Abstract
Advances in whole genome amplification and next-generation sequencing methods have enabled genomic analyses of single cells, and these techniques are now beginning to be used to detect genomic lesions in individual cancer cells. Previous approaches have been unable to resolve genomic differences in complex mixtures of cells, such as heterogeneous tumors, despite the importance of characterizing such tumors for cancer treatment. Sequencing of single cells is likely to improve several aspects of medicine, including the early detection of rare tumor cells, monitoring of circulating tumor cells (CTCs), measuring intratumor heterogeneity, and guiding chemotherapy. In this review we discuss the challenges and technical aspects of single-cell sequencing, with a strong focus on genomic copy number, and discuss how this information can be used to diagnose and treat cancer patients.
Highlights
Background genomic profiling by microarray comparative genomic hybridization has been in clinical use for constitutional genetic disorders for some time, its use in profiling cancers has been largely limited to basic research
In contrast to previous studies that measure copy number from sequence read depth using fixed bin intervals across the human genome [33,34,35,36,37], we have developed an algorithm that uses variable length bins to correct for artifacts associates with whole genome amplification (WGA) and mapping
Our analysis showed that one tumor (T16) was monogenomic, consisting of cells with tightly conserved copy number profiles throughout the tumor mass, and was apparently the result of a single major clonal expansion (Figure 3b)
Summary
Genomic profiling by microarray comparative genomic hybridization (aCGH) has been in clinical use for constitutional genetic disorders for some time, its use in profiling cancers has been largely limited to basic research. Using samples of millions of cells, recent studies in cervical cancer treated with cisplatinum [79] and ovarian carcinomas treated with chemoradiotherapy [91] have begun to investigate these questions by profiling tumors for genomic copy number before and after treatment Both studies reported detecting some heterogeneous tumors with pre-existing resistant subpopulations that expanded further after treatment. Since these studies are based on signals derived from populations of cells, their results are likely to underestimate the total extent of genomic heterogeneity and frequency of resistant clones in the primary tumors These questions are better addressed using single-cell sequencing methods, because they can provide a fuller picture of the extent of genomic
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