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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.).
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“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).”
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“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]
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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
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Items 201–300 of 1,049
Quantitative Imaging in Cancer Evolution and Ecology
Gatenby, R. A., Grove, O., & Gillies, R. J. (2013) · Radiology · doi:10.1148/radiol.13122697 · Cited by 515
Landscape of somatic mutations and clonal evolution in mantle cell lymphoma
Beà, S., Valdés‐Mas, R., Navarro, A., Salaverría, I., Martin‐García, D., Jares, P., Giné, E., Pinyol, M., Royo, C., Nadeu, F., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1314608110 · Cited by 527
Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal
Mitchell, T. J., Turajlic, S., Rowan, A., Nicol, D. L., Farmery, J. H. R., O’Brien, T., Martincorena, I., Tarpey, P. S., Angelopoulos, N., Yates, L. R., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.020 · Cited by 522
“Recent exome sequencing studies have highlighted the considerable intra-tumoral heterogeneity of clear cell renal cell carcinomas (Gerlinger et al., 2012, 2014).”
BackgroundSelf-citationSpatially resolved transcriptomics and beyond
Crosetto, N., Bienko, M., & van Oudenaarden, A. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3832 · Cited by 509
Drug Resistance Driven by Cancer Stem Cells and Their Niche
Prieto‐Vila, M., Takahashi, R., Usuba, W., Kohama, I., & Ochiya, T. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122574 · Cited by 526
“Indeed, massively parallel sequencing studies show that spatial and temporal heterogeneity are phenomena that occur commonly in tumors [102].”
BackgroundRenal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Escudier, B. J., Porta, C., Schmidinger, M., Rioux-Leclercq, N. C., Bex, A., Khoo, V. S., Gruenvald, V., & Horwich, A. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw328 · Cited by 504
Studying clonal dynamics in response to cancer therapy using high-complexity barcoding
Bhang, H.-E. C., Ruddy, D. A., Krishnamurthy Radhakrishna, V., Caushi, J. X., Zhao, R., Hims, M. M., Singh, A. P., Kao, I., Rakiec, D., Shaw, P., et al. (2015) · Nature Medicine · doi:10.1038/nm.3841 · Cited by 507
Implementing Genome-Driven Oncology
Hyman, D. M., Taylor, B. S., & Baselga, J. M. (2017) · Cell · doi:10.1016/j.cell.2016.12.015 · Cited by 518
Genomic and phenotypic heterogeneity in prostate cancer
Haffner, M. C., Zwart, W. T., Roudier, M. P., True, L. D., Nelson, W. G., Epstein, J. I., Marzo, A. M. D., Nelson, P. S., & Yegnasubramanian, S. (2020) · Nature Reviews Urology · doi:10.1038/s41585-020-00400-w · Cited by 544
Rational combinations of targeted cancer therapies: background, advances and challenges
Jin, H., Wang, L., & Bernards, R. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00615-z · Cited by 503
Integrating spatial gene expression and breast tumour morphology via deep learning
He, B., Bergenstråhle, L., Stenbeck, L., Abid, A., Andersson, A., Borg, Å., Maaskola, J., Lundeberg, J., & Zou, J. (2020) · Nature Biomedical Engineering · doi:10.1038/s41551-020-0578-x · Cited by 507
Addressing overdiagnosis and overtreatment in cancer: a prescription for change
Esserman, L. J., Thompson, I. M., Reid, B. J., Nelson, P. S., Ransohoff, D. F., Welch, H. G., Hwang, S. E., Berry, D. A., Kinzler, K. W., Black, W. C., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70598-9 · Cited by 506
Detecting ultralow-frequency mutations by Duplex Sequencing
