Yap ta, gerlinger m, futreal pa, pusztai l, swanton c. Landscape of intratumor heterogeneity at the copy number level. Futreal pa, gerliner m, pusztai l, swanton c, yap ta. Mar 23, 2018 intratumor heterogeneity of somatic mtdna mutations. Being a result of clonal diversity within the same tumor, intratumor heterogeneity can be manifested in variability of genetic and epigenetic status, gene and protein expression, morphological structure, and other. A look inside its heterqenaus nature intratumor heterogeneity. Yap ta1, gerlinger m, futreal pa, pusztai l, swanton c. Comprehensive sampling techniques and measuring heterogeneity. Early evolutionary divergence between papillary and. Intratumor heterogeneity can manifest as spatial and temporal patterns of genetic diversity. Envisaging tumor growth as a darwinian tree with the trunk representing ubiquitous mutations and the branches representing heterogeneous mutations may help in drug discovery and. In a study of lung cancer and melanoma, mcgranahan et al. We collected data on somatic mutations and cnas from publications, to add to the cancertracer database. Accumulating evidence suggests that intratumor heterogeneity likely is the key to understanding treatment failure.
Nowadays, the interest in this field is raising again with the emergence of need for. Branched tree evolution model glioblastoma multiforme. A novel representation of intersite tumour heterogeneity from pretreatment computed tomography textures classifies ovarian cancers by clinical outcome. Most advanced solid tumors remain incurable, with resistance to chemotherapeutics and targeted therapies a common cause of poor clinical outcome. One contributing factor in antitumor immunity is the repertoire of neoantigens created by genetic mutations within tumor cells. Spatial intratumoral heterogeneity and temporal clonal. Recent technological advances in the field of molecular diagnostics including bloodbased tumor genotyping allow the measurement of clonal evolution in patients with cancer, thus adding a new dimension to precision medicine. Deciphering intratumor heterogeneity using cancer genome.
The clinical implications of such heterogeneity are profound, given that the identification of distinct subpopulations within a tumor may predict disease outcome or treatment response. The team noted a wide range of allelic variant frequencies in. A substantial obstacle to appropriate selection of precision therapies is intratumor genetic heterogeneity. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. Drugresistant subclones are present at a low frequency in tissues at the time of biopsy, but can also arise as a result of acquired somatic mutations. One important concept about intratumor genomic heterogeneity is the genomeaxis evolution model, which describes that gene evolution can increase the survival. Swanton c 2012 intratumor heterogeneity and branched evolution. Purpose this phase i study assessed the safety, tolerability, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible panerbb inhibitor, in patients with human epidermal growth factor receptor 2 her2positive metastatic breast cancer. Background intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalizedmedicine strategies that depend on results from single tumorbiopsy samples. Below the plot are illustrative phylogenetic trees that demonstrate the spectrum of intratumor heterogeneity, from high left to low right. Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma.
Background intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalizedmedicine strategies that depend on results from. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Therefore the aim of this study was to characterise intratumor heterogeneity in esophageal adenocarcinoma. Jun 01, 2016 intratumor heterogeneity within individual cancer tissues underlies the numerous phenotypes of cancer. Intratumoral heterogeneity ith has increasingly being described for multiple cancers as the root cause of therapy resistance. Molecular clonality analysis of esophageal adenocarcinoma. Oct 10, 2014 cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity ith. Intratumor heterogeneity manifests in spatial and temporal patterns of genetic, phenotypic, and functional diversity 18. Detection of ubiquitous and heterogeneous mutations in cell. Patients and methods pyrotinib was administered continuously, orally, once per day to patients who did not have prior. A example of intratumor heterogeneity based on pdgfra aberrations in patient sp49. Through the analysis of structural variations and allelic frequencies in a primary basal breast cancer, a xenograft, and a brain metastasis from the same patient, ding and colleagues showed that the metastasis may derive from a lowfrequency subclone within the primary.
Intratumor heterogeneity in localized lung adenocarcinomas. Heterogeneous components of lung adenocarcinomas confer. Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity ith. We propose that intratumor genetic heterogeneity combined with the polygenic nature of drug resistance may impede both the implementation of.
