Big Bang Tumor Growth and Clonal Evolution

Sun, Ruping; Hu, Zheng; Curtis, Christina

doi:10.1101/cshperspect.a028381

Cited by 41 publications

(39 citation statements)

References 96 publications

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“…This model places macro-cellular evolution (where genome re-organization dominates) prior to micro-cellular evolution (where cancer gene mutation promotes population growth) and emphasizes the importance of CIN for generating new cancer genomes. This model fits well with both karyotype data and sequencing data from various cancer models [ 3 , 10 , 21 , 71 , 79 , 80 , 81 , 82 , 83 ]. More validation experiments are needed to examine this model.…”

Section: Conclusion and Future Perspectivesupporting

confidence: 52%

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Sharpe

Heng

2020

Genes

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When discussing chromosomal instability, most of the literature focuses on the characterization of individual molecular mechanisms. These studies search for genomic and environmental causes and consequences of chromosomal instability in cancer, aiming to identify key triggering factors useful to control chromosomal instability and apply this knowledge in the clinic. Since cancer is a phenomenon of new system emergence from normal tissue driven by somatic evolution, such studies should be done in the context of new genome system emergence during evolution. In this perspective, both the origin and key outcome of chromosomal instability are examined using the genome theory of cancer evolution. Specifically, chromosomal instability was linked to a spectrum of genomic and non-genomic variants, from epigenetic alterations to drastic genome chaos. These highly diverse factors were then unified by the evolutionary mechanism of cancer. Following identification of the hidden link between cellular adaptation (positive and essential) and its trade-off (unavoidable and negative) of chromosomal instability, why chromosomal instability is the main player in the macro-cellular evolution of cancer is briefly discussed. Finally, new research directions are suggested, including searching for a common mechanism of evolutionary phase transition, establishing chromosomal instability as an evolutionary biomarker, validating the new two-phase evolutionary model of cancer, and applying such a model to improve clinical outcomes and to understand the genome-defined mechanism of organismal evolution.

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Section: Conclusion and Future Perspectivesupporting

confidence: 52%

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Sharpe

Heng

2020

Genes

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“…Importantly, however, the presence of numerous heterogeneous or private driving mutations in both precursor and endometrial carcinoma populations, most at clonal CCF, indicates a fitness advantage to these mutations regardless of histologic appearance or spatial proximity. Phylogenetic analysis thus supports extensive branched evolution in both precursor and endometrial carcinoma populations, consistent with branched evolution in LGEC development, in agreement with mechanisms in most other profiled cancers (23,24).…”

Section: Clonal Sweep Of Heterogeneous Mutations Is Common In Lgecsupporting

confidence: 74%

Multiclonality and Marked Branched Evolution of Low-Grade Endometrioid Endometrial Carcinoma

Vega

Samaha

et al. 2019

Molecular Cancer Research

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The molecular events driving low-grade endometrioid endometrial carcinoma (LGEC) development-like in many cancers-are incompletely understood. Hence, here we performed multiregion, comprehensive somatic molecular profiling of routinely processed formalin-fixed, paraffin-embedded (FFPE) material from 13 cases of LGEC totaling 64 minute, spatially defined cell populations ranging from presumed precursor lesions through invasive LGEC. Shared driving PTEN, PIK3R1, or PIK3CA mutations support clonal origin of the samples in each case, except for two cases with two clonally distinct neoplastic populations, consistent with unexpected multiclonality in LGEC development. Although substantial heterogeneity in driving somatic alterations was present across populations in nearly all cases, these alterations were usually clonal in a given population, supporting continued selection and clonal sweeping of driving alterations in populations with both precursor and LGEC histology. Importantly, CTNNB1 mutational status, which has been proposed as both prognos-tic and predictive in LGEC, was frequently heterogeneous and subclonal, occurring both exclusively in precursor or cancer populations in different cases. Whole-transcriptome profiling of coisolated RNA from 12 lesions (from 5 cases) was robust and confirmed histologic and molecular heterogeneity, including activated Wnt signaling in CTNNB1-mutant versus wild-type populations. Taken together, we demonstrate clinically relevant multiclonality and intratumoral heterogeneity during LGEC development with important implications for diagnosis, prognosis, and therapeutic prediction. More broadly, our methodology is broadly scalable to enable highthroughput genomic and transcriptomic characterization of precursor and invasive cancer populations from routine FFPE specimens.Implications: Multiregion profiling of LGEC populations using a highly scalable approach demonstrates clinically relevant multiclonality and intratumoral heterogeneity.