Kennedy, S. R., Schmitt, M. W., Fox, E. J., Kohrn, B. F., Salk, J. J., Ahn, E. H., Prindle, M. J., Kuong, K. J., Shen, J.-C., Risques, R.-A., et al. (2014) · Nature Protocols · doi:10.1038/nprot.2014.170 · Cited by 503
Tracking the clonal origin of lethal prostate cancer
Haffner, M. C., Mosbruger, T. L., Esopi, D., Fedor, H. L., Heaphy, C. M., Walker, D. A., Adejola, N., Gurel, M., Hicks, J. L., Meeker, A. K., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci70354 · Cited by 506
Integrating Artificial Intelligence and Nanotechnology for Precision Cancer Medicine
Adir, O., Poley, M., Chen, G., Froim, S., Krinsky, N., Shklover, J., Shainsky‐Roitman, J., Lammers, T., & Schroeder, A. (2020) · Advanced Materials · doi:10.1002/adma.201901989 · Cited by 496
Targeting the HIF2–VEGF axis in renal cell carcinoma
Choueiri, T. K., & Kaelin, W. G. (2020) · Nature Medicine · doi:10.1038/s41591-020-1093-z · Cited by 477
Emerging patterns of somatic mutations in cancer
Watson, I. R., Takahashi, K., Futreal, P. A., & Chin, L. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3539 · Cited by 497
Self-citationFunctional genomic landscape of cancer-intrinsic evasion of killing by T cells
Lawson, K. A., Sousa, C. M., Zhang, X., Kim, E., Akthar, R., Caumanns, J. J., Yao, Y., Mikolajewicz, N., Ross, C., Brown, K. R., et al. (2020) · Nature · doi:10.1038/s41586-020-2746-2 · Cited by 443
Intratumor Heterogeneity: Seeing the Wood for the Trees
Yap, T. A., Gerlinger, M., Futreal, P. A., Pusztai, L., & Swanton, C. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003854 · Cited by 501
Self-citationMaeda, H., & Khatami, M. (2018) · Clinical and Translational Medicine · doi:10.1186/s40169-018-0185-6 · Cited by 491
Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer
Jia, Q., Wu, W., Wang, Y., Alexander, P. B., Sun, C., Gong, Z., Cheng, J.-N., Sun, H., Guan, Y., Xia, X., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07767-w · Cited by 486
Self-citationAPOBEC Enzymes: Mutagenic Fuel for Cancer Evolution and Heterogeneity
Swanton, C., McGranahan, N., Starrett, G. J., & Harris, R. S. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0344 · Cited by 492
Self-citationChan, K. A., Jiang, P., Zheng, Y. W. L., Liao, G. J. W., Sun, H., Wong, J., Siu, S. S. N., Chan, W. C., Chan, S. L., Chan, A. T. �., et al. (2012) · Clinical Chemistry · doi:10.1373/clinchem.2012.196014 · Cited by 487
Aggarwal, C., Thompson, J. C., Black, T. A., Katz, S. I., Fan, R., Yee, S. S., Chien, A. L., Evans, T. L., Bauml, J. M., Alley, E. W., et al. (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2018.4305 · Cited by 488
Interactions of nanomaterials and biological systems: Implications to personalized nanomedicine
Zhang, X., Xu, X., Bertrand, N., Pridgen, E. M., Swami, A., & Farokhzad, O. C. (2012) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.08.005 · Cited by 494
A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity
Waclaw, B., Božić, I., Pittman, M. E., Hruban, R. H., Vogelstein, B., & Nowak, M. A. (2015) · Nature · doi:10.1038/nature14971 · Cited by 485
“Page 2 particularly the drivers, are present in 30%-80% of cells in the primary tumor as well as in metastatic lesions derived from it [2,3,4,5].”
Origins of lymphatic and distant metastases in human colorectal cancer
Naxerova, K., Reiter, J. G., Brachtel, E. F., Lennerz, J. K., van de Wetering, M., Rowan, A., Cai, T., Clevers, H. C., Swanton, C., Nowak, M. A., et al. (2017) · Science · doi:10.1126/science.aai8515 · Cited by 485
“We still do not know whether a single metastatic subclone evolves in the primary tumor, subsequently spreading to lymph nodes and distant sites (18-21), or whether multiple subclones in the primary tumor independently seed lymphatic and distant metastases (22-24).”
