomic concordance between different steps of malignant progression as primary tumors often are used as surrogates of systemic disease. Based on exome sequencing we performed copy number profiling and point mutation detection on successive steps of breast cancer progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis. We identify a remarkable landscape of somatic mutations, retained throughout breast cancer progression and with new mutational events emerging at each step. Our data, contrary to the proposed model of early dissemination of metastatic cells and parallel progression of primary tumors and metastases, provide evidence of linear progression of breast cancer with relatively late dissemination from the primary tumor. The genomic discordance between the different stages of tumor evolution in this patient emphasizes the importance of molecular profiling of metastatic tissue directing molecularly targeted therapy at recurrence.