Abstract In cancer personalized medicine, targeted treatments can produce dramatic tumor regression, but responses are often short-lived because of arisen resistant cancer cells. The major strategy proposed for overcoming resistance is a combination therapy. This approach requires a new method of diagnosis, the molecular fingerprint, an analysis of the tumor's genetic changes. A periodic monitoring of genetic changes has crucial role in targeted therapy. With the desire for this monitoring, a demand for non-invasive, indirect sampling without uncomfortable and painful biopsy has been increased. Fortunately, cell-free DNA in the blood consists of DNA derived from cancer tissues and has been studied for non-invasive diagnostic procedures. Nevertheless, this circulating DNA is rare in blood, and its detection is considered as a technical challenge. A number of methods have been examined, but identifying low level somatic mutations will continue to be a challenge for researchers because of limited sensitivity and specificity. Here, we developed a mutant specific enrichment system for somatic mutation to increase resolution of low level somatic changes within a high background of wild-types, and which is built into the InsightTM Onco Panel and is available in Next Generation Sequencer. This NGS based InsightTM Onco Lung Multiplex panel have been available with multiple analysis (about 60 mutations within EGFR, BRAF, KRAS, PIK3CA and HER2 genes) which can detect as few as 0.05% somatic changes in the background of wild-type DNA. We investigated analytic performance of the multiplex panel. Sensitivity was assessed using mixture of cell line DNA with low level of mutant alleles. Mutant-type (SW48, PC9, H1975, SNU601, Colo205 and HCT116) and wild-type (Hela) cell lines were processed to produce artificial mixture of mutant. Sample mixtures were analyzed by the InsightTM panel and general 454 sequencing. Furthermore, diagnostic possibility in the non-invasive samples was assessed using clinical plasma samples. The InsightTM Onco Lung Multiplex Panel showed significant detection of serially diluted target libraries as low as 0.05% of somatic mutations with dose-response manner. Moreover, the panel revealed a remarkable detection of low level somatic mutations in only 5ng of plasma DNA with significant concordant with mutant enrichment based q-PCR result (PNAClamp Real Time PCR). Moreover, these plasma results similarly reflect the results of 15ng of tissue FFPE samples. In conclusion, the InsightTM Onco Panel provides a reliable direction for non-invasive validation of acquired resistance to cancer therapy as well as mutant characterization for drug discovery and development. Citation Format: Deokhwe Hur, Minsik Song, Jinwook Jung, Heekyung Park. Ultra-sensitive multiplex analysis of somatic mutations in plasma DNA by InsightTM Onco mutant enrichment parallel sequencing for cancer personalized medicine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3565. doi:10.1158/1538-7445.AM2014-3565

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