The causes and consequences of genetic heterogeneity in cancer evolution

Burrell, Rebecca A.; McGranahan, Nicholas; Bártek, Jiří; Swanton, Charles

doi:10.1038/nature12625

Cited by 1,986 publications

(1,661 citation statements)

References 123 publications

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“…Several studies either sequencing tumour bulks or single tumour cells have demonstrated that breast cancer subtypes exhibit considerable spatial and temporal heterogeneity on the genetic level within the primary, during metastatic progression and in patient‐derived xenografts 24, 25, 26, 27, 28, 29, 30, 31. This genomic diversity within breast cancers is a result of but also facilitates cellular evolution 34 allowing the tumour to dynamically adapt to external or internal stimuli as originally conceptualized by Nowell in 1976 54.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, recent genomic profiling studies 24, 25, 26, 27, 28, 29, 30, 31 suggested a substantial degree of intra‐ and inter‐tumour heterogeneity fuelling selection processes during evolution of breast cancer 32, 33, which may complicate prognostication as well as prediction and impede cancer precision medicine approaches 34. In this context, it is worth recalling that just as the molecular phenotype, the morphological phenotype of the tumour, including tumour grade and tumour size is essentially a result of accumulated genetic aberrations over time, thereby reflecting tumour evolution at the phenotypic level.…”

Section: Introductionmentioning

confidence: 99%

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Classical pathology and mutational load of breast cancer – integration of two worlds

Budczies

Bockmayr

Denkert

et al. 2015

The Journal of Pathology CR

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Breast cancer is a complex molecular disease comprising several biological subtypes. However, daily routine diagnosis is still based on a small set of well‐characterized clinico‐pathological variables. Here, we try to link the two worlds of surgical pathology and multilayered molecular profiling by analyzing the relationships between clinico‐pathological phenotypes and mutational loads of breast cancer. We evaluated the number of mutated genes with somatic non‐silent mutations in different subgroups of breast cancer based on clinico‐pathological, including immunohistochemical and tumour characteristics. The analysis was performed for a cohort of 687 primary breast cancer patients with mutational profiling, gene expression and clinico‐pathological data available from The Cancer Genome Atlas (TCGA) project. The number of mutated genes was strongly positively associated with higher tumour grade (p = 1.4e−14) and with the different immunohistochemical and PAM50 molecular subtypes of breast cancer (p = 1.4e−10 and p = 4.3e−10, respectively). We observed significant associations (|R| > 0.4) between the abundance of mutated genes and expression levels of genes related to proliferation in the overall cohort and hormone receptor positive cohort, including the Recurrence Score gene signature (e.g., MYBL2 and BIRC5). Specific mutated genes (TP53, NCOR1, NF1, PTPRD and RB1) were highly significantly associated with high loads of mutated genes. Multivariate analysis for overall survival (OS) revealed a worse survival for patients with high numbers of mutated genes (hazard ratio = 4.6, 95% CI: 1.0 – 20.0, p = 0.044). Here, we report a strong association of the number of mutated genes with immunohistochemical and PAM50 subtypes and tumour grade in breast cancer. We provide evidence that specific levels of the mutational load underlie different morphological and biological phenotypes, which collectively constitute the current basis of pathological diagnosis. Our study is a step towards genomics‐informed breast pathology and will provide a basis for future studies in this field bridging the gap between morphology, tumour biology and medical oncology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Classical pathology and mutational load of breast cancer – integration of two worlds

Budczies

Bockmayr

Denkert

et al. 2015

The Journal of Pathology CR

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“…Labeling of individual cell clones and modeling of their in vivo expansion can facilitate the understanding of clonal development and adaptation during tumor progression within the heterogeneous landscape in cancer. 1,2 Furthermore, the ability to label and trace individual cells is demanded in many other research areas, including stem cell biology, neuronal networks, or testing of advanced biologicals like oncolytic viruses. Unfortunately, in vivo tracking of single-cell clones has been technically challenging.…”

Section: Introductionmentioning

confidence: 99%

Optical Barcoding for Single-Clone Tracking to Study Tumor Heterogeneity

et al. 2017

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Intratumoral heterogeneity has been identified as one of the strongest drivers of treatment resistance and tumor recurrence. Therefore, investigating the complex clonal architecture of tumors over time has become a major challenge in cancer research. We developed a new fluorescent "optical barcoding" technique that allows fast tracking, identification, and quantification of live cell clones in vitro and in vivo using flow cytometry (FC). We optically barcoded two cell lines derived from malignant glioma, an exemplary heterogeneous brain tumor. In agreement with mathematical combinatorics, we demonstrate that up to 41 clones can unambiguously be marked using six fluorescent proteins and a maximum of three colors per clone. We show that optical barcoding facilitates sensitive, precise, rapid, and inexpensive analysis of clonal composition kinetics of heterogeneous cell populations by FC. We further assessed the quantitative contribution of multiple clones to glioblastoma growth in vivo and we highlight the potential to recover individual viable cell clones by fluorescence-activated cell sorting. In summary, we demonstrate that optical barcoding is a powerful technique for clonal cell tracking in vitro and in vivo, rendering this approach a potent tool for studying the heterogeneity of complex tissues, in particular, cancer.

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“…In addition to evident applications in biological systems and resource management [42], the reported results are also highly applicable in the eld of cancer therapeutics, where inter-and intra-tumor heterogeneity plays a key role in the identi cation of treatments for cancer [3].…”

Section: Managing Cancer As a Heterogeneous Consumer-resource Type Symentioning

confidence: 99%

Resource Consumption, Sustainability, and Cancer

2014

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Preserving a system's viability in the presence of diversity erosion is critical if the goal is to sustainably support biodiversity. Reduction in population heterogeneity, whether inter-or intraspecies, may increase population fragility, either decreasing its ability to adapt e ectively to environmental changes or facilitating the survival and success of ordinarily rare phenotypes. The latter may result in over-representation of individuals who may participate in resource utilization patterns that can lead to over-exploitation, exhaustion, and, ultimately, collapse of both the resource and the population that depends on it. Here, we aim to identify regimes that can signal whether a consumer-resource system is capable of supporting viable degrees of heterogeneity. The framework used here is an expansion of a previously introduced consumer-resource type system of a population of individuals classi ed by their resource consumption. Application of the Reduction Theorem to the system enables us to evaluate the health of the system through tracking both the mean value of the parameter of resource (over)consumption, and the population variance, as both change over time. The article concludes with a discussion that highlights applicability of the proposed system to investigation of systems that are a ected by particularly devastating overly-adapted populations, namely, cancerous cells. Potential intervention approaches for system management are discussed in the context of cancer therapies.

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The causes and consequences of genetic heterogeneity in cancer evolution

Cited by 1,986 publications

References 123 publications

Classical pathology and mutational load of breast cancer – integration of two worlds

Classical pathology and mutational load of breast cancer – integration of two worlds

Optical Barcoding for Single-Clone Tracking to Study Tumor Heterogeneity

Resource Consumption, Sustainability, and Cancer

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