BackgroundSelf-citationMurtaza, M., Dawson, S., McNamara, K. L., Rueda, O. M., Provenzano, E., Grant, J. W., Chin, S., Tsui, D. W. Y., Marass, F., Gale, D. G., et al. (2015) · Nature Communications · doi:10.1038/ncomms9760 · Cited by 486
“A mutation was identified if (1) no mutant reads for an allele were observed in germline DNA (N1) at a locus that was covered at least 10-fold, (2) at least five reads supporting the mutant were observed in any tumour or plasma sample with at least one read on each strand (forward and reverse) and (3) the binomial pro…”
BackgroundmTOR: Role in cancer, metastasis and drug resistance
Murugan, A. K. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.07.003 · Cited by 483
Liquid Biopsies, What We Do Not Know (Yet)
Bardelli, A., & Pantel, K. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.01.002 · Cited by 482
Spatial genomic heterogeneity within localized, multifocal prostate cancer
Boutros, P. C., Fraser, M. E., Harding, N. J., de Borja, R., Trudel, D., Lalonde, E., Meng, A. X., Hennings-Yeomans, P. H., McPherson, A., Sabelnykova, V. Y., et al. (2015) · Nature Genetics · doi:10.1038/ng.3315 · Cited by 472
Characterization of PET/CT images using texture analysis: the past, the present… any future?
Hatt, M., Tixier, F., Pierce, L. A., Kinahan, P. E., Rest, C. C. L., & Visvikis, D. (2016) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-016-3427-0 · Cited by 494
“Tumours are heterogeneous entities at all scales (macroscopic, physiological, microscopic, genetic) [1].”
BackgroundPrimary Tumor Location as a Prognostic Factor in Metastatic Colorectal Cancer
Loupakis, F., Yang, D., Yau, L., Feng, S., Cremolini, C., Zhang, W., Maus, M. K. H., Antoniotti, C., Langer, C., Scherer, S. J., et al. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dju427 · Cited by 477
“characterized simultaneously by intratumor heterogeneity and the preservation of ancestral aberrations within the primary tumor and corresponding metastatic sites (13,14).”
BackgroundKapur, P., Peña‐Llopis, S., Christie, A. L., Zhrebker, L., Pavía-Jiménez, A., Rathmell, W. K., Xie, X., & Brugarolas, J. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70584-3 · Cited by 466
Luminal breast cancer: from biology to treatment
Ignatiadis, M., & Sotiriou, C. P. (2013) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2013.124 · Cited by 481
Pfister, S. X., Ahrabi, S., Zalmas, L., Sarkar, S., Aymard, F., Bachrati, C. Z., Helleday, T., Legube, G., Thangue, N. B. L., Porter, A. C. G., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.05.026 · Cited by 496
Histone lysine methyltransferases in biology and disease
Husmann, D., & Gozani, O. (2019) · Nature Structural & Molecular Biology · doi:10.1038/s41594-019-0298-7 · Cited by 495
Lindeman, N. I., Cagle, P. T., Beasley, M. B., Chitale, D. A., Đačić, S., Giaccone, G., Jenkins, R. B., Kwiatkowski, D. J., Saldivar, J., Squire, J. A., et al. (2013) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2013.03.001 · Cited by 461
PD‐1/PD‐L1 pathway: Basic biology and role in cancer immunotherapy
Salmaninejad, A., Valilou, S. F., Shabgah, A. G., Aslani, S., Alimardani, M., Pasdar, A., & Sahebkar, A. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28358 · Cited by 445
“focal expression, and diffuse expression (Gerlinger et al., 2012).”
