Tumor heterogeneity, a notable feature of cancer, has recently been studied in breast cancer, esophageal cancer, renal cancer 6, 7 and lung cancer 8, 9 through multiregion sequencing of tumor masses. Similarly, many mutations that appeared to be private in the targeted sequencing data were revealed to be branched in the ultra. Intratumor heterogeneity can manifest as spatial and temporal. Intratumor heterogeneity in localized lung adenocarcinomas. Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. Recent evidence supports a model of branched evolution leading to variable. Such branched evolutionary growth was first demonstrated in hematological cancers and more recently in renal cancer through multiregion exome sequencing and in medulloblastoma. Intratumor heterogeneity and branched evolution revealed. Multiregion sequencing has revealed the landscapes of ith for renal 1,2, breast 3, esophageal 4,5, lung 6,7, ovarian 8, prostate 9,10, pancreatic 11, and other types of cancer. Intratumor heterogeneity and branched evolution revealed by. Chawla sn, crispen pl, hanlon al, greenberg re, chen dy, uzzo rg. Trunk and branch model representing intratumor heterogeneity. Results phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Inter and intratumor heterogeneity in hepatocellular.
J rowan, s horswell, j larkin, d endesfelder, e gronroos, p martinez, n matthews, a stewart, p tarpey, i varela, b phillimore, s begum, n. In the recent years the rapid scientific innovation in the evaluation of the individuals genome have allowed the identification of variants associate. Ith has recently been elucidated in substantial detail in several cancer types with the use of nextgeneration sequencing ngs approaches 714. Today, clinical evaluation of tumor heterogeneity is an emergent issue to improve clinical oncology. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing article pdf available in new england journal of medicine 36610. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. Jan 01, 20 the new england journal of medicine recently published a report by gerlinger et al. 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. Translational implications of tumor heterogeneity clinical. Minimal functional driver gene heterogeneity among. Pdf intratumor heterogeneity may foster tumor evolution and adaptation and.
Deciphering intratumor heterogeneity and temporal acquisition. Intratumor heterogeneity and branched evolution revealed by mul. Multiregional sequencing elucidates the evolution of. Impact of tumor heterogeneity on patient treatment decisions. The vast amounts of complex information that can be obtained from basic genetic sequencing tests must be stored, analyzed, and interpreted, creating challenges for clinicians, researchers, and regulatory staff who are concerned with complex ethical, security, and legal issues surrounding patients personal genetic data in the digital age. In particular, intra tumor heterogeneity ith is closely related to cancer progression, resistance to therapy, and recurrences.
Clear cell renal cell carcinoma growth correlates with. The aim of this study was to comprehensively characterize morphologic intratumor heterogeneity in hcc. Genomic architecture and evolution of clear cell renal cell carcinomas defined. Jul 03, 2019 intratumor heterogeneity and branched evolution revealed by multiregion sequencing pdf admin july 3, 2019 0 comments intratumor heterogeneity and branched evolution revealed by multiregion sequencing. A linear evolutionary pattern, whereby successive acquisition of advantageous mutations results in fitter clones that outgrow ancestral clones, results in a relatively homogeneous tumor. The comprehensive genetic characterization revealed marked heterogeneity within and between metastatic lesions from the same patient. Although many tumors follow a branched evolutionary pattern, presumably.
Gerlinger m, rowan aj, horswell s, larkin j, endesfelder d, gronroos e et al. Overview on clinical relevance of intratumor heterogeneity. Advances in nextgeneration sequencing and bioinformatics have led to an unprecedented view of the cancer genome and its evolution. Multiregion sequencing reveals the intratumor heterogeneity of driver mutations in tp53. Pdf intratumor heterogeneity and branched evolution revealed by. Jul 23, 2018 multiregion sequencing has revealed the landscapes of ith for renal 1,2, breast 3, esophageal 4,5, lung 6,7, ovarian 8, prostate 9,10, pancreatic 11, and other types of cancer. Intratumor heterogeneity may foster the selection of a resistant subclone, sometimes detectable prior to treatment. The extent to which metastatic tumors further evolve by accumulating additional mutations is unclear and has yet to be addressed extensively using nextgeneration sequencing of highgrade serous ovarian cancer. Recent studies have shown that intratumor heterogeneity contributes to drug resistance in advanced disease. Impact of tumor heterogeneity on patient treatment. Intratumor heterogeneity inferred from targeted deep. Branched evolutionary growth was detected in this analysis with evidence of. Branched evolutionary growth was detected in this analysis with evidence of convergent evolution.
Intratumor heterogeneity ith may have impacts on tumor biopsy strategy, characterization of actionable targets, treatment planning, and drug resistance 16. Heterogeneous distribution of egfr mutations is extremely rare in. See commentary intratumor heterogeneity and branched evolution. Pdf intratumor heterogeneity and branched evolution revealed.