Deciphering intratumor heterogeneity and temporal acquisition. Seeing the wood for the trees, abstract most advanced solid tumors remain incurable, with resistance to chemotherapeutics and targeted therapies a common cause of poor clinical outcome. Envisaging tumor growth as a darwinian tree with the trunk representing ubiquitous. The team noted a wide range of allelic variant frequencies in the. Spatial and temporal diversity in genomic instability processes defines. The new engl and journal of medicine 22 n engl j med 366. The goal of this study is to assess the consistency of these hrd measures in different biopsies from distinct areas. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mtor inhibitor therapy. Intratumor heterogeneity in human glioblastoma reflects. Evidence of intra tumor genetic heterogeneity was, however, observed, given that the liver metastasis was enriched for mutations either only present at low allele fractions in the primary tumor i. Intratumor heterogeneity inherent in the majority of human cancers is a major obstacle for a highly efficient diagnosis and successful prognosis and treatment of these diseases.
On average, 76% of all mutations and 20 out of 21 known. One important concept about intratumor genomic heterogeneity is the genomeaxis evolution model, which describes that gene evolution can increase the. Intratumor heterogeneity may have impacts on tumor biopsy strategy, characterization of actionable targets, treatment planning, and drug resistance 16. The goal of this study is to assess the consistency of these hrd measures in different biopsies from distinct. In essence, it means considering as a target not only. Intratumour heterogeneity and evolutionary bottlenecking. B for each patient, the number of fragments that exhibit cnas in a putative driver. Michor, polyak, and colleagues investigated changes in intratumor cellular diversity during neoadjuvant chemotherapy in breast cancer. We applied multiregion wholeexome sequencing wes on 11 localized lung adenocarcinomas. An mr may be an unfavorable prognostic factor and are suspected with tumor genetic heterogeneity 5. Bioinformatics tools such as absolute and pyclone integrate data on variant allele frequency, local copy number and tumor purity, and can give estimates of the clonality of somatic events, even within individual tumor biopsies. Kimuras neutral theory provides the whole theoretical basis of the behavior of mutations in a wrightfisher population. Intratumor heterogeneity has been demonstrated in several cancer types, following a model of branched evolution.
Intratumor heterogeneity may contribute to this failure by initiating phenotypic diversity enabling drug resistance to emerge and by introducing tumor sampling bias. The 3biomarker homologous recombination deficiency hrd assay measures the number of telomeric allelic imbalances, loss of heterozygosity, and largescale state transitions in tumor dna and combines these metrics into a single score that reflects dna repair deficiency. Intratumor heterogeneity and evolutionary bottlenecking. Oct 10, 2014 intratumor heterogeneity may have impacts on tumor biopsy strategy, characterization of actionable targets, treatment planning, and drug resistance 16. On average, 76% of all mutations and 20 out of 21 known cancer gene. Identification of a therapeutic strategy targeting amplified fgf19 in liver cancer by oncogenomic screening. View the article pdf and any associated supplements and figures for a period of 48 hours. Ith has recently been elucidated in substantial detail in several cancer types using nextgeneration sequencing ngs approaches 714. Nov 14, 20 intratumor heterogeneity inherent in the majority of human cancers is a major obstacle for a highly efficient diagnosis and successful prognosis and treatment of these diseases. Increasing evidence supports the existence of intratumor heterogeneity in various solid tumor types, including nonsmallcell lung cancer nsclc 1 x 1. Mar 28, 2012 intratumor heterogeneity may contribute to this failure by initiating phenotypic diversity enabling drug resistance to emerge and by introducing tumor sampling bias. Yap ta, gerlinger m, futreal pa, pusztai l, swanton c 2012 intratumor heterogeneity.
Tumor heterogeneity and the biology of cancer invasion and metastasis. Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm suspicious for a follicular neoplasm cytology by thyroseq v2 nextgeneration sequencing. It is unknown to which extent intratumor heterogeneity is applicable to esophageal adenocarcinoma. Aug 14, 2014 a substantial obstacle to appropriate selection of precision therapies is intratumor genetic heterogeneity. Glioblastoma gb is the most common and aggressive primary brain malignancy, with poor prognosis and a lack of effective therapeutic options.