BackgroundNeoantigen landscape dynamics during human melanoma–T cell interactions
Verdegaal, E. M. E., de Miranda, N. F. C. C., Visser, M., Harryvan, T. J., van Buuren, M. M., Andersen, R. S., Hadrup, S. R., van der Minne, C. E., Schotte, R., Spits, H., et al. (2016) · Nature · doi:10.1038/nature18945 · Cited by 464
Jiménez-Sánchez, A., Memon, D., Pourpe, S., Veeraraghavan, H., Li, Y., Vargas, H. A., Gill, M. B., Park, K. J., Zivanovic, O., Konner, J. A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.07.025 · Cited by 456
“…genomic and immune profiling of multiple lesions in patients have also shed light on tumor heterogeneity and its implications on tumor evolution (Gerlinger et al., 2012), disease progression (Ascierto et al., 2017), and immune control (McGranahan et al., 2016; Sxenbabao glu et al., 2016;…”
BackgroundPiotrowska, Z., Niederst, M. J., Karlovich, C., Wakelee, H. A., Neal, J. W., Mino-Kenudson, M. A., Fulton, L. E., Hata, A. N., Lockerman, E. L., Kalsy, A., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0399 · Cited by 467
“However, this simple approach may not accurately reflect the complexities of tumor heterogeneity, which has been well described among NSCLC and other malignancies(7-9).”
BackgroundEvolution of Metastases in Space and Time under Immune Selection
Angelova, M., Mlecnik, B., Vasaturo, A., Bindea, G., Fredriksen, T., Lafontaine, L., Buttard, B., Morgand, E., Bruni, D., Jouret‐Mourin, A., et al. (2018) · Cell · doi:10.1016/j.cell.2018.09.018 · Cited by 457
“Currently the most widely accepted, the branched evolution model posits multiple co-existing clonal expansions that diverge from a common ancestor and evolve in parallel (Gerlinger et al., 2012).”
Aichler, M., & Walch, A. K. (2015) · Laboratory Investigation · doi:10.1038/labinvest.2014.156 · Cited by 472
Grabiner, B. C., Nardi, V., Birsoy, K., Possemato, R., Shen, K., Sinha, S., Jordan, A. C., Beck, A. H., & Sabatini, D. M. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0929 · Cited by 470
T cell‐targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity
Schmid, D., Park, C. G., Hartl, C. A., Subedi, N., Cartwright, A. N., Puerto, R. B., Zheng, Y., Maiarana, J., Freeman, G. J., Wucherpfennig, K. W., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01830-8 · Cited by 449
“Adaptation is vital because cytotoxic agents select for resistant cancer clones, as tumors are heterogeneous and evolve when confronted with selection pressure 35 .”
BackgroundNi, X., Zhuo, M., Su, Z., Duan, J., Gao, Y., Wang, Z., Zong, C., Bai, H., Chapman, A. R., Zhao, J., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1320659110 · Cited by 454
Miller, C. A., White, B. S., Dees, N. D., Griffith, M., Welch, J. S., Griffith, O. L., Vij, R., Tomasson, M. H., Graubert, T. A., Walter, M. J., et al. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003665 · Cited by 461
Moris, D., Palta, M., Kim, C., Allen, P. J., Morse, M. A., & Lidsky, M. E. (2022) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21759 · Cited by 457
Dewhurst, S. M., McGranahan, N., Burrell, R. A., Rowan, A., Gronroos, E. C., Endesfelder, D., Joshi, T., Mouradov, D., Gibbs, P., Ward, R. L., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0285 · Cited by 455
Self-citationA conduit to metastasis: circulating tumor cell biologyPreprint
Micalizzi, D. S., Maheswaran, S., & Haber, D. A. (2017) · Genes & Development · doi:10.1101/gad.305805.117 · Cited by 458
“Recent work using multiple tumor biopsies of the same tumor and sequencing of different regions of a resection specimen has demonstrated significant intratumoral heterogeneity for gene mutations, gene expression signatures, and overall cell ploidy (Gerlinger et al. 2012).”
