The mutational footprints of cancer therapies

Pich, Oriol; Muiños, Ferran; Lolkema, Martijn P.; Steeghs, Neeltje; González-Pérez, Abel; López‐Bigas, Núria

doi:10.1038/s41588-019-0525-5

Cited by 252 publications

(280 citation statements)

References 49 publications

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“…dacarbazine, temozolomide), platinum-based therapies (e.g. cisplatin, carboplatin) or radiotherapy, which all may increase TMB by inducing novel subclonal mutations [23][24][25][26]. The concept behind TMB as a biomarker for immunotherapy response is that a higher burden of mutations increases the probability of generating immunogenic neoantigens which can trigger a T-cell-mediated antitumour response.…”

Section: Discussionmentioning

confidence: 99%

Tumour mutational burden: primary versus metastatic tissue creates systematic bias

Schnidrig

Turajlic

Litchfield

2019

Immuno-Oncology Technology

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Tumour mutational burden (TMB) has emerged as a reproducible biomarker to predict immunotherapy response across multiple cancer types. However, a key aspect of TMB measurement that is often overlooked is the source of tissue sample used, which creates a potential for systematic bias. The predominant source is either primary or metastatic tumour tissue. Primary tumours are more heterogeneous and reflect a longer period of tumour evolution, whereas metastases tend to have a more monoclonal structure and potentially different TMB scores. Studies to date measuring TMB have used a heterogeneous set of primary and metastatic tissues, which may explain some of the variability in predictive TMB values across studies. This paper presents data to show that there is a systematic difference whereby metastatic TMB is biased towards higher values than primary TMB (36% higher, paired Wilcoxon, P ¼ 0.0008). However, effectiveness in predicting overall survival during immune checkpoint inhibitor therapy was found to be equivalent between primary and metastatic TMB. We highlight that lower TMB in primary tissue may be important in cases with borderline primary TMB, where assaying metastatic TMB may lead to a different treatment stratification result. As TMB progresses towards clinical implementation, particularly in classically non-immunogenic tumour types, it is important to have better curated trials with either the source of tissue annotated or a prospective study assessing concordance between paired primary and metastatic tissue.

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Section: Discussionmentioning

confidence: 99%

Tumour mutational burden: primary versus metastatic tissue creates systematic bias

Schnidrig

Turajlic

Litchfield

2019

Immuno-Oncology Technology

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“…We propose two potential explanations for this observation. First, according to the recently proposed single-cell expansion model, cells acquiring melphalan-induced mutations must undergo clonal expansion for those mutations to be detectable by bulk WGS 42 . Conversely, in a setting of neutral evolution 25 , where no single cell has a major growth advantage, newly acquired mutations would not reach the threshold for detection by WGS (Fig.…”

Section: Discussionmentioning

confidence: 99%

Timing the initiation of multiple myeloma

et al. 2020

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The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2 nd -3 rd decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the premalignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.

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“…2c, Extended Data Fig. 1b-e) and a signature characterised predominantly by T>G mutations in an individual treated with capecitabine 43,44 (Fig. 2f).…”

Section: Mutational Signaturesmentioning

confidence: 97%

“…2a). Two therapy-associated signatures were identified; an SBS35-like signature which is associated with platinum-based chemotherapy 9,43 in an individual treated with oxaliplatin ( Fig. 2c, Extended Data Fig.…”

Section: Mutational Signaturesmentioning

confidence: 99%

“…HDP10 was found to be due to platinum-based chemotherapy, as it is constituted of SBS31 and SBS35. However, the report of a spectrum of signatures due to these chemotherapy agents 43 and the relatively poor reconstitution using SBS31 and SBS35 only, prompted us to retain HDP10 without further decomposition hence, we name it SBS35-like. A similar approach was used for the capecitabine-related HDP12 component, which resembles SBS17b but has closer similarity to previously reported therapy-related signatures 43,44 .…”

Section: Mutational Signature Analysismentioning

confidence: 99%

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Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

Robinson

Coorens

Palles

et al. 2020

Preprint

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Mutation accumulation over time in normal somatic cells contributes to cancer development and is proposed as a cause of ageing. DNA polymerases Pol e and Pol d replicate DNA with high fidelity during normal cell divisions. However, in some cancers defective proofreading due to acquired mutations in the exonuclease domains of POLE or POLD1 causes markedly elevated somatic mutation burdens with distinctive mutational signatures. POLE and POLD1 exonuclease domain mutations also cause familial cancer predisposition when inherited through the germline. Here, we sequenced normal tissue DNA from individuals with germline POLE or POLD1 exonuclease domain mutations. Increased mutation burdens with characteristic mutational signatures were found to varying extents in all normal adult somatic cell types examined, during early embryogenesis and in sperm. Mutation burdens were further markedly elevated in neoplasms from these individuals. Thus human physiology is able to tolerate ubiquitously elevated mutation burdens. Indeed, with the exception of early onset cancer, individuals with germline POLE and POLD1 exonuclease domain mutations are not reported to show abnormal phenotypic features, including those of premature ageing. The results, therefore, do not support a simple model in which all features of ageing are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.POLE and POLD1 exonuclease domain mutations can also be inherited through the germline causing a rare autosomal dominant familial cancer predisposition syndrome, known as Polymerase Proofreading Associated Polyposis (PPAP), characterised primarily by early-onset colorectal and endometrial tumours 16,17 . It is plausible that an increased somatic mutation rate underlies this cancer predisposition and high somatic mutation loads have been reported in the small number of neoplasms analysed from such individuals 17 . However, whether the mutation rate is elevated in normal cells, or just in neoplastic cells, is not known. If elevated in normal cells, the magnitude of the increase, whether it is raised over the whole lifespan, the range of tissues and fraction of cells in each tissue it affects, and the impact of subsequent neoplastic change are important questions to address in elucidating the pathogenesis of neoplastic transformation.Accrual of somatic mutations has been proposed as the primary biological mechanism underlying ageing 18-21 . This hypothesis is based on the premises that a) mutations accumulate throughout life; and b) higher mutation loads cause widespread malfunction of cell biology. Recent reports have confirmed that the somatic mutation burden in normal cells does increase during life in a more or less linear manner 22-30 , compatible with a causal role for somatic mutations in ageing. However, somatic mutations could, in principle, accumulate without significant biological consequences. Thus, study of individuals with inherited POLE or POLD1 exonuclease domain mutations could provide insi...

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The mutational footprints of cancer therapies

Cited by 252 publications

References 49 publications

Tumour mutational burden: primary versus metastatic tissue creates systematic bias

Tumour mutational burden: primary versus metastatic tissue creates systematic bias

Timing the initiation of multiple myeloma

Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

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