Strelka2: fast and accurate calling of germline and somatic variants

Kim, Sangtae; Scheffler, Konrad; Halpern, Aaron L.; Bekritsky, Mitchell A.; Noh, Eunho; Källberg, Morten; Chen, Xiaoyu; Kim, Yeonbin; Beyter, Doruk; Krusche, Peter; Saunders, Christopher T.

doi:10.1038/s41592-018-0051-x

Cited by 1,135 publications

(842 citation statements)

References 16 publications

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“…Somatic variants (SV), that include Single Somatic Mutations (SSMs) and indels were identified by two different variant callers, MuTect2 (version 2.1) 22,23 and Strelka2 (version 2.9.10). 24 The variants filtering as "Passed" by both variant callers were used for downstream analysis. The functional effects of SVs were identified by the Variant Effect Predictor (VEP) (version 95.2).…”

Section: Bioinformatic Analysismentioning

confidence: 99%

Branched evolution and genomic intratumor heterogeneity in the pathogenesis of cutaneous T-cell lymphoma

Iyer

Hennessey

OʼKeefe

et al. 2019

Preprint

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Mycosis fungoides (MF) is a slowly progressive cutaneous T-cell lymphoma (CTCL) for which there is no cure. In the early plaque stage the disease is indolent, but development of tumors heralds an increased risk of metastasis and death. Previous research into the genomic landscape of CTCL revealed a complex pattern of >50 driver mutations implicated in more than a dozen of signaling pathways. However, the genomic mechanisms governing disease progression and treatment resistance remain unknown. Building on our previous discovery of the clonotypic heterogeneity of MF, we hypothesized that this lymphoma does not progress in a linear fashion as currently thought, but comprises heterogeneous mutational subclones. We sequenced exomes of 49 cases of MF and identified 28 previously unreported putative driver genes. MF exhibited extensive intratumoral heterogeneity (ITH) of a median of six subclones showing branched pattern of phylogenetic relationships. Stage progression was correlated with an increase in ITH and redistribution of mutations from the stem to the clades. The pattern of clonal driver mutations was highly variable with no consistent mutations between patients. A similar intratumoral heterogeneity was detected in leukemic CTCL (Sézary syndrome). Based on these findings we propose a model of the pathogenesis of MF comprising neutral, divergent evolution of cancer subclones and discuss how ITH impacts the efficacy of targeted drug therapies and immunotherapies of CTCL.

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Section: Bioinformatic Analysismentioning

confidence: 99%

Branched evolution and genomic intratumor heterogeneity in the pathogenesis of cutaneous T-cell lymphoma

Iyer

Hennessey

OʼKeefe

et al. 2019

Preprint

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“…Somatic SNV and indels. To obtain somatic SNV/InDel calls Strelka2 (Kim et al, 2018) was run under paired tumor and 294 normal mode with default parameters using hg19-based references. Somatic SNV and indels were obtained only for those cases 295 where tumor and normal BAMs were available (2494 out of 2833 cases).…”

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confidence: 99%

Novel patterns of complex structural variation revealed across thousands of cancer genome graphs

Hadi

Yao

et al. 2019

Preprint

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Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g. deletion, translocation) or complex (e.g. chromothripsis, chromoplexy) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,833 tumor whole genome sequences (WGS), we introduce three complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early replicating regions and superenhancers, and are enriched in breast and ovarian cancers. Rigma comprise "chasms" of low-JCN deletions at late-replicating fragile sites in esophageal and other gastrointestinal (GI) adenocarcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold back inversions that are enriched in acral but not cutaneous melanoma and associated with a previously uncharacterized mutational process of non-APOBEC kataegis. Clustering of tumors according to genome graph-derived features identifies subgroups associated with DNA repair defects and poor prognosis. Cancer genomics | Structural variation | DNA rearrangements | Mutational Processes | Genome graphs | Copy number alterationsCorrespondence: mski@mskilab.org K. Hadi, X.Yao, J. Behr et al. | bioRχiv | November 12, 2019 | 1-8

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“…Whilst only precise GRIDSS calls passed filtering and were included in the call set, imprecise Manta calls had a similar validation rate (40/288, 14%) to Manta private calls with all validated imprecise manta calls called by GRIDSS precisely. Since the default minimum reported event sizes of GRIDSS and Manta are 32 and 50bp respectively, we compared 32-50bp events to the short indel caller, Strelka [18]. Again, in this range GRIDSS has superior calling performance with 329 of 343 (96%) calls validated against 142 of 182 (78%) Strelka calls (figure 2e).…”

Section: Somatic Structural Variation (Gridss)mentioning

confidence: 99%

GRIDSS, PURPLE, LINX: Unscrambling the tumor genome via integrated analysis of structural variation and copy number

Cameron

Baber²,

Shale³

et al. 2019

Preprint

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We have developed a novel, integrated and comprehensive purity, ploidy, structural variant and copy number somatic analysis toolkit for whole genome sequencing data of paired tumor/normal samples. We show that the combination of using GRIDSS for somatic structural variant calling and PURPLE for somatic copy number alteration calling allows highly sensitive, precise and consistent copy number and structural variant determination, as well as providing novel insights for short structural variants and regions of complex local topology. LINX, an interpretation tool, leverages the integrated structural variant and copy number calling to cluster individual structural variants into higher order events and chains them together to predict local derivative chromosome structure. LINX classifies and extensively annotates genomic rearrangements including simple and reciprocal breaks, LINE, viral and pseudogene insertions, and complex events such as chromothripsis. LINX also comprehensively calls genic fusions including chained fusions. Finally, our toolkit provides novel visualisation methods providing insight into complex genomic rearrangements.

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Strelka2: fast and accurate calling of germline and somatic variants

Cited by 1,135 publications

References 16 publications

Branched evolution and genomic intratumor heterogeneity in the pathogenesis of cutaneous T-cell lymphoma

Branched evolution and genomic intratumor heterogeneity in the pathogenesis of cutaneous T-cell lymphoma

Novel patterns of complex structural variation revealed across thousands of cancer genome graphs

GRIDSS, PURPLE, LINX: Unscrambling the tumor genome via integrated analysis of structural variation and copy number

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