DELLY: structural variant discovery by integrated paired-end and split-read analysis

Rausch, Tobias; Zichner, Thomas; Schlattl, Andreas; Stütz, Adrian M.; Beneš, Vladimír; Korbel, Jan O.

doi:10.1093/bioinformatics/bts378

Cited by 1,999 publications

(1,833 citation statements)

References 32 publications

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“…Somatic structural variant discovery. Somatic structural variant discovery was pursued across all whole-genome sequenced samples (high-quality structural variants available for n = 539 primary tumours) using the DELLY ICGC Pan-Cancer analysis workflow (https://github.com/ICGC-TCGA-PanCancer/ pcawg_delly_workflow) 85 . A high-stringency structural variant set was obtained by additionally filtering somatic structural variants detected in 1% or more of a set of 1,105 germline samples from healthy individuals belonging to phase I of the 1000 Genomes Project and by removing somatic structural variants present in any of the paediatric germline samples of this study 86 .…”

Section: Discussionmentioning

confidence: 99%

The landscape of genomic alterations across childhood cancers

Gröbner¹,

Worst²,

Weischenfeldt³

et al. 2018

Nature

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The landscape of genomic alterations across childhood cancers a list of authors and affiliations appears at the end of the paper. OPENPan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.Cure rates for childhood cancers have increased to about 80% in recent decades, but cancer is still the leading cause of death by disease in the developed world among children over one year of age 1,2 . Furthermore, many children who survive cancer suffer from long-term sequelae of surgery, cytotoxic chemotherapy, and radiotherapy, including mental disabilities, organ toxicities, and secondary cancers 3 . A crucial step in developing more specific and less damaging therapies is the unravelling of the complete genetic repertoire of paediatric malignancies, which differ from adult malignancies in terms of their histopathological entities and molecular subtypes 4 . Over the past few years, many entityspecific sequencing efforts have been launched, but the few paediatric pan-cancer studies thus far have focused only on mutation frequencies, germline predisposition, and alterations in epigenetic regulators [4][5][6] .We have carried out a broad exploration of cancers in children, adolescents, and young adults, by incorporating small mutations and copy-number or structural variants on somatic and germline levels, and by identifying putative cancer genes and comparing them to those previously reported in adult cancers by The Cancer Genome Atlas (TCGA) 7 . We have also examined mutational signatures and potential drug targets. The compendium of genetic alterations presented here is available to the scientific community at http://www.pedpancan.com.This integrative analysis includes 24 types of cancer and covers all major childhood cancer entities, many of which occur exclusively in children 8 (Fig. 1, Supplementary Table 1). Ninety-five per cent of the patients in this study were diagnosed during childhood or adolescence (aged 18 years or younger) and 5% as young adults (up to 25 years) (Extended Data ...

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Section: Discussionmentioning

confidence: 99%

The landscape of genomic alterations across childhood cancers

Gröbner¹,

Worst²,

Weischenfeldt³

et al. 2018

Nature

1,235

1,156

View full text Add to dashboard Cite

show abstract

“…Structural variation methods, such as GASV (Sindi et al 2009), SegSeq (Chiang et al 2009), DELLY (Rausch et al 2012b), HYDRA (Quinlan et al 2010), AGE (Abyzov and Gerstein 2011), and others (Lee et al 2008; for review, see Snyder et al 2010;Alkan et al 2011), generally utilize (1) read-pair (RP) discordance, (2) increase or reduction in sequence coverage, (3) split reads that span breakpoints, and (4) exact assembly of breakpoint sequences. These tools were primarily designed for variant detection from a single data set, such as a normal genome, and are suited for cataloguing structural polymorphisms in the human population (Kidd et al 2008(Kidd et al , 2010Mills et al 2011).…”

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confidence: 99%

Discovery of recurrent structural variants in nasopharyngeal carcinoma

et al. 2013

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We present the discovery of genes recurrently involved in structural variation in nasopharyngeal carcinoma (NPC) and the identification of a novel type of somatic structural variant. We identified the variants with high complexity mate-pair libraries and a novel computational algorithm specifically designed for tumor-normal comparisons, SMASH. SMASH combines signals from split reads and mate-pair discordance to detect somatic structural variants. We demonstrate a >90% validation rate and a breakpoint reconstruction accuracy of 3 bp by Sanger sequencing. Our approach identified three in-frame gene fusions (YAP1-MAML2, PTPLB-RSRC1, and SP3-PTK2) that had strong levels of expression in corresponding NPC tissues. We found two cases of a novel type of structural variant, which we call ''coupled inversion,'' one of which produced the YAP1-MAML2 fusion. To investigate whether the identified fusion genes are recurrent, we performed fluorescent in situ hybridization (FISH) to screen 196 independent NPC cases. We observed recurrent rearrangements of MAML2 (three cases), PTK2 (six cases), and SP3 (two cases), corresponding to a combined rate of structural variation recurrence of 6% among tested NPC tissues.

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“…Candidate SVs were identified using the DELLY software (v.0.7.1) 17 (details are provided in Supplementary Methods).…”

Section: Wgs and Identification Of Structural Variants (Svs)mentioning

confidence: 99%

MYC-containing amplicons in acute myeloid leukemia: Genomic structures, evolution, and transcriptional consequences

et al. 2017

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Double minutes (dmin), homogeneously staining regions, and ring chromosomes are vehicles of gene amplification in cancer. The underlying mechanism leading to their formation as well as their structure and function in acute myeloid leukemia (AML) remain mysterious. We combined a range of highresolution genomic methods to investigate the architecture and expression pattern of amplicons involving chromosome band 8q24 in 23 cases of AML (AML-amp). This revealed that different MYC-dmin architectures can coexist within the same leukemic cell population, indicating a step-wise evolution rather than a single event origin, such as through chromothripsis. This was supported also by the analysis of the chromothripsis criteria, that poorly matched the model in our samples. Furthermore, we found that dmin could evolve toward ring chromosomes stabilized by neocentromeres. Surprisingly, amplified genes (mainly PVT1) frequently participated in fusion transcripts lacking a corresponding DNA template. We also detected a significant overexpression of the circular RNA of PVT1 (circPVT1) in AML-amp cases versus AML with a normal karyotype. Our results show that 8q24 amplicons in AML are surprisingly plastic DNA structures with an unexpected association to novel fusion transcripts and circular RNAs.

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DELLY: structural variant discovery by integrated paired-end and split-read analysis

Cited by 1,999 publications

References 32 publications

The landscape of genomic alterations across childhood cancers

The landscape of genomic alterations across childhood cancers

Discovery of recurrent structural variants in nasopharyngeal carcinoma

MYC-containing amplicons in acute myeloid leukemia: Genomic structures, evolution, and transcriptional consequences

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