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“…To the best of our knowledge, to date no information is available on phenotypic heterogeneity within primary breast cancer with respect to functional signaling pathway activity. Knowledge on signaling pathway heterogeneity is limited to studies on variations in ER and HER2 IHC staining, and on spatial variations observed in specific gene mutations and copy number changes across the tumor (17,18,(34)(35)(36)(37). However, this does not provide information on variations in functional signaling pathway activity.…”

Section: Within Tumor Heterogeneity Of Signaling Pathway Activitymentioning

confidence: 99%

“…Similar problems exist when choosing targeted therapy for treatment of patients with metastatic disease, where therapy choice is generally based on analysis of a tissue sample from the PT, although marked genotypic and phenotypic differences between PT and distant site (DS) metastases have been described (15,16). Unfortunately, limited knowledge is available on heterogeneity in signaling pathway activity within a PT and between PT and LN and DS metastases (17,18). One reason has been lack of reliable assays to measure signaling pathway activity in formalin fixed paraffin embedded (FFPE) tissue samples used in the routine diagnostic setting.…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity in signaling pathway activity within primary and between primary and metastatic breast cancer

Inda

Swinderen

Brussel

et al. 2020

Preprint

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BackgroundTargeted drug treatment aims to block tumor driving signaling pathways, and is generally based on analysis of one primary tumor (PT) biopsy. Phenotypic heterogeneity within primary and between primary and metastatic lesions was investigated.MethodsActivity of androgen and estrogen receptor, PI3K-FOXO, Hedgehog, TGFβ, and Wnt signaling pathways was measured in breast cancer samples using a novel mRNA-based assay platform. Macro-scale heterogeneity analysis was performed on multiple spatially distributed PT tissue blocks from 17 luminal A-like, 9 luminal B-like, and 9 ER-negative primary breast cancers; micro-scale heterogeneity analysis was performed on four “quadrant” samples of a single tissue block of respectively 9, 4, and 4 matched PT. Samples from 6 PT with matched lymph node (LN, n=23) and 9 PT with distant metastatic sites (DS, n=12) were analyzed. Statistical variance analysis was performed with linear mixed models. A “checkerboard” model was introduced to explain the observed heterogeneity in PT.ResultsWithin PT, macro-scale heterogeneity in signaling pathway activity was similar to micro-scale heterogeneity, with a possible exception of the PI3K pathway. Variation was significantly higher on microscale for Hedgehog and TGFβ pathways. While pathway activity scores correlated significantly between different locations in the PT, positive correlations decreased between PT and LN, and even more between PT and DS metastases, including the emergence of a negative correlation for the ER pathway.ConclusionWith a possible exception of the PI3K pathway, variation in signaling pathway activity within a single PT tissue block was generally representative for the whole PT, but not for DS or LN metastases. The higher variation in TGFβ and HH pathway activity on microscale suggested the presence of multiple small cancer cell clones. While analysis of multiple sub-samples of a single biopsy block may be sufficient to predict PT response to some targeted therapies, such as hormonal therapy, metastatic breast cancer treatment requires analysis of metastatic biopsies. The findings on phenotypic intra-tumor heterogeneity are compatible with currently emerging ideas on a Big Bang type of cancer evolution.

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Big Bang Tumor Growth and Clonal Evolution

Cited by 41 publications

References 96 publications

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Origins and Consequences of Chromosomal Instability: From Cellular Adaptation to Genome Chaos-Mediated System Survival

Multiclonality and Marked Branched Evolution of Low-Grade Endometrioid Endometrial Carcinoma

Heterogeneity in signaling pathway activity within primary and between primary and metastatic breast cancer

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