Abstract
Annotation of structural variations (SVs) and base-level karyotyping in cancer cells remains challenging. Here, we present Integrative Framework for Genome Reconstruction (InfoGenomeR)-a graph-based framework that can reconstruct individual SVs into karyotypes based on whole-genome sequencing data, by integrating SVs, total copy number alterations, allele-specific copy numbers, and haplotype information. Using whole-genome sequencing data sets of patients with breast cancer, glioblastoma multiforme, and ovarian cancer, we demonstrate the analytical potential of InfoGenomeR. We identify recurrent derivative chromosomes derived from chromosomes 11 and 17 in breast cancer samples, with homogeneously staining regions for CCND1 and ERBB2, and double minutes and breakage-fusion-bridge cycles in glioblastoma multiforme and ovarian cancer samples, respectively. Moreover, we show that InfoGenomeR can discriminate private and shared SVs between primary and metastatic cancer sites that could contribute to tumour evolution. These findings indicate that InfoGenomeR can guide targeted therapies by unravelling cancer-specific SVs on a genome-wide scale.
Highlights
Annotation of structural variations (SVs) and base-level karyotyping in cancer cells remains challenging
Using WGS data from The Cancer Genome Atlas (TCGA)20–22 and European Genome–phenome Archive (EGA)23, we show that InfoGenomeR can reconstruct the karyotypes of cancer cells and distinguish between private and shared SVs in primary and metastatic cancer cells, and reveal tumour evolution
Integer CNs are divided into ASCNs using negative binomial models for the different depths of heterozygous single nucleotide polymorphisms (SNPs), and the expectation–maximisation (EM) algorithm is used for estimating parameters
Summary
Annotation of structural variations (SVs) and base-level karyotyping in cancer cells remains challenging. Recurrent chromosomal structural variations (SVs) have been linked to tumorigenesis, including simple SVs such as tandem duplications, deletions, inversions and insertions, which have been extensively studied, as well as more complex SVs such as translocations, fold-back inversions, chromothripsis, homogeneously staining regions (HSRs, representing repetitive gene amplification) and double minutes (DMs, extrachromosomal DNA). Recurrent chromosomal structural variations (SVs) have been linked to tumorigenesis, including simple SVs such as tandem duplications, deletions, inversions and insertions, which have been extensively studied, as well as more complex SVs such as translocations, fold-back inversions, chromothripsis, homogeneously staining regions (HSRs, representing repetitive gene amplification) and double minutes (DMs, extrachromosomal DNA)3,4 Traditional karyotyping techniques, such as G-banding and fluorescent in situ hybridisation (FISH) can reveal the presence of complex SVs in derivative chromosomes (by-product of the recombination of multiple chromosomes with intact centromeres) or marker chromosomes (abnormal chromosomes with unidentified genomic segments). Using WGS data from The Cancer Genome Atlas (TCGA) and European Genome–phenome Archive (EGA), we show that InfoGenomeR can reconstruct the karyotypes of cancer cells and distinguish between private and shared SVs in primary and metastatic cancer cells, and reveal tumour evolution
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