5-Fluorouracil treatment induces characteristic T&gt;G mutations in human cancer

Christensen, Sharon; Roest, Bastiaan van der; Besselink, Nicolle; Janssen, Roel; Boymans, Sander; Martens, John W.M.; Yaspo, Marie–Laure; Priestley, Peter; Kuijk, Ewart; Cuppen, Edwin; Hoeck, Arne van

doi:10.1038/s41467-019-12594-8

Cited by 177 publications

(151 citation statements)

References 71 publications

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“…S5). Indeed, all treated colorectal metastases (n=7) were biopsied after 5-fluorouracil (5-FU) chemotherapy in this cohort, which was recently shown to be associated with this mutational pattern 32,33 .…”

Section: The Landscape Of Genomic Alterations In Paired Primary Tumormentioning

confidence: 99%

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

et al. 2019

Preprint

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Metastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and patterns of systemic spread are poorly understood. We analyzed exome sequencing data from 458 paired primary tumors (P) or metastasis (M) samples from 136 breast, colorectal and lung cancer patients, including both untreated (n=98) and treated (n=101) metastases. We find that treated metastases often harbored private driver gene mutations whereas untreated metastases did not, suggesting that treatment promotes clonal evolution. Polyclonal seeding was common in lymph node metastases (n=19/35, 54%; mostly untreated) and untreated distant metastases (n=20/70, 29%), but less frequent in treated metastases (n=9/90, 10%). The low number of metastasis-private clonal mutations is consistent with early metastatic seeding, which commonly occurred several years prior to diagnosis in breast (2.4 years, range 0−3.3), lung (3.6 years, range 2.8 − 3.7) and colorectal (4.1 years, range 3.1 − 4.6) cancers. Thus, this pan-cancer analysis reveals early systemic spread in three common cancer types. Further, these data suggest that the natural course of metastasis is selectively relaxed relative to early tumor development and that metastasis-private mutations are not drivers of cancer spread but are instead associated with drug resistance.

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Section: The Landscape Of Genomic Alterations In Paired Primary Tumormentioning

confidence: 99%

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

et al. 2019

Preprint

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“…The only exception to this rule is TS20-N[T>G]T (SBS17a,b), which showed a slight decrease in the outward facing minor groove, while the inwards facing showed elevated mutation rates 23 . TS20 is likely caused by incorporation of dUTP or oxo-dTTP 20 , possibly, but not necessarily, due to 5-FU treatment 31 .…”

Section: Genomic Properties Modulate Signatures With Epigenetic Statmentioning

confidence: 99%

Learning mutational signatures and their multidimensional genomic properties with TensorSignatures

Vöhringer

Gerstung

2019

Preprint

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Key findings• Simultaneous inference of mutational signatures across mutation types and genomic features refines signature spectra and defines their genomic determinants • Two distinct mutational signatures of UV exposure found in active and quiescent chromatin, which may be attributed to differential activity of nucleotide excision repair • Transcription-associated mutagenesis manifesting as A[T>C] mutations is found in a range of cancer types • APOBEC mutagenesis produces two signatures reflecting highly clustered, double strand break repair initiated and lowly clustered replication-driven mutagenesis, respectively • Somatic hypermutation produces a strongly clustered, TSS-associated signature in lymphoid cancers, which is distinct from a weakly clustered TLS signature found in multiple tumour types. AbstractMutational signature analysis is an essential part of the cancer genome analysis toolkit. Conventionally, mutational signature analysis extracts patterns of different mutation types across many cancer genomes. Here we present TensorSignatures, an algorithm to learn mutational signatures jointly across all variant categories and their genomic context. The analysis of 2,778 cancer genomes of the PCAWG consortium shows that practically all signatures operate dynamically in response to various genomic and epigenomic states. The analysis pins differential spectra of UV mutagenesis found in active and inactive chromatin to global genome nucleotide excision repair. TensorSignatures accurately characterises transcription-associated mutagenesis, which is detected in 7 different cancer types. The analysis also unmasks replication and double strand break repair driven APOBEC mutagenesis, which manifests with differential numbers and length of mutation clusters indicating a differential processivity of the two triggers. As a fourth example, TensorSignatures detects a signature of somatic hypermutation generating highly clustered variants around the transcription start sites of active genes in lymphoid leukaemia, distinct from a more general and less clustered signature of Polη-driven TLS found in a broad range of cancer types. Directional effectsMutation rates may differ between template and coding strand, because RNA polymerase II recruits transcription coupled nucleotide excision repair (TC-NER) upon lesion recognition

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“…Somatic mutations arising through endogenous and exogenous processes mark the genome with distinctive patterns, termed mutational signatures [1][2][3][4] . While there have been advancements in analytical aspects of deriving mutational signatures from human cancers [5][6][7] , there is an emerging need for experimental substantiation, elucidating etiologies and mechanisms underpinning these mutational patterns [8][9][10][11] . Cellular models have been used to systematically study mutagenesis arising from exogenous sources of DNA damage 8,11 .…”

Section: Introductionmentioning

confidence: 99%

Dissecting mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage

Zou

Koh

Nanda

et al. 2020

Preprint

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Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. Here, we generate isogenic CRISPR-Cas9 knockouts (Δ) of 43 genes in human induced pluripotent stem cells, culture them in the absence of added DNA damage, and perform wholegenome sequencing of 173 daughter subclones. ΔOGG1, ΔUNG, ΔEXO1, ΔRNF168, ΔMLH1, ΔMSH2, ΔMSH6, ΔPMS1, and ΔPMS2 produce marked mutational signatures indicative of being critical mitigators of endogenous DNA changes. Detailed analyses reveal that 8-oxo-dG removal by different repair proteins is sequence-context-specific while uracil clearance is sequencecontext-independent. Signatures of mismatch repair (MMR) deficiency show components of C>A transversions due to oxidative damage, T>C and C>T transitions due to differential misincorporation by replicative polymerases, and T>A transversions for which we propose a ‘reverse template slippage’ model. ΔMLH1, ΔMSH6, and ΔMSH2 signatures are similar to each other but distinct from ΔPMS2. We validate these gene-specificities in cells from patients with Constitutive Mismatch Repair Deficiency Syndrome. Based on these experimental insights, we develop a classifier, MMRDetect, for improved clinical detection of MMR-deficient tumors.

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5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

Cited by 177 publications

References 71 publications

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

Learning mutational signatures and their multidimensional genomic properties with TensorSignatures

Dissecting mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage

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