StructuralVariantAnnotation: a R/Bioconductor foundation for a caller-agnostic structural variant software ecosystem

Cameron, Daniel; Dong, Ruining; Papenfuss, Anthony T.

doi:10.1093/bioinformatics/btac042

Cited by 5 publications

(4 citation statements)

References 12 publications

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“…Structural variants were identified with an ensemble of GRIDSS2 52 and Manta 48 intersected with the BioConductor package StructuralVariantAnotation 53 . Copy number variants were identified with Battenberg 54 for WGS or Sequenza 55 for WES.…”

Section: Methodsmentioning

confidence: 99%

Relapse timing is associated with distinct evolutionary dynamics in DLBCL

Hilton

Ngu

Collinge

et al. 2023

Preprint

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Diffuse large B-cell lymphoma (DLBCL) is cured in over 60% of patients, but outcomes are poor for patients with relapsed or refractory disease (rrDLBCL). Here, we performed whole genome/exome sequencing (WGS/WES) on tumors from 73 serially-biopsied patients with rrDLBCL. Based on the observation that outcomes to salvage therapy/autologous stem cell transplantation are related to time-to-relapse, we stratified patients into groups according to relapse timing to explore the relationship to genetic divergence and sensitivity to salvage immunochemotherapy. The degree of mutational divergence increased with time between biopsies, yet tumor pairs were mostly concordant for cell-of-origin, oncogene rearrangement status and genetics-based subgroup. In patients with highly divergent tumors, several genes acquired exclusive mutations independently in each tumor, which, along with concordance of genetics-based subgroups, suggests that the earliest mutations in a shared precursor cell constrain tumor evolution. These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naive disease.

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Section: Methodsmentioning

confidence: 99%

Relapse timing is associated with distinct evolutionary dynamics in DLBCL

Hilton

Ngu

Collinge

et al. 2023

Preprint

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“…52 Structural variants were called using GRIDSS (v2.13.2) 53,54 and annotated using StructuralVariantAnnotation (Version 1.12.0). 55 Single nucleotide variants were checked against the ClinVar public archive of reports of the relationships among human variations and phenotypes (https://www.ncbi.nlm.nih.gov/clinvar/), and in-silico predictor of pathogenicity MutationTaster, 56 using dbNSFP v4.2a. 57…”

Section: Methodsmentioning

confidence: 99%

The microtubule inhibitor eribulin demonstrates efficacy in platinum-resistant and refractory high-grade serous ovarian cancer patient-derived xenograft models

Ho,

Vandenberg,

Lim

et al. 2023

Ther Adv Med Oncol

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Background: Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have de novo platinum-refractory disease. Objectives: To determine the potential of anti-microtubule agent (AMA) therapy (paclitaxel, vinorelbine and eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing response in patient-derived xenograft (PDX) models of HGSC. Design and methods: Of 13 PRR HGSC PDX, six were primary PRR, derived from chemotherapy-naïve samples (one was BRCA2 mutant) and seven were from samples obtained following chemotherapy treatment in the clinic (five were mutant for either BRCA1 or BRCA2 ( BRCA1/2), four with prior PARPi exposure), recapitulating the population of individuals with aggressive treatment-resistant HGSC in the clinic. Molecular analyses and in vivo treatment studies were undertaken. Results: Seven out of thirteen PRR PDX (54%) were sensitive to treatment with the AMA, eribulin (time to progressive disease (PD) ⩾100 days from the start of treatment) and 11 out of 13 PDX (85%) derived significant benefit from eribulin [time to harvest (TTH) for each PDX with p < 0.002]. In 5 out of 10 platinum-refractory HGSC PDX (50%) and one out of three platinum-resistant PDX (33%), eribulin was more efficacious than was cisplatin, with longer time to PD and significantly extended TTH (each PDX p < 0.02). Furthermore, four of these models were extremely sensitive to all three AMA tested, maintaining response until the end of the experiment (120d post-treatment start). Despite harbouring secondary BRCA2 mutations, two BRCA2-mutant PDX models derived from heavily pre-treated individuals were sensitive to AMA. PRR HGSC PDX models showing greater sensitivity to AMA had high proliferative indices and oncogene expression. Two PDX models, both with prior chemotherapy and/or PARPi exposure, were refractory to all AMA, one of which harboured the SLC25A40-ABCB1 fusion, known to upregulate drug efflux via MDR1. Conclusion: The efficacy observed for eribulin in PRR HGSC PDX was similar to that observed for paclitaxel, which transformed ovarian cancer clinical practice. Eribulin is therefore worthy of further consideration in clinical trials, particularly in ovarian carcinoma with early failure of carboplatin/paclitaxel chemotherapy.

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“…The predicted SVs were then filtered to reduce false positives using the following criteria: (1) spanning paired-end reads >= 10 or split reads >= 10; and (2) both ends of the inspected SV located within the capture kit intervals. The filtered SVs were then used to detect potential gene fusions using the R package StructuralVariantAnnotation v3.15, (Cameron et al 2022) with a specific focus on the TMPRSS2:ERG gene fusion. The identified TMPRSS2:ERG gene fusions were then manually investigated with the Arriba v2.3.0 draw fusion.R script (Uhrig et al 2021).…”

Section: Structural Variant Detection and Annotationmentioning

confidence: 99%

Prostate cancer patient stratification by molecular signatures in the Veterans Precision Oncology Data Commons

Hernandez,

Venkat,

Elbers

et al. 2023

Cold Spring Harb Mol Case Stud

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Veterans are at an increased risk for prostate cancer, a disease with extraordinary clinical and molecular heterogeneity, compared to the general population. Yet, little is known about the underlying molecular heterogeneity within the veteran population, and its impact on patient management and treatment. Using clinical and targeted tumor sequencing data from the national Veterans Affairs health system, we conducted a retrospective cohort study on 45 patients with advanced prostate cancer in the Veterans Precision Oncology Data Commons (VPODC), most of whom were metastatic castration resistant. We characterized the mutational burden in this cohort and conducted unsupervised clustering analysis to stratify patients by molecular alterations. Veterans with prostate cancer exhibited a mutational landscape broadly similar to prior studies, including KMT2A and NOTCH1 mutations associated with neuroendocrine prostate cancer phenotype, previously reported to be enriched in veterans. We also identified several potential novel mutations in PTEN, MSH6, VHL, SMO and ABL1. Hierarchical clustering analysis revealed two subgroups containing therapeutically targetable molecular features with novel mutational signatures distinct from those reported in the Catalogue of Somatic Mutations in Cancer database. The clustering approach presented in this study can potentially be used to clinically stratify patients based on their distinct mutational profiles and identify actionable somatic mutations for precision oncology.

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StructuralVariantAnnotation: a R/Bioconductor foundation for a caller-agnostic structural variant software ecosystem

Cited by 5 publications

References 12 publications

Relapse timing is associated with distinct evolutionary dynamics in DLBCL

Relapse timing is associated with distinct evolutionary dynamics in DLBCL

The microtubule inhibitor eribulin demonstrates efficacy in platinum-resistant and refractory high-grade serous ovarian cancer patient-derived xenograft models

Prostate cancer patient stratification by molecular signatures in the Veterans Precision Oncology Data Commons

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