The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing
Open accessAbstract
BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. METHODS: To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. RESULTS: Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. 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. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. CONCLUSIONS: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“A greater degree of divergence may be attributed to intra-tumor spatial heterogeneity and sampling bias: tumors can be spatially diverse, and organoids generated from a specific portion may lack the representativeness of distant regions130,131.”
From Organoids (2022) · cites this paper as [130]
Experimental — accuracy not yet measuredIn the citing paper
“a small needle biopsy of a single lesion may fail to reflect the true underlying intra- and inter-tumor genetic heterogeneity (15–17).”
In the citing paper
“It is now appreciated that most clinically relevant solid tumors are highly heterogeneous at the phenotypic, physiologic, and genomic levels (13–15) and that they continue to evolve over time.”
From Radiomics: Images Are More than Pictures, They Are Data (2016) · cites this paper as [14]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Integrated genomic analyses of ovarian carcinoma
Perou, C. M. (2019) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/hvp3-wg08 · Cited by 7,927
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses
Jones, S., Zhang, X., Parsons, D. W., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Kamiyama, H., Jimeno, A., et al. (2008) · Science · doi:10.1126/science.1164368 · Cited by 3,969
The Consensus Coding Sequences of Human Breast and Colorectal Cancers
Sjöblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., Mandelker, D. L., Leary, R. J., Ptak, J., Silliman, N., et al. (2006) · Science · doi:10.1126/science.1133427 · Cited by 3,161
Tumour evolution inferred by single-cell sequencing
Navin, N., Kendall, J., Troge, J., Andrews, P., Rodgers, L., McIndoo, J., Cook, K., Stepansky, A., Levy, D., Esposito, D., et al. (2011) · Nature · doi:10.1038/nature09807 · Cited by 2,598
Distant metastasis occurs late during the genetic evolution of pancreatic cancer
Yachida, S., Jones, S., Bozic, I., Antal, T., Leary, R., Fu, B., Kamiyama, M., Hruban, R. H., Eshleman, J. R., Nowak, M. A., et al. (2010) · Nature · doi:10.1038/nature09515 · Cited by 2,502
Recurring mutations found by sequencing an acute myeloid leukemia genome
Mardis, E. R., Ding, L., Dooling, D. J., Larson, D. E., McLellan, M. D., Chen, K., Koboldt, D. C., Fulton, R. S., Delehaunty, K. D., McGrath, S. D., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0903840 · Cited by 2,219
Cancer as an evolutionary and ecological process
Merlo, L. M. F., Pepper, J. W., Reid, B. J., & Maley, C. C. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2013 · Cited by 1,743
Flanigan, R. C., Salmon, S. E., Blumenstein, B. A., Bearman, S. I., Roy, V., McGrath, P. C., Caton, J. R., Munshi, N. C., & Crawford, E. D. (2001) · New England Journal of Medicine · doi:10.1056/nejmoa003013 · Cited by 1,710
Detection of Mutations in EGFR in Circulating Lung-Cancer Cells
Maheswaran, S., Sequist, L. V., Nagrath, S., Ulkus, L., Brannigan, B., Collura, C. V., Inserra, E., Diederichs, S., Iafrate, A. J., Bell, D. W., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0800668 · Cited by 1,617
Flagged first, then by citations
Cited by
Sorted by citations
Items 401–500 of 1,049
Molecularly targeted cancer therapy: some lessons from the past decade
Huang, M., Shen, A., Ding, J., & Geng, M. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.11.004 · Cited by 296
Mroz, E. A., Tward, A. D., Hammon, R. J., Ren, Y., & Rocco, J. W. (2015) · PLoS Medicine · doi:10.1371/journal.pmed.1001786 · Cited by 294
Fontebasso, A. M., Schwartzentruber, J., Khuong-Quang, D.-A., Liu, X.-Y., Sturm, D., Korshunov, A., Jones, D., Witt, H., Kool, M., Albrecht, S., et al. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1095-8 · Cited by 303
Self-citationThe rebel angel: mutant p53 as the driving oncogene in breast cancer
Walerych, D., Napoli, M., Collavin, L., & Sal, G. D. (2012) · Carcinogenesis · doi:10.1093/carcin/bgs232 · Cited by 301
Marked for death: Targeting epigenetic changes in cancer
Pfister, S. X., & Ashworth, A. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.256 · Cited by 288
Genetic and Clonal Dissection of Murine Small Cell Lung Carcinoma Progression by Genome Sequencing
McFadden, D. G., Papagiannakopoulos, T. Y., Taylor-Weiner, A. N., Stewart, C., Carter, S. L., Cibulskis, K., Bhutkar, A. J., McKenna, A., Dooley, A. L., Vernon, A. N., et al. (2014) · Cell · doi:10.1016/j.cell.2014.02.031 · Cited by 284
Feist, P. E., & Hummon, A. B. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16023537 · Cited by 306
Cancer heterogeneity—a multifaceted view
Melo, F. D. S. E., Vermeulen, L., Fessler, E., & Medema, J. P. (2013) · EMBO Reports · doi:10.1038/embor.2013.92 · Cited by 287
Fan, Y., Liu, X., Hughes, D., Zhang, J. J., Zhang, J., Futreal, P. A., Wheeler, D. A., & Wang, W. (2016) · Genome biology · doi:10.1186/s13059-016-1029-6 · Cited by 284
“The presence of both normal cells and tumor subclones in the sample causes this phenomenon to vary from sample to sample [7, 8].”