These evolutionary models are not mutually exclusive and may coexist within tumors. Intratumor heterogeneity in primary kidney cancer revealed by. This study investigated the effects of tumor heterogeneity and everolimus treatment on identification of mutations and. Of these mutations, 37 88% were specifically validated in regions in which they were initially identified fig. These changes can be represented by chromosomal and.
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing european urology. Nextgeneration sequencing is enabling the phylogenetic reconstruction of a cancers life history and has revealed different modes of cancer evolution. Highthroughput sequencing has revealed evidence of variegated clonal architectures in breast cancer and other malignancies, including linear, branching, neutral, and punctuated evolution. Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine. We confirmed that intratumor heterogeneity, as characterized by both cna and snv landscapes, exists among cell clusters in close proximity even in very early stage melanoma. Neutral evolution along with clonal evolution is a principal cause of ith and fosters advanced crc. Aug 23, 2019 intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The new engl and journal of medicine 22 n engl j med 366. Indeed, heterogeneity defined as the proportion of nontruncal mutations in the tumor estimated in the ultra. There are two models used to explain the heterogeneity of tumour cells. Cancer evolution and heterogeneity mimori 2018 annals. 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.
Q mcdonald, a butler, d jones, k raine, c latimer, c. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin mtor kinase, correlating with s6 and 4ebp phosphorylation in vivo and constitutive activation of mtor kinase activity in vitro. Eleven spatially separated tumor samples from the primary tumor and associated metastatic sites and two normal samples were obtained from a stage iiic ovarian cancer patient during. The value of multiregion sequencing for phylogenetic reconstruction was first.
Jump to content jump to main navigation jump to main navigation. Apr 19, 2018 extensive multiregional wholegenome and exome sequencing performed in tumors from patients with localized, as well as metastatic, clear cell renal cell carcinoma provides a comprehensive description of the tumor origin, intratumoral heterogeneity, evolution, and route to metastasis, laying the foundation for the development of precision clinical management. Multiregion sequencing reveals the intratumor heterogeneity. Intratumor heterogeneity molecular cancer research. To examine intratumor heterogeneity, we performed exome sequencing, chromosome. Mar 28, 2012 such branched evolutionary growth was first demonstrated in hematological cancers and more recently in renal cancer through multiregion exome sequencing and in medulloblastoma. Evolution and heterogeneity of nonhereditary colorectal cancer revealed by singlecell exome sequencing skip to main content thank you for visiting. Tumor evolution and intratumor heterogeneity of an epithelial. Understanding the features of cancer can lead to effective cancer therapy. Intratumor heterogeneity is usually revealed by diverse genetic alterations. Intratumor heterogeneity may foster the selection of a resistant subclone, sometimes dete.
Multiregion sequencing identifies intratumor heterogeneity in. Genomic heterogeneity and branched evolution of early stage. Tumor evolution and intratumor heterogeneity of an. Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalizedmedicine strategies that depend on results from single tumorbiopsy samples. Mccullough and others published intratumor heterogeneity and branched evolution revealed by multiregion sequencing find, read and cite all the research you need. Our results revealed the universal spatial heterogeneity of driver mutations in nsclc and demonstrated that the molecular timing of acquisition of driver mutations. In this model, each cell gradually accumulates driver mutations as well as accompanying passenger mutations, which do. Intratumor heterogeneity in hepatocellular carcinoma. Oct 10, 2014 cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity ith.
Intratumor heterogeneity ith and branched evolution were commonly observed, and the complexity of the tumor tissue composition was beyond. Intratumor heterogeneity and evolutionary bottlenecking. These are the cancer stem cell model and the clonal evolution model. Reliability of wholeexome sequencing for assessing. Morphologic intratumor heterogeneity is well known to exist in hepatocellular carcinoma hcc, but very few systematic analyses of this phenomenon have been performed. Circulating tumor dna ctdna has recently emerged as a minimally invasive liquid biopsy tool in precision medicine. Mar 08, 2012 intratumor heterogeneity and branched evolution revealed by multiregion sequencing article pdf available in new england journal of medicine 36610.
Nextgeneration sequencing revealed subclonal diversification and diverse mutational processes. Aug 27, 2014 in brief, tumor evolution can follow either a branched or a linear pattern, both of which can result in intratumor heterogeneity figure 1. In this study, we studied metabolic features to comprehend intratumor heterogeneity. A, evolutionary mechanisms of intratumor heterogeneity. We applied multiregion wholeexome sequencing wes on 11 localized lung adenocarcinomas. To address this challenge and elucidate the evolutionary history of melanoma, we performed wholeexome and transcriptome sequencing of 41 multiple. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger rna expression. The impact of tumor heterogeneity on patient treatment. Hepatocellular carcinoma hcc is structurally complex system undergoing different molecular and phenotypic changes during tumor development. Background intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalizedmedicine strategies that depend on results from single tumorbiopsy samples. Heterogeneous distribution of egfr mutations is extremely rare in lung adenocarcinoma.
