1. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA.
- Author
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Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, Parkinson C, Chin SF, Kingsbury Z, Wong AS, Marass F, Humphray S, Hadfield J, Bentley D, Chin TM, Brenton JD, Caldas C, and Rosenfeld N
- Subjects
- Alleles, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Class I Phosphatidylinositol 3-Kinases, DNA Mutational Analysis, Drug Resistance, Neoplasm drug effects, ErbB Receptors genetics, Evolution, Molecular, Exome genetics, Female, Genome, Human genetics, Genomics, Humans, Intercellular Signaling Peptides and Proteins genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Mediator Complex Subunit 1 genetics, Neoplasms pathology, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology, Phosphatidylinositol 3-Kinases genetics, Retinoblastoma Protein genetics, Antineoplastic Agents therapeutic use, DNA, Neoplasm analysis, DNA, Neoplasm genetics, Drug Resistance, Neoplasm genetics, Neoplasms drug therapy, Neoplasms genetics, Plasma chemistry
- Abstract
Cancers acquire resistance to systemic treatment as a result of clonal evolution and selection. Repeat biopsies to study genomic evolution as a result of therapy are difficult, invasive and may be confounded by intra-tumour heterogeneity. Recent studies have shown that genomic alterations in solid cancers can be characterized by massively parallel sequencing of circulating cell-free tumour DNA released from cancer cells into plasma, representing a non-invasive liquid biopsy. Here we report sequencing of cancer exomes in serial plasma samples to track genomic evolution of metastatic cancers in response to therapy. Six patients with advanced breast, ovarian and lung cancers were followed over 1-2 years. For each case, exome sequencing was performed on 2-5 plasma samples (19 in total) spanning multiple courses of treatment, at selected time points when the allele fraction of tumour mutations in plasma was high, allowing improved sensitivity. For two cases, synchronous biopsies were also analysed, confirming genome-wide representation of the tumour genome in plasma. Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance. These included an activating mutation in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) following treatment with paclitaxel; a truncating mutation in RB1 (retinoblastoma 1) following treatment with cisplatin; a truncating mutation in MED1 (mediator complex subunit 1) following treatment with tamoxifen and trastuzumab, and following subsequent treatment with lapatinib, a splicing mutation in GAS6 (growth arrest-specific 6) in the same patient; and a resistance-conferring mutation in EGFR (epidermal growth factor receptor; T790M) following treatment with gefitinib. These results establish proof of principle that exome-wide analysis of circulating tumour DNA could complement current invasive biopsy approaches to identify mutations associated with acquired drug resistance in advanced cancers. Serial analysis of cancer genomes in plasma constitutes a new paradigm for the study of clonal evolution in human cancers.
- Published
- 2013
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