BackgroundSelf-citationIrianto, J., Xia, Y., Pfeifer, C. R., Athirasala, A., Ji, J., Alvey, C. M., Tewari, M., Bennett, R. R., Harding, S. M., Liu, A. J., et al. (2016) · Current Biology · doi:10.1016/j.cub.2016.11.049 · Cited by 289
WNT Signaling in Tumors: The Way to Evade Drugs and Immunity
Martín‐Orozco, E., Sanchez-Fernandez, A., Ortiz-Parra, I., & Nicolás, M. A.-S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02854 · Cited by 306
“(2) Blocking antibodies targeting CD44.”
BackgroundBreast Tumor Heterogeneity: Source of Fitness, Hurdle for Therapy
Koren, S., & Bentires‐Alj, M. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.10.031 · Cited by 289
“Similarly, multi-region genetic analysis (exome sequencing, chromosome aberration analysis, and ploidy profiling) of renal carcinoma and matched metastases has revealed branched evolutionary tumor growth (Gerlinger et al., 2012).”
BackgroundExosomes Increase the Therapeutic Index of Doxorubicin in Breast and Ovarian Cancer Mouse Models
Hadla, M., Palazzolo, S., Corona, G., Caligiuri, I., Canzonieri, V., Toffoli, G., & Rizzolio, F. (2016) · Nanomedicine · doi:10.2217/nnm-2016-0154 · Cited by 289
Pisco, A. O., & Huang, S. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.146 · Cited by 294
“…of CSC into multiple cell types, long thought to be an one-way process, supports the emerging notion that CSCs do not represent a static mutant clone but rather a functional state that can be induced in some cells under some conditions (Gupta et al, 2009a; Dirks, 2010; Gerlinger et al, 2012).”
BackgroundWalker, B. A., Wardell, C. P., Melchor, L., Brioli, A., Johnson, D. C., Kaiser, M., Mirabella, F., López‐Corral, L., Humphray, S., Murray, L., et al. (2013) · Leukemia · doi:10.1038/leu.2013.199 · Cited by 289
HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond
Maxwell, P. H., & Eckardt, K. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.193 · Cited by 288
An, T., Qin, S., Xu, Y., Tang, Y., Huang, Y., Situ, B., Inal, J. M., & Zheng, L. (2015) · Journal of Extracellular Vesicles · doi:10.3402/jev.v4.27522 · Cited by 280
Lee, G., Lee, H. Y., Park, H., Schiebler, M. L., van Beek, E. J. R., Ohno, Y., Seo, J. B., & Leung, A. N. C. (2016) · European Journal of Radiology · doi:10.1016/j.ejrad.2016.09.005 · Cited by 281
Emerging concepts in liquid biopsies
Perakis, S. O., & Speicher, M. R. (2017) · BMC Medicine · doi:10.1186/s12916-017-0840-6 · Cited by 288
“Such a sampling method is thus inadequate for the comprehensive characterization of a patient’s tumor, as it has been demonstrated that various areas within the primary tumor or metastases can in fact harbor different genomic profiles [4].”
MethodPersonalized Medicine: Recent Progress in Cancer Therapy
Gambardella, V., Tarazona, N., Cejalvo, J. M., Lombardi, P., Huerta, M., Roselló, S., Fleitas, T., Roda, D., & Cervantes, A. M. R. (2020) · Cancers · doi:10.3390/cancers12041009 · Cited by 301
“In acquired resistance, the evolutionary pressure of therapy can drive outgrowth of distinct tumor sub-clones harboring independent resistance mechanisms within an individual patient, within different metastatic lesions, or even within the same lesion [87].”