BackgroundAmino acids and mTORC1: from lysosomes to disease
Efeyan, A., Zoncu, R., & Sabatini, D. M. (2012) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2012.05.007 · Cited by 436
“In addition, it is intriguing that only a very few mutations in mTOR have been found in human sporadic cancers [100,101].”
McDermott, D. F., Drake, C. G., Sznol, M., Choueiri, T. K., Powderly, J. D., Smith, D. C., Brahmer, J. R., Carvajal, R. D., Hammers, H. J., Puzanov, I. J., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.58.1041 · Cited by 437
“Importantly, the significant heterogeneity seen in kidney cancers may make the development of predictive biomarkers challenging.(34) For example, preliminary correlative studies have demonstrated that although tumor PD-L1 expression by immunohistochemistry may increase the likelihood of benefit with anti–PD-1, it fail…”
BackgroundLi, J., Chen, Z., Tian, L., et al. (2014) · Gut · doi:10.1136/gutjnl-2013-305806 · Cited by 439
Odegaard, J. I., Vincent, J. J., Mortimer, S., Vowles, J. V., Ulrich, B. C., Banks, K. C., Fairclough, S. R., Zill, O. A., Sikora, M., Mokhtari, R. B., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3831 · Cited by 437
the ICGC Prostate Group, Cooper, C. S., Eeles, R. A., Wedge, D. C., Loo, P. V., Gundem, G., Alexandrov, L. B., Kremeyer, B., Butler, A. P., Lynch, A. G., et al. (2015) · Nature Genetics · doi:10.1038/ng.3221 · Cited by 431
Self-citationArmstrong, A. J., Halabi, S., Eisen, T. G., Broderick, S., Stadler, W. M., Jones, R. J., Garcia, J. A., Vaishampayan, U. N., Picus, J., Hawkins, R. E., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00515-x · Cited by 427
Self-citationLindeman, N. I., Cagle, P. T., Beasley, M. B., Chitale, D. A., Đačić, S., Giaccone, G., Jenkins, R. B., Kwiatkowski, D. J., Saldivar, J., Squire, J. A., et al. (2013) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2012-0720-oa · Cited by 426
Classifying the evolutionary and ecological features of neoplasms
Maley, C. C., Aktipis, A., Graham, T. A., Sottoriva, A., Boddy, A. M., Janiszewska, M., Silva, A. S., Gerlinger, M., Yuan, Y., Pienta, K. J., et al. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.69 · Cited by 435
Self-citationBashashati, A., Ha, G., Tone, A. A., Ding, J., Prentice, L., Roth, A. J. L., Rosner, J., Shumansky, K., Kalloger, S. E., Senz, J., et al. (2013) · The Journal of Pathology · doi:10.1002/path.4230 · Cited by 423
PhyloWGS: Reconstructing subclonal composition and evolution from whole-genome sequencing of tumors
Deshwar, A. G., Vembu, S., Yung, C. K., Jang, G. H., Stein, L. D., & Morris, Q. (2015) · Genome biology · doi:10.1186/s13059-015-0602-8 · Cited by 423
Tumour heterogeneity and the evolution of polyclonal drug resistance
Burrell, R. A., & Swanton, C. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.06.005 · Cited by 435
Self-citationMroz, E. A., & Rocco, J. W. (2012) · Oral Oncology · doi:10.1016/j.oraloncology.2012.09.007 · Cited by 413
Acquired Resistance to Crizotinib from a Mutation in CD74 – ROS1
Awad, M. M., Katayama, R., McTigue, M. A., Liu, W., Deng, Y.-L., Brooun, A., Friboulet, L., Huang, D., Falk, M. D., Timofeevski, S. L., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1215530 · Cited by 425
Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing
Rasche, L., Chavan, S. S., Stephens, O. W., Patel, P. H., Tytarenko, R., Ashby, C., Bauer, M., Stein, C., Deshpande, S., Wardell, C., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00296-y · Cited by 417
“t(4;14) HY MYC t(8,22) amp(1q) del(13) del(6q) + 30 SNV L1”
Limits to Personalized Cancer Medicine
Tannock, I. F., & Hickman, J. A. (2016) · New England Journal of Medicine · doi:10.1056/nejmsb1607705 · Cited by 428
Suda, K., Nakaoka, H., Yoshihara, K., Ishiguro, T., Tamura, R., Mori, Y., Yamawaki, K., Adachi, S., Takahashi, T., Kase, H., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.07.037 · Cited by 414
“Genomic Homogeneity and Heterogeneity in Multiregional Sequencing We scrutinized the spatial distribution of somatic mutations in endometriotic and uterine endometrial epithelium samples by using multiregional sampling of several sites from the same individuals (Gerlinger et al., 2012; Yates et al., 2015).”
