Cancer evolution: Darwin and beyond

Vendramin, Roberto; Litchfield, Kevin; Swanton, Charles

doi:10.15252/embj.2021108389

Cited by 157 publications

(131 citation statements)

References 272 publications

(381 reference statements)

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“…Thus, it might be speculated that the metastases are derived from the bilateral tumour. In general, several competing models of tumour evolution, namely linear, branching, neutral, and punctuated, or even mixed models, are currently discussed [ 31 ]. Our findings show that cases share a set of mutations, which indicates a common evolutionary origin, but our approach does not enable us to resolve admixtures of clones.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Genetic Heterogeneity in Recurrent Metastases of Renal Cell Carcinoma

Sauter-Meyerhoff

Bohnert

Mazzola

et al. 2021

Cancers

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Metastatic renal cell carcinoma (RCC) exhibits poor prognosis. Better knowledge of distant metastases is crucial to foster personalized treatment strategies. Here, we aimed to investigate the genetic landscape of metastases, including synchronous and/or recurrent metastases to elucidate potential drug target genes and clinically relevant mutations in a real-world setting of patients. We assessed 81 metastases from 56 RCC patients, including synchronous and/or recurrent metastases of 19 patients. Samples were analysed through next-generation sequencing with a high coverage (~1000× mean coverage). We therefore established a novel sequencing panel comprising 32 genes with impact on RCC development. We observed a high frequency of mutations in known RCC driver genes (e.g., >40% carriers of VHL and PBRM1 mutations) in metastases irrespective of the metastatic site. The somatic mutational composition was significantly associated with cancer-specific survival (p(logrank) = 0.03). Moreover, we identified in 34 patients at least one drug target gene as well as clinically relevant mutations listed in the VICC Meta-Knowledgebase in 7%. In addition to significantly higher mutational burden in recurrent metastases compared to earlier ones, synchronous and/or recurrent metastases of individual patients, even after a time-period >2 yrs, shared a high proportion of somatic events. Our data demonstrate the importance of somatic profiling in metastases for precision medicine in RCC.

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Section: Discussionmentioning

confidence: 99%

Characterization of Genetic Heterogeneity in Recurrent Metastases of Renal Cell Carcinoma

Sauter-Meyerhoff

Bohnert

Mazzola

et al. 2021

Cancers

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“…Tumour evolution is a complex process and nowadays it is extensively known that beyond genetic alterations, genomic aberrations, such as discordant inheritance or DNA macroalterations, and non-genetic determinants of evolution also play an important role [44]. Together, all these processes are shaping phenotypic plasticity, suggesting that deterministic dynamics could fail to explain the sequence of events observed in tumour evolution.…”

Section: Discussionmentioning

confidence: 99%

Stochastic fluctuations drive non-genetic evolution of proliferation in clonal cancer cell populations

Ortega-Sabater

2021

Preprint

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Evolutionary dynamics allows to understand many changes happening in a broad variety of biological systems, ranging from individuals to complete ecosystems. It is also behind a number of remarkable organizational changes that happen during the natural history of cancers. These reflect tumour heterogeneity, which is present at all cellular levels, including the genome, proteome and phenome, shaping its development and interrelation with its environment. An intriguing observation in different cohorts of oncological patients is that tumours exhibit an increased proliferation as the disease progresses, while the timescales involved are apparently too short for the fixation of sufficient driver mutations to promote an explosive growth. In this paper we discuss how phenotypic plasticity, emerging from a single genotype, may play a key role and provide a ground for a continuous acceleration of the proliferation rate of clonal populations with time. Here we address this question by means of stochastic and deterministic mathematical models that capture proliferation trait heterogeneity in clonal populations and elucidate the contribution of phenotypic transitions on tumour growth dynamics.

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“… 14 Recently, some excellent reviews have summarized the historical developments and new advances in tumorigenesis models. 15 , 16 These models incorporated non-genetic determinants into stochastic model and TSC models and highlighted the tumorigenic epigenetic changes via cellular reprogramming or microenvironmental stress. All of these models are reasonable hypotheses to describe tumorigenesis and tumor heterogeneity, but each model is insufficient to explain how the linear relationship between the cellular origin and the biological behavior of tumors are formed.…”

Section: Limitations In Understanding Of the Cellular Origin Of Tumor...mentioning

confidence: 99%

“…These models well demonstrated the intratumoral heterogeneity caused by accumulated genetic and epigenetic mutations, and microenvironment stress. 15 , 158 Different from previous models, we currently attempted to discuss the influence of the intrinsic stemness of TIC on parenchymal and stromal heterogeneity of a tumor, and to describe the epigenetic regularity behind tumor heterogeneity.…”

Section: The Cellular Origin Of Tic Can Determine Both Tumor Parenchy...mentioning

confidence: 99%

Epigenetic Inheritance From Normal Origin Cells Can Determine the Aggressive Biology of Tumor-Initiating Cells and Tumor Heterogeneity

Ji-liang

Zhao

et al. 2022

Cancer Control

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The acquisition of genetic- and epigenetic-abnormalities during transformation has been recognized as the two fundamental factors that lead to tumorigenesis and determine the aggressive biology of tumor cells. However, there is a regularity that tumors derived from less-differentiated normal origin cells (NOCs) usually have a higher risk of vascular involvement, lymphatic and distant metastasis, which can be observed in both lymphohematopoietic malignancies and somatic cancers. Obviously, the hypothesis of genetic- and epigenetic-abnormalities is not sufficient to explain how the linear relationship between the cellular origin and the biological behavior of tumors is formed, because the cell origin of tumor is an independent factor related to tumor biology. In a given system, tumors can originate from multiple cell types, and tumor-initiating cells (TICs) can be mapped to different differentiation hierarchies of normal stem cells, suggesting that the heterogeneity of the origin of TICs is not completely chaotic. TIC’s epigenome includes not only genetic- and epigenetic-abnormalities, but also established epigenetic status of genes inherited from NOCs. In reviewing previous studies, we found much evidence supporting that the status of many tumor-related “epigenetic abnormalities” in TICs is consistent with that of the corresponding NOC of the same differentiation hierarchy, suggesting that they may not be true epigenetic abnormalities. So, we speculate that the established statuses of genes that control NOC’s migration, adhesion and colonization capabilities, cell-cycle quiescence, expression of drug transporters, induction of mesenchymal formation, overexpression of telomerase, and preference for glycolysis can be inherited to TICs through epigenetic memory and be manifested as their aggressive biology. TICs of different origins can maintain different degrees of innate stemness from NOC, which may explain why malignancies with stem cell phenotypes are usually more aggressive.

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Cancer evolution: Darwin and beyond

Cited by 157 publications

References 272 publications

Characterization of Genetic Heterogeneity in Recurrent Metastases of Renal Cell Carcinoma

Characterization of Genetic Heterogeneity in Recurrent Metastases of Renal Cell Carcinoma

Stochastic fluctuations drive non-genetic evolution of proliferation in clonal cancer cell populations

Epigenetic Inheritance From Normal Origin Cells Can Determine the Aggressive Biology of Tumor-Initiating Cells and Tumor Heterogeneity

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