BackgroundChakravarty, D., Johnson, A., Sklar, J., Lindeman, N. I., Moore, K. N., Ganesan, S., Lovly, C. M., Perlmutter, J., Gray, S. W., Hwang, J., et al. (2022) · Journal of Clinical Oncology · doi:10.1200/jco.21.02767 · Cited by 301
“Studies have supported the concept of branched evolution, with variable ITH in different tumor types.(185,186) The presence of additional cancer drivers or specific coalterations may limit targeted therapy efficacy.”
BackgroundBhat, G. R., Sethi, I., Sadida, H. Q., Rah, B., Mir, R., Algehainy, N. A., Albalawi, I. A., Masoodi, T., Subbaraj, G. K., Jamal, F., et al. (2024) · Cancer and Metastasis Reviews · doi:10.1007/s10555-024-10172-z · Cited by 330
“This leads to a spectrum of cancers, from simple clonal malignancies with minimal heterogeneity (e.g., BCR-ABL-positive CML) to highly complex mosaic cancers with extensive differences between subclones [172–174].”
BackgroundHanna, W. M., Rüschoff, J., Bilous, M., Coudry, R. A., Dowsett, M., OSAMURA, R. Y., Penault-Llorca, F. M., van de Vijver, M. J., & Viale, G. (2013) · Modern Pathology · doi:10.1038/modpathol.2013.103 · Cited by 284
Wagle, N., Grabiner, B. C., Allen, E. M. V., Hodis, E., Jacobus, S. J., Supko, J. G., Stewart, M. L., Choueiri, T. K., Gandhi, L., Cleary, J. M., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0353 · Cited by 282
Next-generation sequencing to guide cancer therapy
Gagan, J., & Allen, E. M. V. (2015) · Genome Medicine · doi:10.1186/s13073-015-0203-x · Cited by 293
“However, as DNA mutations accumulate within a tumor, there can be considerable sequence heterogeneity even within a single primary tumor [17].”
BackgroundAdvanced Applications of RNA Sequencing and Challenges
Han, Y., Gao, S., Muegge, K., Zhang, W., & Zhou, B. (2015) · Bioinformatics and Biology Insights · doi:10.4137/bbi.s28991 · Cited by 303
Precision Oncology: Who, How, What, When, and When Not?
Schwartzberg, L. S., Kim, E. S., Liu, D., & Schrag, D. (2017) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_174176 · Cited by 294
Impact of Metabolic Heterogeneity on Tumor Growth, Invasion, and Treatment Outcomes
Robertson‐Tessi, M., Gillies, R. J., Gatenby, R. A., & Anderson, A. R. A. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-1428 · Cited by 278
“However, a potential issue was recently highlighted by Gerlinger and colleagues (9), who showed that multiple biopsies from the same tumor display distinct genetic profiles and yet are phenotypically similar.”
BackgroundEmergence of Multiple EGFR Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer
Arena, S., Bellosillo, B., Siravegna, G., Martínez, A., Cañadas, I., Lazzari, L., Ferruz, N., Russo, M., Misale, S., González, I., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2821 · Cited by 271
Liquid biopsies: Potential and challenges
Heidrich, I., Ačkar, L., Mohammadi, P. M., & Pantel, K. (2020) · International Journal of Cancer · doi:10.1002/ijc.33217 · Cited by 284
“often present in different organs at the same time and have one strong, partly organ-dependent heterogeneity.(1,3,4) This diagnostic dilemma led to the development of the “liquid biopsy” (LB) concept.”
BackgroundAryee, M. J., Liu, W., Engelmann, J. C., Nuhn, P., Gurel, M., Haffner, M. C., Esopi, D., Irizarry, R. A., Getzenberg, R. H., Nelson, W. G., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005211 · Cited by 282
Stockley, T. L., Oza, A. M., Berman, H. K., Leighl, N. B., Knox, J. J., Shepherd, F. A., Chen, E. X., Krzyzanowska, M. K., Dhani, N. C., Joshua, A. M., et al. (2016) · Genome Medicine · doi:10.1186/s13073-016-0364-2 · Cited by 276
“Fresh biopsy of a current metastatic lesion for molecular profiling at the time of study enrolment may have yielded different results due to clonal evolution or tumor heterogeneity [28].”
