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Dynamic Emergence of Observed and Hidden Intra-tumor Heterogeneity.

ABSTRACT: Intra-tumor heterogeneity is frequently observed in cancer patients, and it is associated with therapeutic resistance and disease relapse. However, its systematic assessment is still limited and often unfeasible. Here, we use a mathematical model of tumor progression to decipher how multiple clones emerge and organize into complex architectures. We found a trade-off between cancer cell alteration and proliferation rates that defines a transition between low and high heterogeneity, the latter characterized by branching tumor phylogenies. We predict the existence of observed and hidden intra-tumor heterogeneity, which challenges the correct estimation of intrinsic tumor complexity. Although the numbers of observed and hidden clones do not always correlate, we demonstrate that population frequencies of observed clones can be used to estimate the extent of hidden heterogeneity in both simulated and human tumors. The characterization of complex clonal architectures is a critical first step toward understanding their organizing principles and predicting their emergence.

SUBMITTER: Raynaud F

PROVIDER: S-EPMC6820272 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Dynamic Emergence of Observed and Hidden Intra-tumor Heterogeneity.

Raynaud Franck F Mina Marco M Ciriello Giovanni G

iScience 20191010

Intra-tumor heterogeneity is frequently observed in cancer patients, and it is associated with therapeutic resistance and disease relapse. However, its systematic assessment is still limited and often unfeasible. Here, we use a mathematical model of tumor progression to decipher how multiple clones emerge and organize into complex architectures. We found a trade-off between cancer cell alteration and proliferation rates that defines a transition between low and high heterogeneity, the latter cha ...[more]

PMID: 31655256

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Project description:Colorectal cancer arises in part from the cumulative effects of multiple gene lesions. Recent studies in selected cancer types have revealed significant intra-tumor genetic heterogeneity and highlighted its potential role in disease progression and resistance to therapy. We hypothesized the existence of significant intra-tumor genetic heterogeneity in rectal cancers involving variations in localized somatic mutations and copy number abnormalities. Two or three spatially disparate regions from each of six rectal tumors were dissected and subjected to the next-generation whole-exome DNA sequencing, Oncoscan SNP arrays, and targeted confirmatory sequencing and analysis. The resulting data were integrated to define subclones using SciClone. Mutant-allele tumor heterogeneity (MATH) scores, mutant allele frequency correlation, and mutation percent concordance were calculated, and copy number analysis including measurement of correlation between samples was performed. Somatic mutations profiles in individual cancers were similar to prior studies, with some variants found in previously reported significantly mutated genes and many patient-specific mutations in each tumor. Significant intra-tumor heterogeneity was identified in the spatially disparate regions of individual cancers. All tumors had some heterogeneity but the degree of heterogeneity was quite variable in the samples studied. We found that 67-97% of exonic somatic mutations were shared among all regions of an individual's tumor. The SciClone computational method identified 2-8 shared and unshared subclones in the spatially disparate areas in each tumor. MATH scores ranged from 7 to 41. Allele frequency correlation scores ranged from R(2)=0.69-0.96. Measurements of correlation between samples for copy number changes varied from R(2)=0.74-0.93. All tumors had some heterogeneity, but the degree was highly variable in the samples studied. The occurrence of significant intra-tumor heterogeneity may allow selected tumors to have a genetic reservoir to draw from in their evolutionary response to therapy and other challenges.

Project description:BackgroundMalignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples.MethodsIntra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed.ResultsSequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients.ConclusionsThis comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.

Dataset Information

Dynamic Emergence of Observed and Hidden Intra-tumor Heterogeneity.

Publications

Dynamic Emergence of Observed and Hidden Intra-tumor Heterogeneity.

Similar Datasets

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