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Genomic analysis of flow-sorted clonal tumor populations from breast cancer patients: Assessment of the clinically relevant genomic heterogeneity and clonal evolution

Research Project
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01.11.2011
 - 31.10.2013

Breast carcinomas are composed of different clonal populations with distinct population-specific genomic aberrations. This so-called genomic heterogeneity impacts the response to therapeutic regimens. The development of therapy resistance and metastases in breast cancer are clonal processes that are driven by genomic aberrations. It is generally accepted that cancer is caused and driven by a sequential accumulation of genomic aberrations (so-called mutations) in cancer-relevant genes. These mutations might affect only one or a few nucleotides (small scale mutations) or larger segments with an effect on the structure of a chromosome, as it is the case for deletions, amplifications and translocations. Although hundreds of these mutations have been reported in cancer and in breast cancer in particular, the impact of these mutations on cancer development has not been completely elucidated yet. Nevertheless, the detection of a genomic aberration can impact the cancer treatment decision and predict therapeutic response. Trastuzumab against HER2 amplified breast cancer and erlotinib against EGFR mutated lung cancer are two of the most prominent examples of such targeted cancer treatment. In the last decade, the rapid development and accessibility of novel technologies (such as array-CGH and deep-sequencing) has led to multiple genomic profiling studies with large patient cohorts, but only interrogating one tissue specimen per patient. Although intratumoral heterogeneity is a phenomenon that is widely accepted by clinicians and pathologist, it is usually not taken into consideration in the design of these studies. Heterogeneous tumors usually consist of multiple clonal tumor populations and these distinct populations can carry different genomic aberrations: a phenomenon called ?genomic heterogeneity?. This might be profoundly important since in the era of personalized medicine, the selection of patients for targeted therapeutics is more and more based on the presence of genomic aberrations. For this reason, in the last four years, we have developed an innovative and robust methodology for the detection and isolation of distinct clonal tumor populations from frozen patient biopsies. After separation, the distinct tumor populations are genomically characterized by array-CGH and deep sequencing. We have recently published this novel methodology and a proof of concept study in the journal PNAS. The primary objective of this study is the comprehensive analysis of the genomic heterogeneity in tumor biopsies from breast cancer patients. This study will provide novel information about the clonal composition of breast cancer, the population-specific genomic aberrations and their potential clinical relevance. Further, the analysis of multiple samples from the same patients (over time and during metastasis) will allow us to infer the genomic evolution and help us to understand which clonal populations and which specific genomic aberrations are responsible for the metastasis process and for the response to therapy in these breast cancer patients. The prevalence of novel population-specific genomic aberrations and the expression of the involved protein products will be determined by using a large tissue microarray with more than 2?300 breast cancer samples and complete clinical follow-up data.

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Lukas Bubendorf

Principal Investigator