BackgroundResultCurrent treatment strategies for inhibiting mTOR in cancer
Chiarini, F., Evangelisti, C., McCubrey, J. A., & Martelli, A. M. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.11.004 · Cited by 279
Pichler, M., Hutterer, G. C., Stoeckigt, C., Chromecki, T. F., Stojaković, T., Golbeck, S. V., Eberhard, K., Gerger, A., Mannweiler, S., Pummer, K., et al. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.28 · Cited by 276
Almendro, V., Cheng, Y.-K., Randles, A. P., Itzkovitz, S., Marusyk, A., Ametller, E., González, X., Muñoz-Mateu, M., Russnes, H. G., Helland, Å., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2013.12.041 · Cited by 274
Mechanism-based cancer therapy: resistance to therapy, therapy for resistance
Ramos, P. M., & Bentires‐Alj, M. (2014) · Oncogene · doi:10.1038/onc.2014.314 · Cited by 287
Selection and adaptation during metastatic cancer progression
Klein, C. A. (2013) · Nature · doi:10.1038/nature12628 · Cited by 275
Treatment of HER2-positive breast cancer
Magalhães, M. C. F., Jelovac, D., Connolly, R. M., & Wolff, A. C. (2013) · The Breast · doi:10.1016/j.breast.2013.11.011 · Cited by 294
Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma
Nikbakht, H., Panditharatna, E., Mikael, L. G., Li, R., Gayden, T., Osmond, M., Ho, C.-Y., Kambhampati, M., Hwang, E. I., Faury, D., et al. (2016) · Nature Communications · doi:10.1038/ncomms11185 · Cited by 252
Krug, A. K., Enderle, D., Karlovich, C., Priewasser, T., Bentink, S., Spiel, A., Brinkmann, K., Emenegger, J., Grimm, D. G., Castellanos-Rizaldos, E., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx765 · Cited by 277
“The occurrence of a relatively high rate of T790M tumor negatives that are consistently plasma positive has been observed before [35, 39] and suggests that tumor heterogeneity or divergent metastatic lesions [40, 41] lead to false-negative results in tissue.”
BackgroundPolytherapy and Targeted Cancer Drug Resistance
Chatterjee, N., & Bivona, T. G. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.02.003 · Cited by 277
Epigenetic heterogeneity in cancer
Guo, M., Peng, Y., Gao, A., Du, C., & Herman, J. G. (2019) · Biomarker Research · doi:10.1186/s40364-019-0174-y · Cited by 288
Karlo, C. A., Paolo, P. L. D., Chaim, J. L., Hakimi, A. A., Ostrovnaya, I., Russo, P., Hricak, H., Motzer, R. J., Hsieh, J. J.-D., & Akın, O. (2013) · Radiology · doi:10.1148/radiol.13130663 · Cited by 270
Dual Chromatin and Cytoskeletal Remodeling by SETD2
Park, I. Y., Powell, R. T., Tripathi, D. N., Dere, R., Ho, T. H., Blasius, T. L., Chiang, Y.-C., Davis, I. J., Fahey, C. C., Hacker, K. E., et al. (2016) · Cell · doi:10.1016/j.cell.2016.07.005 · Cited by 285
Goul, C., Peruzzo, R., & Zoncu, R. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00641-8 · Cited by 280
“…machinery for mTORC1 have recently begun to emerge and have further expanded the disease conditions associated with dysregulated mTORC1, including not only cancers but also neurological diseases such as epilepsies, malformations of cortical development and neurodevelopmental disorders.”
BackgroundCT Radiogenomic Characterization of EGFR, K-RAS, and ALK Mutations in Non-Small Cell Lung Cancer
Rizzo, S., Petrella, F., Buscarino, V., Maria, F. D., Raimondi, S., Barberis, M. C. P., Fumagalli, C., Spitaleri, G., Rampinelli, C., de Marinis, F., et al. (2015) · European Radiology · doi:10.1007/s00330-015-3814-0 · Cited by 280
Zi, Y., Yang, K., He, J., Wu, Z., Liu, J., & Zhang, W. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114449 · Cited by 268
Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance?
Hölzel, M., Bovier, A., & Tüting, T. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3498 · Cited by 275
Gallaher, J. A., Enríquez‐Navas, P. M., Luddy, K. A., Gatenby, R. A., & Anderson, A. R. A. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-2649 · Cited by 269
Kim, K., Lee, H. W., Lee, H., Kim, S. C., Seo, Y. J., Chung, W., Eum, H. H., Nam, D., Kim, J., Joo, K. M., et al. (2015) · Genome biology · doi:10.1186/s13059-015-0692-3 · Cited by 269
“Intra-tumoral heterogeneity results from mutation and clonal selection dynamics during tumor growth [13, 14, 16], where individual tumor cells accumulate cell-specific genetic changes [12].”