Intratumor heterogeneity ith refers to the variability within a tumor, which is characterized by the presence of different cell populations with distinct genetic and phenotypic traits. Detection of ubiquitous and heterogeneous mutations in. Phase i study and biomarker analysis of pyrotinib, a novel. Clinical applications and limitations of next generation. Recent evidence supports a model of branched evolution leading to variable ith in different. Recent evidence supports a model of branched evolution leading to variable ith in different tumors 9. Recent studies have started to explore the scope of ith in glioblastoma gbm, a highly aggressive and fatal form of brain tumor, to explain its inevitable therapy resistance and disease relapse. There is a growing evidence of intratumor heterogeneity in different types of cancers including breast cancer 19, renal carcinomas 20, 21, and glioblastomas 22. Cai yr, dong yj, wu hb, liu zc, zhou lj, su d, chen xj, zhang l. British journal of cancer advance online publication, 8 january.
Intratumoral heterogeneity has become the main obstacle in treatment of malignant diseases. We here discuss how it can be applied to a cancer cell population, in which there is an increasing interest in genetic variation within a tumor. Mar 05, 20 glioblastoma gb is the most common and aggressive primary brain malignancy, with poor prognosis and a lack of effective therapeutic options. However, the extent of intratumor heterogeneity as a result of tumor evolution is still poorly understood. Intratumor heterogeneity within individual cancer tissues underlies the numerous phenotypes of cancer. Intratumor heterogeneity of somatic mtdna mutations. The impact of genetic heterogeneity on biomarker development. Tumor subclones ultimately affect therapeutic outcomes due to their distinct molecular features.
Deciphering genetic intratumor heterogeneity can reveal the temporal composition of genetic events that take place during the disease course. Like the corresponding mutations, these neoantigens show intratumoral heterogeneity. Intratumor heterogeneity and branched evolution revealed by. Tumor evolution as a therapeutic target cancer discovery. Green and yellow bars indicate private and shared mutations, respectively. Intratumor heterogeneity of homologous recombination. Genomic studies in breast, liver, pancreas, and kidney tumors have revealed regionally diverse mutational landscapes in primary tumors as well as metastatic sites and sites of local recurrence after treatment 5 8. Although aggressive minimum depth filtering would not improve the false detection rate of subclonal mutations, excluding mutations in lowmappability regions or in certain mutational contexts could help. Forest ecosystem processes depend on local interactions that are modified by the spatial pattern of trees and resources. Apr 28, 2016 yap ta, gerlinger m, futreal pa, pusztai l, swanton c 2012 intratumor heterogeneity. Tumor heterogeneity a contemporary concept founded on historical insights and predictions. Seeing the wood for the trees clonal evolution in cancer c. Although it has been known for decades, that several morphologically different subpopulations of tumor cells do exist within an individual malignant tumor, the interest in this issue has been limited for a long time. They found that lower pretreatment genetic diversity is associated with better response to treatment, pre and posttreatment diversity is the same in patients who failed to achieve pathologic complete response, and the frequency of phenotypically distinct cell.
Multiregional targeted sequencing of four commonly. Some are present in all tumor cells clonal, and others are present in only a fraction of cells subclonal. Aug 27, 2014 deciphering genetic intratumor heterogeneity can reveal the temporal composition of genetic events that take place during the disease course. Clonal neoantigens elicit t cell immunoreactivity and. Effects of resource supplies on processes such as regeneration are increasingly well understood, yet we have few tools to compare resource heterogeneity among forests that differ in structural complexity. Neutral theory in cancer cell population genetics molecular. This intratumor heterogeneity ith contributes to tumor progression, metastasis, and resistance to therapy. Intratumor heterogeneity reflects clinical disease course. Intratumor heterogeneity and branched evolution revealed. Such advances have shown bewildering intertumor heterogeneity with limited somatic alterations. Spatial separation of subclones within an individual tumor is usually investigated by multiregion sequencing.
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