Comprehensive characterization of complex structural variations in cancer by directly comparing genome sequence reads
- Nature Biotechnology
- 32,
- 1106–1112
- doi:10.1038/nbt.3027
- Received
- Accepted
- Published online
Abstract
The development of high-throughput sequencing technologies has advanced our understanding of cancer. However, characterizing somatic structural variants in tumor genomes is still challenging because current strategies depend on the initial alignment of reads to a reference genome. Here, we describe SMUFIN (somatic mutation finder), a single program that directly compares sequence reads from normal and tumor genomes to accurately identify and characterize a range of somatic sequence variation, from single-nucleotide variants (SNV) to large structural variants at base pair resolution. Performance tests on modeled tumor genomes showed average sensitivity of 92% and 74% for SNVs and structural variants, with specificities of 95% and 91%, respectively. Analyses of aggressive forms of solid and hematological tumors revealed that SMUFIN identifies breakpoints associated with chromothripsis and chromoplexy with high specificity. SMUFIN provides an integrated solution for the accurate, fast and comprehensive characterization of somatic sequence variation in cancer.
Figure 3: Identification and validation of chromoplexy in mantle cell lymphoma tumor M003.
FromComprehensive characterization of complex structural variations in cancer by directly comparing genome sequence reads
- Nature Biotechnology
- 32,
- 1106–1112
- doi:10.1038/nbt.3027
- Received
- Accepted
- Published online
(a) Three chimeric chromosomes formed by parts of chromosomes 3, 4 and 12 and the primary hallmark MCL translocation t(11;14). These rearrangements were identified by SMUFIN and all were experimentally verified by PCR. (b) A representative 24-color multicolor-FISH (mFISH) karyogram (top) that shows an unbalanced karyotype, with the t(11;14)(q13;q32) (BKP 10 and 11), a centromeric deletion of 17p, and several rearrangements between chromosomes 3, 4 and 12, all of them consistent with the breakpoints identified by SMUFIN. Bottom image shows a metaphase hybridized with whole-chromosome painting (WCP) 4 (green) and 12 (orange) probes showing four derivative chromosomes with material of these two chromosomes. Combination of mFISH and WCP analysis confirmed the presence of two different derivative chromosomes der(3)t(3;4;12), one der(12)t(3;4;12), and identified a fourth, der(4)t(4;12), which is not detectable by SMUFIN owing to the centromeric location of the breakpoint in chromosome 4. Scale bar, 10 μm. (c) Genes affected by chromoplexy—a reciprocal fusion of two genes (ANK2, in green and SOX5, in red) and a truncated chromatin remodeler (ARID2). Coding and noncoding exons are displayed as taller and shorter boxes, respectively.
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