Choosing the right cell line for renal cell cancer research
Brodaczewska, K. K., Szczylik, C. A., Fiedorowicz, M., Porta, C., & Czarnecka, A. M. (2016) · Molecular Cancer · doi:10.1186/s12943-016-0565-8 · Cited by 279
“This in vivo heterogeneity of tumors can be mimicked in vitro with use of a panel of cell lines in the place of multiple biopsy derived samples [87].”
BackgroundA Convergence-Based Framework for Cancer Drug Resistance
Konieczkowski, D. J., Johannessen, C. M., & Garraway, L. A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.025 · Cited by 258
Ibrahim, A., Primakov, S. P., Beuque, M. P. L., Woodruff, H. C., Halilaj, I., Wu, G., Refaee, T., Granzier, R. W. Y., Widaatalla, Y., Hustinx, R., et al. (2020) · Methods · doi:10.1016/j.ymeth.2020.05.022 · Cited by 278
Nucleic Acid Tests for Clinical Translation
Li, M., Yin, F., Song, L., Mao, X., Li, F., Fan, C., Zuo, X., & Xia, Q. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00241 · Cited by 274
The current state of molecular testing in the treatment of patients with solid tumors, 2019
El‐Deiry, W. S., Goldberg, R. M., Lenz, H., Shields, A. F., Gibney, G. T., Tan, A. R., Brown, J., Eisenberg, B., Heath, E. I., Phuphanich, S., et al. (2019) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21560 · Cited by 264
Misale, S., Arena, S., Lamba, S., Siravegna, G., Lallo, A., Hobor, S., Russo, M., Buscarino, M., Lazzari, L., Sartore-Bianchi, A., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007947 · Cited by 263
Schultheis, A. M., Ng, C. K. Y., Filippo, M. R. D., Piscuoglio, S., Macedo, G. S., Gatius, S., Perez‐Mies, B., Soslow, R. A., Lim, R. S., Viale, A. J., et al. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djv427 · Cited by 257
Intratumor DNA Methylation Heterogeneity Reflects Clonal Evolution in Aggressive Prostate Cancer
Brocks, D., Assenov, Y., Minner, S. J. P., Bogatyrova, O., Simon, R., Koop, C., Oakes, C. C., Zucknick, M., Lipka, D. B., Weischenfeldt, J., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.06.053 · Cited by 268
Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples
Russano, M., Napolitano, A., Ribelli, G., Iuliani, M., Simonetti, S., Citarella, F., Pantano, F., Dell’Aquila, E., Anesi, C., Silvestris, N., et al. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01601-2 · Cited by 267
Mazor, T., Pankov, A., Johnson, B., Hong, C., Hamilton, E. G., Bell, R. J. A., Smirnov, I. V., Reis, G. F., Phillips, J. J., Barnes, M. J., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.07.012 · Cited by 270
“As a result, human tumors can display substantial intratumoral heterogeneity, including discordant genetic alterations between initial tumors and their associated local recurrences or distant metastases (Gerlinger et al., 2012; Okosun et al., 2014; Wu et al., 2012; Yachida et al., 2010).”
BackgroundIron and thiol redox signaling in cancer: an exquisite balance to escape ferroptosis
Toyokuni, S., Ito, F., Yamashita, K., Okazaki, Y., & Akatsuka, S. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.04.024 · Cited by 252
“This is especially evident for a cancer with a definite causal gene, such as renal clear cell carcinoma with the VHL tumor suppressor gene [10].”
BackgroundHakimi, A. A., Voss, M. H., Kuo, F., Sánchez, A., Liu, M., Nixon, B. G., Vuong, L. H., Ostrovnaya, I., Chen, Y., Reuter, V. E., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0957 · Cited by 263
“We recognize that these findings are based on a detailed characterization of a single region of the primary tumor, and ccRCC demonstrates significant intratumor heterogeneity (36).”
