Signatures of copy number alterations in human cancer

Steele, Christopher D.; Abbasi, Ammal; Asm, Islam; Khandekar, Azhar; Haase, Kerstin; Hames-Fathi, Shadi; Tarabichi, Maxime; Lesluyes, Tom; Flanagan, Adrienne M.; Mertens, Fredrik; P, Van Loo; Alexandrov, Ludmil B.; Pillay, Nischalan

doi:10.1101/2021.04.30.441940

Cited by 15 publications

(30 citation statements)

References 73 publications

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“…9). Copy number signature analysis 27 identified 18 distinct signatures (Extended Data Fig. 5a) and confirmed an enrichment of signatures related to LOH in MPNSTs with loss of H3K27me3 (Fig.…”

Section: Resultsmentioning

confidence: 60%

“…For the remaining samples, the decomposition that best explained the data (highest cosine similarity) was retained. For WES data, samples were decomposed into previously identified pan-cancer copy number signatures using sigProfilerSingleSample 27 .…”

Section: Methodsmentioning

confidence: 99%

“…For homozygous deletions, segment lengths were restricted to 0-{100kb, 100kb-1Mb, >1Mb}. See 27 for a full description of the development of these categories.…”

Section: Methodsmentioning

confidence: 99%

“…For WGS data, non-negative matrix factorisation as implemented in sigProfilerExtractor was employed to extract de novo copy number signatures from sequential subsets of the dataset as previously described 69 : all samples (n=81), excluding hypersegmented samples (nsegs<1000; n=79), remaining poorly explained samples (cosine similarity<0.85; n=35), samples with a high proportion of LOH (pLOH>; n=12). In each case, the de novo signatures were decomposed into previously identified pan-cancer copy number signatures 27 using the function sigProfilerSingleSample. For hypersegmented samples, a novel signature was identified, for which the attribution was taken from the all-samples extraction.…”

Section: Copy Number Signature Analysismentioning

confidence: 99%

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Genomic patterns of malignant peripheral nerve sheath tumour (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA

Cortés-Ciriano

Steele

Piculell

et al. 2022

Preprint

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Malignant peripheral nerve sheath tumour (MPNST) is an aggressive soft-tissue sarcoma that arises in peripheral nerves. MPNST occurs either sporadically or in people with neurofibromatosis type 1 (NF1), a common cancer predisposition syndrome caused by germline pathogenic variants in NF1. Although MPNST is the most common cause of death and morbidity for individuals with NF1, the molecular underpinnings of MPNST pathogenesis remain unclear. Here, we report the analysis of whole-genome sequencing, multi-regional exome sequencing, transcriptomic and methylation profiling data for 95 MPNSTs and precursor lesions (64 NF1-related; 31 sporadic) from 77 individuals. Early events in tumour evolution include biallelic inactivation of NF1 followed by inactivation of CDKN2A and in some cases also TP53 and polycomb repressive complex 2 (PRC2) genes. Subsequently, both sporadic and NF1-related MPNSTs acquire a high burden of somatic copy number alterations (SCNAs). Our analysis revealed distinct pathways of tumour evolution and immune infiltration associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumours with loss of H3K27me3 evolve through extensive chromosomal losses with retention of chromosome 8 heterozygosity followed by whole genome doubling and chromosome 8 amplification. These tumours show lower levels of immune cell infiltration with low cytotoxic activity and low expression of immune checkpoints. In contrast, tumours with retention of H3K27me3 evolve through extensive genomic instability in the absence of recurrent alterations and exhibit an immune cell-rich phenotype. Specific SCNAs detected in both tumour samples and cell-free DNA (cfDNA) act as a surrogate for loss of H3K27me3 and immune infiltration, and predict prognosis. Our results suggest that SCNA profiling of tumour or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups.

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Section: Resultsmentioning

confidence: 60%

Section: Methodsmentioning

confidence: 99%

“…For homozygous deletions, segment lengths were restricted to 0-{100kb, 100kb-1Mb, >1Mb}. See 27 for a full description of the development of these categories.…”

Section: Methodsmentioning

confidence: 99%

Section: Copy Number Signature Analysismentioning

confidence: 99%

See 2 more Smart Citations

Genomic patterns of malignant peripheral nerve sheath tumour (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA

Cortés-Ciriano

Steele

Piculell

et al. 2022

Preprint

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“…6b). Signatures of other mutation types, including copy number variations and structural variations, are less well studied [15,[66][67][68]. We expect that MuSiCal will facilitate future developments of these signatures when their proper definitions are developed.…”

Section: Discussionmentioning

confidence: 99%

Accurate and sensitive mutational signature analysis with MuSiCal

Gulhan

Ben-Isvy

et al. 2022

Preprint

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Mutational signature analysis is a recent computational approach for interpreting somatic mutations in the genome. Its application to cancer data has enhanced our understanding of mutational forces driving tumorigenesis and demonstrated its potential to inform prognosis and treatment decisions. However, methodological challenges remain for discovering new signatures and assigning proper weights to existing signatures, thereby hindering broader clinical applications. We present MuSiCal (Mutational Signature Calculator), a rigorous analytical framework with novel algorithms that solves fundamental problems in the standard workflow. Our simulation studies demonstrate that MuSiCal outperforms state-of-the-art algorithms for both signature discovery and assignment. By reanalyzing over 2,700 cancer genomes, we provide an improved reference catalog of signatures and their assignments, discover nine indel signatures absent in the current catalog, resolve long-standing issues with the ambiguous ‘flat’ signatures, and give insights into signatures with unknown etiologies. We expect MuSiCal and the improved catalog to be a step towards establishing best practices for mutational signature analysis.

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An overview of mutational and copy number signatures in human cancer

Steele

Pillay

Alexandrov

2022

The Journal of Pathology

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The genome of each cell in the human body is constantly under assault from a plethora of exogenous and endogenous processes that can damage DNA. If not successfully repaired, DNA damage generally becomes permanently imprinted in cells, and all their progenies, as somatic mutations. In most cases, the patterns of these somatic mutations contain the tell‐tale signs of the mutagenic processes that have imprinted and are termed mutational signatures. Recent pan‐cancer genomic analyses have elucidated the compendium of mutational signatures for all types of small mutational events, including (1) single base substitutions, (2) doublet base substitutions, and (3) small insertions/deletions. In contrast to small mutational events, where, in most cases, DNA damage is a prerequisite, aneuploidy, which refers to the abnormal number of chromosomes in a cell, usually develops from mistakes during DNA replication. Such mistakes include DNA replication stress, mitotic errors caused by faulty microtubule dynamics, or cohesion defects that contribute to chromosomal breakage and can lead to copy number (CN) alterations (CNAs) or even to structural rearrangements. These aberrations also leave behind genomic scars which can be inferred from sequencing as CN signatures and rearrangement signatures. The analyses of mutational signatures of small mutational events have been extensively reviewed, so we will not comprehensively re‐examine them here. Rather, our focus will be on summarising the existing knowledge for mutational signatures of CNAs. As studying CN signatures is an emerging field, we briefly summarise the utility that mutational signatures of small mutational events have provided in basic science, cancer treatment, and cancer prevention, and we emphasise the future role that CN signatures may play in each of these fields. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Signatures of copy number alterations in human cancer

Cited by 15 publications

References 73 publications

Genomic patterns of malignant peripheral nerve sheath tumour (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA

Genomic patterns of malignant peripheral nerve sheath tumour (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA

Accurate and sensitive mutational signature analysis with MuSiCal

An overview of mutational and copy number signatures in human cancer

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