Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA

摘要: Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection. Repeat biopsies study genomic therapy are difficult, invasive may be confounded by intra-tumour heterogeneity. Recent studies have shown that alterations in solid cancers can characterized massively parallel sequencing circulating cell-free tumour DNA released from cancer cells into plasma, representing non-invasive liquid biopsy. Here we report exomes serial plasma samples track metastatic response therapy. Six patients with advanced breast, ovarian lung were followed over 1-2 years. For each case, exome was performed on 2-5 (19 total) spanning multiple courses treatment, at selected time points when the allele fraction mutations high, allowing improved sensitivity. two cases, synchronous also analysed, confirming genome-wide representation genome plasma. Quantification fractions identified increased mutant alleles association emergence resistance. These included an activating mutation PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following paclitaxel; truncating RB1 (retinoblastoma 1) cisplatin; MED1 (mediator complex tamoxifen trastuzumab, subsequent lapatinib, splicing GAS6 (growth arrest-specific 6) same patient; resistance-conferring EGFR (epidermal growth factor receptor; T790M) gefitinib. results establish proof principle exome-wide analysis could complement current biopsy approaches identify associated acquired drug cancers. Serial genomes constitutes new paradigm for human