BackgroundProgression from ductal carcinoma in situ to invasive breast cancer: Revisited
Cowell, C. F., Weigelt, B., Sakr, R. A., Ng, C. K. Y., Hicks, J. B., King, T. A., & Reis-Filho, J. S. (2013) · Molecular Oncology · doi:10.1016/j.molonc.2013.07.005 · Cited by 259
Brain Tumor Cells in Circulation Are Enriched for Mesenchymal Gene Expression
Sullivan, J. P., Nahed, B. V., Madden, M. W., Oliveira, S. M., Springer, S. U., Bhere, D., Chi, A. S., Wakimoto, H., Rothenberg, S. M., Sequist, L. V. D., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0471 · Cited by 258
Liauw, S. L., Connell, P. P., & Weichselbaum, R. R. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005148 · Cited by 260
Marie-Egyptienne, D. T., Lohse, I., & Hill, R. P. (2012) · Cancer Letters · doi:10.1016/j.canlet.2012.11.019 · Cited by 264
Rini, B. I., Goddard, A. D., Knezevic, D., Maddala, T., Zhou, M., Aydın, H., Campbell, S. C., Elson, P. J., Koscielny, S., Lopatin, M., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)70167-1 · Cited by 254
Molecular profiling of single circulating tumor cells with diagnostic intention
Polzer, B., Medoro, G., Pasch, S., Fontana, F., Zorzino, L., Pestka, A., Andergassen, U., Meier-Stiegen, F., Czyż, Z. T., Alberter, B., et al. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201404033 · Cited by 267
McKay, R. R., Kroeger, N., Xie, W., Lee, J., Knox, J. J., Bjarnason, G. A., MacKenzie, M. J., Wood, L. A., Srinivas, S., Vaishampayan, U. N., et al. (2013) · European Urology · doi:10.1016/j.eururo.2013.08.012 · Cited by 253
Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure
Pagliarini, R. A., Shao, W., & Sellers, W. R. (2015) · EMBO Reports · doi:10.15252/embr.201439949 · Cited by 264
DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer
Teschendorff, A. E., Gao, Y., Jones, A., Ruebner, M., Beckmann, M. W., Wachter, D. L., Fasching, P. A., & Widschwendter, M. (2016) · Nature Communications · doi:10.1038/ncomms10478 · Cited by 252
Cancer evolution: Darwin and beyond
Vendramin, R., Litchfield, K., & Swanton, C. (2021) · The EMBO Journal · doi:10.15252/embj.2021108389 · Cited by 269
“…next-generation sequencing (NGS), that the full breath of ITH could start to be fully resolved (Campbell et al , 2010 ; Navin et al , 2010 ; Gerlinger et al , 2012 ; Nik-Zainal et al , 2012 b; Walter et al , 2012 ; Patel et al , 2014 ; Sottoriva et al , 2015 ; Jamal-Hanjani et al , 2017 ;…”
Self-citationTracking tumor biology with radiomics: a systematic review utilizing a radiomics quality score
Sanduleanu, S., Woodruff, H. C., de Jong, E. E. C., van Timmeren, J. E., Jochems, A., Dubois, L., & Lambin, P. (2018) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2018.03.033 · Cited by 242
“Phylogenetic reconstruction has revealed branched evolutionary tumor growth, wherein nearly 70% of all somatic mutations are not detectable across every tumor region [59].”
BackgroundMolecular Heterogeneity in Glioblastoma: Potential Clinical Implications
Parker, N., Khong, P., Parkinson, J., Howell, V. M., & Wheeler, H. (2015) · Frontiers in Oncology · doi:10.3389/fonc.2015.00055 · Cited by 263
“Such branched tumor evolution underscores the importance of targeting ubiquitous alterations in the trunk of the phylogenetic tree (60).”
BackgroundComprehensive Intrametastatic Immune Quantification and Major Impact of Immunoscore on Survival
Mlecnik, B., den Eynde, M. V., Bindea, G., Church, S., Vasaturo, A., Fredriksen, T., Lafontaine, L., Haicheur, N., Marliot, F., Debetancourt, D., et al. (2017) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djx123 · Cited by 250
The Evolutionary Landscape of Localized Prostate Cancers Drives Clinical Aggression
Espiritu, S. M. G., Liu, L., Rubanova, Y., Bhandari, V., Holgersen, E. M., Szyca, L., Fox, N. S., Chua, M. L. K., Yamaguchi, T. N., Heisler, L. E., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.029 · Cited by 251
Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives
Saunders, N. A., Simpson, F., Thompson, E. W., Hill, M. M. C., Endo‐Munoz, L., Leggatt, G. R., Minchin, R. F., & Guminski, A. D. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201101131 · Cited by 252
Clonal expansion in non-cancer tissues
Kakiuchi, N., & Ogawa, S. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-021-00335-3 · Cited by 252
Cancer Evolution and the Limits of Predictability in Precision Cancer Medicine
Lipinski, K. A., Barber, L. J., Davies, M. N., Ashenden, M., Sottoriva, A., & Gerlinger, M. (2016) · Trends in cancer · doi:10.1016/j.trecan.2015.11.003 · Cited by 256
“carcinogenesis [26] but also late during cancer progression [9].”
