Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence

Moody, Sarah; Senkin, S.; Islam, S. M. Ashiqul; Wang, Jingwei; Nasrollahzadeh, Dariush; Penha, Ricardo Cortez Cardoso; Fitzgerald, Stephen; Bergstrom, Erik N.; Atkins, Joshua; He, Yudou; Khandekar, Azhar; Smith-Byrne, Karl; Carreira, Christine; Gaborieau, Valérie; Latimer, Calli; Thomas, Elaine R.; Abnizova, Irina; Bucciarelli, Pauline E; Jones, David R.; Teague, Jon W.; Abedi‐Ardekani, Behnoush; Serra, Stefano; Scoazec, Jean‐Yves; Saffar, Hiva; Azmoudeh-Ardalan, Farid; Sotoudeh, Masoud; Nikmanesh, Arash; Poustchi, Hossein; Niavarani, Ahmadreza; Gharavi, Samad; Edén, Michael; Richman, P. I.; Campos, Lia S.; Fitzgerald, Rebecca; Ribeiro, Luis Felipe; Soares-Lima, Sheila Coelho; Dzamalala, Charles P.; Mmbaga, Blandina T.; Shibata, Tatsuhiro; Menya, Diana; Goldstein, Alisa M.; Hu, Nan; Malekzadeh, Reza; Fazel, Abdolreza; McCormack, Valerie; McKay, James; Pérdomo, Sandra; Scélo, Ghislaine; Chanudet, Estelle; Humphreys, Laura; Alexandrov, Ludmil B.; Brennan, Paul; Stratton, Michael R.

doi:10.1038/s41588-021-00928-6

Cited by 100 publications

(128 citation statements)

References 56 publications

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“…The first results, including 557 whole genomes of squamous esophageal cancer from diverse high-risk populations such as Iran, East Africa, China, Japan, and Brazil, showed a remarkable similarity in the mutational signatures between these genomes, with no specific mutational signature linked to known or suspected risk factors such as consumption of hot drinks. These results point to the importance of nonmutational processes in cancer development ( 70 ).…”

Section: What Strategies Are Likely To Help Identify Additional Cause...mentioning

confidence: 64%

Identifying Novel Causes of Cancers to Enhance Cancer Prevention: New Strategies Are Needed

Brennan

Smith

2021

JNCI: Journal of the National Cancer Institute

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The burden of cancer from a clinical, societal, and economic viewpoint continues to increase in all parts of the world, along with much debate regarding how to confront this. Projected increases in cancer indicate a 50% increase in the numbers of cases over the next two decades, with the greatest proportional increase in low- and medium-income settings. In contrast to the historic high cancer burden due to viral and bacterial infections in these regions, future increases are expected to be due to cancers linked to ‘westernization’ including breast, colorectum, lung, and prostate cancer. Identifying the reasons underlying these increases will be paramount to informing prevention efforts. Evidence from epidemiological and laboratory studies conducted in high income countries over the last 70 years have led to the conclusion that about 40% of the cancer burden is explained by known risk factors, the two most important being tobacco and obesity in that order, raising the question of what is driving the rest of the cancer burden. International cancer statistics continue to show that about 80% of the cancer burden in high income countries could be preventable in principle, implying that there are important environmental or lifestyle risk factors for cancer that have not yet been discovered. Emerging genomic evidence from population and experimental studies points to an important role for non-mutagenic promoters in driving cancer incidence rates. New research strategies and infrastructures that combine population-based and laboratory research at a global level are required to break this deadlock.

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Section: What Strategies Are Likely To Help Identify Additional Cause...mentioning

confidence: 64%

Identifying Novel Causes of Cancers to Enhance Cancer Prevention: New Strategies Are Needed

Brennan

Smith

2021

JNCI: Journal of the National Cancer Institute

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“…Independent cohorts used to validate kyklonic events were collected from multiple sources. The 61 undifferentiated sarcomas 44 and 187 high-confidence oesophageal squamous cell carcinomas 46 were downloaded from the European Genome-phenome Archive (EGAD00001004162 and EGAD00001006868, respectively). The 280 lung adenocarcinomas 45 were downloaded from dbGaP under the accession number (phs001697.v1.p1).…”

Section: Methodsmentioning

confidence: 99%

“…Kyklonic events were further investigated across 3 additional independent cohorts, including 61 sarcomas 44 , 280 lung cancers 45 and 186 oesophageal squamous cell carcinomas 46 . Comparable rates of clustered mutagenesis were found for both substitutions and indels to the rates reported in PCAWG, with a 2.4- and 5.0-fold enrichment of clustered substitutions and indels within driver events, respectively (Extended Data Fig.…”

Section: Mainmentioning

confidence: 99%

Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA

Bergstrom

Luebeck

Petljak

et al. 2022

Nature

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106

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Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions1–5, diffuse hypermutation termed omikli6, and longer strand-coordinated events termed kataegis3,7–9. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer10. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity6, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.

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“…Currently, on the order of 100 signatures have been discovered in human cancer, but for the majority of them the aetiology remains unknown. This has given rise to a rich new field of mutational signature discovery, as well as linking signatures to various risk factors, in projects like Mutographs [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…mutational signature discovery, as well as linking signatures to various risk factors, in projects like Mutographs [3].…”

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confidence: 99%

MSA: reproducible mutational signature attribution with confidence based on simulations

Senkin

2021

BMC Bioinformatics

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Background Mutational signatures proved to be a useful tool for identifying patterns of mutations in genomes, often providing valuable insights about mutagenic processes or normal DNA damage. De novo extraction of signatures is commonly performed using Non-Negative Matrix Factorisation methods, however, accurate attribution of these signatures to individual samples is a distinct problem requiring uncertainty estimation, particularly in noisy scenarios or when the acting signatures have similar shapes. Whilst many packages for signature attribution exist, a few provide accuracy measures, and most are not easily reproducible nor scalable in high-performance computing environments. Results We present Mutational Signature Attribution (MSA), a reproducible pipeline designed to assign signatures of different mutation types on a single-sample basis, using Non-Negative Least Squares method with optimisation based on configurable simulations. Parametric bootstrap is proposed as a way to measure statistical uncertainties of signature attribution. Supported mutation types include single and doublet base substitutions, indels and structural variants. Results are validated using simulations with reference COSMIC signatures, as well as randomly generated signatures. Conclusions MSA is a tool for optimised mutational signature attribution based on simulations, providing confidence intervals using parametric bootstrap. It comprises a set of Python scripts unified in a single Nextflow pipeline with containerisation for cross-platform reproducibility and scalability in high-performance computing environments. The tool is publicly available from https://gitlab.com/s.senkin/MSA.

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Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence

Abstract: doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Cited by 100 publications

References 56 publications

Identifying Novel Causes of Cancers to Enhance Cancer Prevention: New Strategies Are Needed

Identifying Novel Causes of Cancers to Enhance Cancer Prevention: New Strategies Are Needed

Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA

MSA: reproducible mutational signature attribution with confidence based on simulations

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