Clinical‐grade validation of whole genome sequencing reveals robust detection of low‐frequency variants and copy number alterations in CLL

Klintman, Jenny; Barmpouti, Katerina; Knight, Samantha J. L.; Robbe, Pauline; Dreau, Hélène; Clifford, Ruth; Ridout, Kate; Burns, Adam; Timbs, Adele; Bruce, David; Antoniou, Pavlos; Sosinsky, Alona; Becq, Jennifer; Bentley, David; Hillmen, Peter; Taylor, Jenny C.; Caulfield, Mark J.; Schuh, Anna

doi:10.1111/bjh.15406

Cited by 19 publications

(17 citation statements)

References 16 publications

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“…Although short-read whole-genome sequencing (WGS) of B cell neoplasms should store the information to reconstruct the entire Ig gene, the high genomic complexity of the Ig loci has prevented its analysis using the current bioinformatic pipelines. The decreasing cost of short-read WGS linked with its ability to characterize the entire genomic landscape of these neoplasms in a single experiment 17 , even if complex and heterogeneous 18 , suggests that WGS could enter into the clinical setting in the near future.…”

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confidence: 99%

IgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms

et al. 2020

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Immunoglobulin (Ig) gene rearrangements and oncogenic translocations are routinely assessed during the characterization of B cell neoplasms and stratification of patients with distinct clinical and biological features, with the assessment done using Sanger sequencing, targeted next-generation sequencing, or fluorescence in situ hybridization (FISH). Currently, a complete Ig characterization cannot be extracted from whole-genome sequencing (WGS) data due to the inherent complexity of the Ig loci. Here, we introduce IgCaller, an algorithm designed to fully characterize Ig gene rearrangements and oncogenic translocations from short-read WGS data. Using a cohort of 404 patients comprising different subtypes of B cell neoplasms, we demonstrate that IgCaller identifies both heavy and light chain rearrangements to provide additional information on their functionality, somatic mutational status, class switch recombination, and oncogenic Ig translocations. Our data thus support IgCaller to be a reliable alternative to Sanger sequencing and FISH for studying the genetic properties of the Ig loci.

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confidence: 99%

IgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms

et al. 2020

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“…Diagnostic platforms using whole genome sequencing (WGS) to detect single nucleotide variants and insertion/deletions are being developed and validated for potential usage in clinical practice [ 100 ]. Although these methods will likely provide comprehensive genomic characterisation of CLL and will represent alternative method to recognize the prognostic or predictive role genetic lesions in trials, they still require standardization and a univocal definition of “genome complexity”.…”

Section: Resultsmentioning

confidence: 99%

Biological significance and prognostic/predictive impact of complex karyotype in chronic lymphocytic leukemia

et al. 2018

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The complex karyotype (CK) is an established negative prognostic marker in a number of haematological malignancies. After the introduction of effective mitogens, a growing body of evidence has suggested that the presence of 3 or more aberrations by conventional banding analysis (CBA) is associated with an unfavorable outcome in chronic lymphocytic leukemia (CLL). Thus, the importance of CBA was recognized by the 2018 guidelines of the International Workshop on CLL, which proposed the introduction of CBA in clinical trials to validate the value of karyotype aberrations.Indeed, a number of observational studies showed that cytogenetic aberrations and, particularly, the CK may have a negative independent impact on objective outcome measures (i.e. time to first treatment, progression free survival, time to chemorefractoriness and overall survival) both in patients treated with chemoimmunotherapy and, possibly, in patients receiving novel mechanism-based treatment.Here, we set out to present the scientific evidence supporting the significance of CK as a prognostic marker in CLL and to discuss the biological basis showing that the CK is a consequence of genomic instability.

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“…Whole Genome Sequencing (WGS) is among these and is the most comprehensive approach for characterising and analysing an individual's genetic variation 6 . Substantial reductions in cost mean that WGS has become an increasingly important tool for clinical diagnosis and targeted treatment of rare disease and cancer 4,[7][8][9][10][11] . Of particular importance to precision oncology is the ability of WGS to identify driver mutations (including those in non-coding regions) 12,13 , detect mutational signatures [14][15][16] , characterise structural variation and chromosomal rearrangements 17,18 , and pinpoint the genomic integration sites of oncoviruses, such as human papillomavirus 19 .…”

Section: Introductionmentioning

confidence: 99%

Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma

Roberts

Lopopolo

Pagnamenta

et al. 2020

Preprint

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Recent advances in throughput and accuracy mean that the Oxford Nanopore Technologies (ONT) PromethION platform is a now a viable solution for genome sequencing. Much of the validation of bioinformatic tools for this long-read data has focussed on calling germline variants (including structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated by the effects of tumour purity/subclonality. Here, we evaluate the extent to which Nanopore sequencing enables genome-wide detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma and comparing results with 150bp short-read sequencing of the same samples. Calling germline single nucleotide variants (SNVs) from the long-read data achieved good specificity and sensitivity.However, results of somatic SNV calling highlight the need for the development of specialized joint calling algorithms. We find the comparative performance of different tools varies significantly between structural variant types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants, confirming that a somatic 1.6Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.

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Clinical‐grade validation of whole genome sequencing reveals robust detection of low‐frequency variants and copy number alterations in CLL

Cited by 19 publications

References 16 publications

IgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms

IgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms

Biological significance and prognostic/predictive impact of complex karyotype in chronic lymphocytic leukemia

Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma

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