BackgroundInfluentialSelf-citationHistone methylation and the DNA damage response
Gong, F., & Miller, K. M. (2017) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2017.09.003 · Cited by 265
Identification of functional cooperative mutations of SETD2 in human acute leukemia
Zhu, X., He, F., Zeng, H., Ling, S., Chen, A., Wang, Y., Yan, X., Wei, W., Pang, Y., Cheng, H., et al. (2014) · Nature Genetics · doi:10.1038/ng.2894 · Cited by 254
Microsatellite instability: an update
Yamamoto, H., & Imai, K. (2015) · Archives of Toxicology · doi:10.1007/s00204-015-1474-0 · Cited by 247
Tracking Genomic Cancer Evolution for Precision Medicine: The Lung TRACERx Study
Jamal‐Hanjani, M., Hackshaw, A., Ngai, Y., Shaw, J., Dive, C., Quezada, S. A., Middleton, G., de Bruin, E. C., Quesne, J. P. C. L., Shafi, S., et al. (2014) · PLoS Biology · doi:10.1371/journal.pbio.1001906 · Cited by 247
Self-citationSingle-cell sequencing reveals karyotype heterogeneity in murine and human malignancies
Bakker, B., Taudt, A., Belderbos, M. E., Porubskỳ, D., Spierings, D. C. J., de Jong, T. V., Halsema, N., Kazemier, H. G., Hoekstra-Wakker, K., Bradley, A., et al. (2016) · Genome biology · doi:10.1186/s13059-016-0971-7 · Cited by 238
“cer evolution [17], our platform might become an import-”
BackgroundTumor Heterogeneity and Personalized Medicine
Longo, D. L. (2012) · New England Journal of Medicine · doi:10.1056/nejme1200656 · Cited by 246
CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer
Olivares‐Urbano, M. A., Griñán‐Lisón, C., Marchal, J. A., & Núñez, M. I. (2020) · Cells · doi:10.3390/cells9071651 · Cited by 261
Classification of mitocans, anti-cancer drugs acting on mitochondria
Neužil, J., Dong, L., Rohlena, J., Truksa, J., & Ralph, S. J. (2012) · Mitochondrion · doi:10.1016/j.mito.2012.07.112 · Cited by 255
Targeting Oncogenic BRAF: Past, Present, and Future
Zaman, A., Wu, W., & Bivona, T. G. (2019) · Cancers · doi:10.3390/cancers11081197 · Cited by 252
“A growing body of literature indicates that this evolution of tumors through these different stages is dictated by a heterogeneous combination of multiple molecular drivers and cell states that reflect profound plasticity [80,81].”
BackgroundBirbo, B., Madu, E. E., Madu, C. O., Jain, A., & Lu, Y. W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910317 · Cited by 259
“Heterogeneity within individual tumors can facilitate tumor evolution and adaptation, impeding personalized treatment methods that rely on single tumor biopsy sample results [148].”
BackgroundAssessing the interactions between radiotherapy and antitumour immunity
Grassberger, C., Ellsworth, S. G., Wilks, M. Q., Keane, F. K., & Loeffler, J. S. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0238-9 · Cited by 244
Entering the era of single-cell transcriptomics in biology and medicine
Sandberg, R. (2013) · Nature Methods · doi:10.1038/nmeth.2764 · Cited by 252
Targeted therapies for renal cell carcinoma
Posadas, E. M., Limvorasak, S., & Figlin, R. A. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2017.82 · Cited by 246
The significance of intertumor and intratumor heterogeneity in liver cancer
Liu, J., Dang, H. T., & Wang, X. W. (2018) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.165 · Cited by 255
Wang, Y., Li, L., Douville, C. B., Cohen, J. D., Yen, T., Kinde, I., Sundfelt, K., Kjær, S. K., Hruban, R. H., Shih, I., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aap8793 · Cited by 251
“Another possible explanation is tumor heterogeneity (40).”
