The effects of mutational processes and selection on driver mutations across cancer types

Temko, Daniel; Tomlinson, Ian; Severini, Simone; Schuster-Böckler, Benjamin; Graham, Trevor A.

doi:10.1038/s41467-018-04208-6

Cited by 98 publications

(89 citation statements)

References 33 publications

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“…These findings highlight the dominant association that loss of MMR function has with the development of sebaceous neoplasia in people with Lynch syndrome. Of interest, signatures 20 and 26, have been associated with defective MMR (Helleday, Eshtad, & Nik-Zainal, 2014;Temko, Tomlinson, Severini, Schuster-Bockler, & Graham, 2018; Wellcome Sanger Institute, 2019), but were not observed in the Lynch-related sebaceous skin lesions in this study. Only three MMR-deficient sebaceous lesions were tested in this study and so they may not represent the complete heterogeneity of mutation signatures that are observed in Lynch-related sebaceous neoplasia.…”

Section: Discussionmentioning

confidence: 59%

Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome

Georgeson

Walsh

Clendenning

et al. 2019

Molec Gen & Gen Med

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Background Muir‐Torre syndrome is defined by the development of sebaceous skin lesions in individuals who carry a germline mismatch repair (MMR) gene mutation. Loss of expression of MMR proteins is frequently observed in sebaceous skin lesions, but MMR‐deficiency alone is not diagnostic for carrying a germline MMR gene mutation. Methods Whole exome sequencing was performed on three MMR‐deficient sebaceous lesions from individuals with MSH2 gene mutations (Lynch syndrome) and three MMR‐proficient sebaceous lesions from individuals without Lynch syndrome with the aim of characterizing the tumor mutational signatures, somatic mutation burden, and microsatellite instability status. Thirty predefined somatic mutational signatures were calculated for each lesion. Results Signature 1 was ubiquitous across the six lesions tested. Signatures 6 and 15, associated with defective DNA MMR, were significantly more prevalent in the MMR‐deficient lesions from the MSH2 carriers compared with the MMR‐proficient non‐Lynch sebaceous lesions (mean ± SD =41.0 ± 8.2% vs. 2.3 ± 4.0%, p = 0.0018). Tumor mutation burden was, on average, significantly higher in the MMR‐deficient lesions compared with the MMR‐proficient lesions (23.3 ± 11.4 vs. 1.8 ± 0.8 mutations/Mb, p = 0.03). All four sebaceous lesions observed in sun exposed areas of the body demonstrated signature 7 related to ultraviolet light exposure. Conclusion Tumor mutational signatures 6 and 15 and somatic mutation burden were effective in differentiating Lynch‐related from non‐Lynch sebaceous lesions.

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Section: Discussionmentioning

confidence: 59%

Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome

Georgeson

Walsh

Clendenning

et al. 2019

Molec Gen & Gen Med

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“…At a fine-grained level, it is the individual mutations themselves which are responsible for fitness variations among cells, and the mutational processes are simply a source of variation. We show however, that by considering a multilevel model, fitness across larger time-scales can be driven by a combination of individual mutations and mutational processes, potentially even primarily by the latter as suggested by recent results [8,33].…”

Section: Cyclic and Multilevel Causality In Biologymentioning

confidence: 51%

“…A particular case we consider is cancer evolution. As has been recently demonstrated [1,8,33], tumors not only acquire particular sets of mutations (with positive, negative and neutral effects on growth) over their development, but also acquire prototypical mutational processes. These processes are caused by factors such as disruption of the DNA repair machinery or other cellular mechanisms such as DNA methylation, or environmental effects such as carcinogens, which cause particular mutations to become more prevalent depending on local sequence characteristics or chromosomal position for example.…”

Section: Cyclic and Multilevel Causality In Biologymentioning

confidence: 90%

Cyclic and Multilevel Causation in Evolutionary Processes

Warrell

Gerstein

2019

Preprint

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Many models of evolution are implicitly causal processes. Features such as causal feedback between evolutionary variables and evolutionary processes acting at multiple levels, though, mean that conventional causal models miss important phenomena. We develop here a general theoretical framework for analyzing evolutionary processes drawing on recent approaches to causal modeling developed in the machine-learning literature, which have extended Pearl's 'do'-calculus to incorporate cyclic causal interactions and multilevel causation. We also develop information-theoretic notions necessary to analyze causal information dynamics in our framework, introducing a causal generalization of the Partial Information Decomposition framework. We show how our causal framework helps to clarify conceptual issues in the contexts of complex trait analysis and cancer genetics, including assigning variation in an observed trait to genetic, epigenetic and environmental sources in the presence of epigenetic and environmental feedback processes, and variation in fitness to mutation processes in cancer using a multilevel causal model respectively, as well as relating causally-induced to observed variation in these variables via information theoretic bounds. In the process, we introduce a general class of multilevel causal evolutionary processes which connect evolutionary processes at multiple levels via coarse-graining relationships. Further, we show how a range of 'fitness models' can be formulated in our framework, as well as a causal analog of Price's equation (generalizing the probabilistic 'Rice equation'), clarifying the relationships between realized/probabilistic fitness and direct/indirect selection. Finally, we consider the potential relevance of our

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“…There is evidence that even major and/or cancer-initiating driver mutations (e.g. APC, IDH1/2, KRAS, PIK3CA, etc) are differentially selected depending on cancer type 37 , strongly suggesting a role for the TME, broadly defined, in selecting many of the common driver mutations.…”

Section: Discussionmentioning

confidence: 99%

Why is cancer not more common? A changing microenvironment may help to explain why, and suggests strategies for anti-cancer therapy

Jiang

Tomlinson

2018

Preprint

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AbstractOne of the great unsolved puzzles in cancer biology is not why cancers occur, but rather, explaining why so few cancers occur compared with the theoretical number that could occur given the number of progenitor cells in the body and the normal mutation rate. We hypothesised that a contributory explanation is that the tumour microenvironment (TME) is not fixed, and that this could impair the ability of neoplastic cells to retain a high enough fitness to become a cancer. The TME has implicitly been assumed to be static in most cancer evolution models, and we therefore developed a mathematical model of spatial cancer evolution assuming that the TME, and thus the optimum cancer phenotype, change over time. Based on simulations, we show how cancer cell populations adapt to diverse changing TME conditions and fitness landscapes. Compared with static TMEs which generate neutral dynamics, changing TMEs lead to complex adaptations with spatio-temporal heterogeneity involving variable sub-clonal fitness, mixing, competition and phylogeny patterns. In many cases, cancer cell populations fail to grow or undergo spontaneous regression, and even extinction. Our analyses predict that cancer evolution in a changing TME is challenging, and can help to explain why cancer is neither inevitable nor as common as expected. Should cancer driver mutations with effects dependent of the TME exist, they are likely to be selected. Anti-cancer prevention and treatment strategies based on changing the TME are feasible and potentially effective.

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The effects of mutational processes and selection on driver mutations across cancer types

Cited by 98 publications

References 33 publications

Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome

Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome

Cyclic and Multilevel Causation in Evolutionary Processes

Why is cancer not more common? A changing microenvironment may help to explain why, and suggests strategies for anti-cancer therapy

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