Variable intratumor genomic heterogeneity of multiple. Our results revealed the universal spatial heterogeneity of driver mutations in nsclc and demonstrated that the molecular timing of acquisition of driver mutations, such as tp53 mutation, varies in different tumors. Head and neck squamous cell carcinoma hnscc is characterized by significant genomic instability that could lead to clonal diversity. We found that minor mutations were dominant in advanced crc named neutral evolution. Pdf intratumor heterogeneity and branched evolution. Methods to examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy. Multiregional sequencing elucidates the evolution of clear cell. Original article from the new england journal of medicine intratumor heterogeneity and branched evolution revealed by multiregion sequencing. Extensive multiregional wholegenome and exome sequencing performed in tumors from pa tients with. Multiregion sequencing identifies intratumor heterogeneity. Molecular profiling of tumor biopsies plays an increasingly important role not only in cancer research, but also in the clinical management of cancer. Also, taken into account were wellknown immunohistochemical markers and molecular changes in liver. See other articles in pmc that cite the published article. Intratumor clonal heterogeneity has been proposed as a major attribute underlying tumor evolution, progression, and resistance to chemotherapy and radiation.
Intratumor heterogeneity may foster the selection of a resistant subclone, sometimes. On average, 76% of all mutations and 20 out of 21 known cancer gene. Extensive multiregional wholegenome and exome sequencing performed in tumors from patients with localized, as well as metastatic, clear cell renal cell carcinoma provides a comprehensive description of the tumor origin, intratumoral heterogeneity, evolution, and route to metastasis, laying the foundation for the development of precision clinical management. Multiregional sequencing elucidates the evolution of clear. Variable intratumor genomic heterogeneity of multiple lesions in patients with hepatocellular carcinoma. Multiregion sequencing has revealed the landscapes of ith for renal 1,2, breast 3, esophageal 4,5, lung 6,7, ovarian 8, prostate 9,10, pancreatic 11, and other types of. Colorectal cancer genetic heterogeneity delineated by multi. We analyzed sequencing data for 76 untreated metastases from 20 patients and inferred cancer phylogenies for breast, colorectal, endometrial, gastric, lung, melanoma, pancreatic, and prostate cancers. Multiregion wholeexome sequencing uncovers the genetic. Intratumor heterogeneity revealed by multiregion sequencing n engl j med 366.
Intratumor heterogeneity is likely to pose a challenge for therapeutic strategies in nsclc. Branched evolutionary growth and intratumor heterogeneity results in coexisting cancer cell clones with variegated genotypes and associated phenotypes that may be. These authors examine the extent of intratumoral heterogeneity by multiregion sequencing of primary tumor and associated metastatic lesions in four patients. The models are not mutually exclusive, and it is believed that they both contribute to heterogeneity in varying amounts across different tumour types. Nsclc is characterized by branched evolution and pronounced intratumor genomic heterogeneity. Through our multiregion sequencing analysis of clearcell renalcell carcinomas ccrcc. Background intratumor heterogeneity may foster tumor evolution and. Genomic studies have demonstrated the complex and heterogeneous clonal landscape of tumors of different origins and the potential impact of intratumor heterogeneity on treatment response and resistance, cancer progression, and the risk of disease relapse. Pickering l, stamp g, gore m, szallasi z, downward j, futreal pa, swanton c.
A temporal shift of the evolutionary principle shaping. Evolution and heterogeneity of nonhereditary colorectal. Intratumor genomic heterogeneity has been recently documented in many tumor types including hcc. It is interconnected with complex molecular mechanisms including spatial and temporal phenomena, which are often peculiar for every single patient. We were able to derive the branched evolution process of a melanoma and build its phylogenetic tree using genomic data of phenotypically addressable cell clusters. The new england journal of medicine recently published a report by gerlinger et al. One of the reasons why anticancer drugs have limited efficacy is the existence of intratumor heterogeneity.
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. Genomic heterogeneity and branched evolution of early. In conclusion, this is the first investigation of ith of driver mutations in tp53. Intratumor heterogeneity and branched evolution revealed f. Multiregion sequencing andor longitudinal monitoring of cancer subclones. Ucl discovery is ucls open access repository, showcasing and providing access to ucl research outputs from all ucl disciplines. Colorectal cancer genetic heterogeneity delineated by multiregion sequencing plos one, dec 2019 youwang lu, huifeng zhang, rui liang, zhenrong xie, huayou luo, yujian zeng, yu xu, lamei wang, xiangyang kong, kunhua wang.
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