Jiménez-Sánchez, A., Cybulska, P., Mager, K. L., Koplev, S., Cast, O. M., Couturier, D., Memon, D., Selenica, P., Nikolovski, I., Mazaheri, Y., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0630-5 · Cited by 248
Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer
Li, R., Ferdinand, J. R., Loudon, K. W., Bowyer, G., Laidlaw, S., Muyas, F., Mamanova, L., Neves, J. B., Bolt, L., Fasouli, E. S., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.11.001 · Cited by 254
“Intra-tumoral heterogeneity (ITH) of these subsequent mutational events appears to be a salient feature of ccRCC, as revealed by previous multi-region exome sequencing studies.(5,7,8) In contrast, the ITH of ccRCC at a transcriptional level is less well understood, in part due to the complexity of”
Rich, J. N. (2016) · Medicine · doi:10.1097/md.0000000000004764 · Cited by 255
“different regions of the same tumor, suggesting that intratumor heterogeneity also exists at the RNA-expression level.([13]) Intratumor heterogeneity is postulated to develop across time as CSCs divide and differentiate asymmetrically.”
BackgroundOngoing chromosomal instability and karyotype evolution in human colorectal cancer organoids
Bolhaqueiro, A. C. F., Ponsioen, B., Bakker, B., Klaasen, S. J., Küçükköse, E., van Jaarsveld, R. H., Vivié, J., Verlaan-Klink, I., Hami, N., Spierings, D. C. J., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0399-6 · Cited by 244
Genetic basis of kidney cancer: Role of genomics for the development of disease-based therapeuticsPreprint
Linehan, W. M. (2012) · Genome Research · doi:10.1101/gr.131110.111 · Cited by 243
Impact of Image Reconstruction Settings on Texture Features in 18F-FDG PET
Yan, J., Lim, J., Loi, H. Y., Khor, L. K., Sinha, A. K., Quek, S. T., Tham, I. W. K., & Townsend, D. W. (2015) · Journal of Nuclear Medicine · doi:10.2967/jnumed.115.156927 · Cited by 242
“Recent studies have shown that tumors often display startling intratumoral heterogeneity, which is often associated with adverse tumor biology (1,2).”
Background
Metadata
- Authors
- Gerlinger, M., Rowan, A. J., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., Varela, I., Phillimore, B., Begum, S., McDonald, N. Q., Butler, A., Jones, D., Raine, K., Latimer, C., Santos, C. R., Nohadani, M., Eklund, A. C., Spencer-Dene, B., Clark, G., Pickering, L., Stamp, G., Gore, M., Szallasi, Z., Downward, J., Futreal, P. A., & Swanton, C.
- Affiliations
- Queen Mary University of London (GB)
- ORCID
- Gerlinger, Marco
- Rowan, Andrew J.
- Horswell, Stuart
- Larkin, James
- Endesfelder, David
- Gronroos, Eva
- Martinez, Pierre
- Tarpey, Patrick
- Varela, Ignacio
- Begum, Sharmin
- McDonald, Neil Q.
- Jones, David
- Raine, Keiran
- Latimer, Calli
- Eklund, Aron C.
- Pickering, Lisa
- Stamp, Gordon
- Downward, Julian
- Futreal, P. Andrew
- Swanton, Charles
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-03-08
- Volume
- 366
- Issue
- 10
- Pages
- 883-892
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4878653
- OpenAlex
- W2150575159
- Semantic Scholar
- b97108a8e1dd8cf67ff9f374a8237fabf4c96ad4
- Cited by
- 7,774
- References
- 35
- Citations by year
- 2026: 304 · 2025: 297 · 2024: 306 · 2023: 349 · 2022: 499 · 2021: 571 · 2020: 550 · 2019: 540 · 2018: 632 · 2017: 671 · 2016: 722 · 2015: 691 · 2014: 679 · 2013: 621 · 2012: 326
- FWCI
- 246.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion)
- Funders
- Wellcome Trust (079643)
- Cancer Research UK (10747, 15680)
- National Institute for Health and Care Research
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- intratumoral heterogeneity, tumor evolution, renal carcinoma, metastatic renal cell carcinoma, phylogenetic inference, mTOR, SETD2, PTEN, KDM5C, tumor suppressor mutations, allelic imbalance, aneuploidy, gene expression signatures, biomarker development, personalized medicine
- MeSH terms
- Everolimus, Biopsy, Carcinoma, Renal Cell, Chromosome Aberrations, Humans, Immunosuppressive Agents, Kidney, Kidney Neoplasms, Mutation, Neoplasm Metastasis, Phenotype, Phylogeny, Ploidies, Biomarkers, Tumor, Sequence Analysis, DNA, Genetic Heterogeneity, Evolution, Molecular, Sirolimus, Polymorphism, Single Nucleotide, Exome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