Biomaterials and emerging anticancer therapeutics: engineering the microenvironment
Gu, L., & Mooney, D. J. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2015.3 · Cited by 407
The evolving concept of cancer and metastasis stem cells
Baccelli, I., & Trumpp, A. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201202014 · Cited by 428
Data integration in the era of omics: current and future challenges
Gómez-Cabrero, D., Abugessaisa, I., Maier, D., Teschendorff, A. E., Merkenschlager, M., Gisel, A., Ballestar, E., Bongcam‐Rudloff, E., Conesa, A., & Tegner, J. N. (2014) · BMC Systems Biology · doi:10.1186/1752-0509-8-s2-i1 · Cited by 426
Kim, H., Zheng, S., Amini, S. S., Virk, S. M., Mikkelsen, T., Brat, D. J., Grimsby, J., Sougnez, C., Muller, F., Hu, J., et al. (2015) · Genome Research · doi:10.1101/gr.180612.114 · Cited by 411
“…theepidermal growth factor receptor variant III (EGFRvIII) led to an improved overall survival time among patients with GBM; however, 82% of these patients lost EGFRvIII expression when the tumor recurred, which suggests a competitive advantage for non-EGFRvIII expressing clones in these tumors…”
BackgroundMethodReal-time Liquid Biopsy in Cancer Patients: Fact or Fiction?
Pantel, K., & Alix‐Panabières, C. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-2030 · Cited by 419
Molecular aspects of cancer cell resistance to chemotherapy
Rebucci, M., & Michiels, C. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.02.017 · Cited by 423
Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer
Schödel, J., Grampp, S., Maher, E. R., Moch, H., Ratcliffe, P. J., Russo, P., & Mole, D. R. (2015) · European Urology · doi:10.1016/j.eururo.2015.08.007 · Cited by 420
“[90] Gerlinger M, Rowan AJ, Horswell S, et al.”
Mertins, P., Yang, F., Liu, T., Mani, D. R., Petyuk, V. A., Gillette, M. A., Clauser, K. R., Qiao, J. W., Gritsenko, M. A., Moore, R. J., et al. (2014) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m113.036392 · Cited by 400
André, F., Bachelot, T., Commo, F., Campone, M., Arnedos, M., Dieras, V. C., Lacroix‐Triki, M., Lacroix, L., Cohen, P. A., Gentien, D., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70611-9 · Cited by 417
Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer
Cheng, F., Su, L., & Qian, C. (2016) · Oncotarget · doi:10.18632/oncotarget.9453 · Cited by 421
“For instance, the detection of early-stage tumor or residual lesions is unsatisfactory, and its application in the evaluation of treatment efficacy and prognosis is also limited [1-2].”
BackgroundMakohon-Moore, A. P., Zhang, M., Reiter, J. G., Bozic, I., Allen, B., Kundu, D., Chatterjee, K., Wong, F., Jiao, Y., Kohutek, Z. A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3764 · Cited by 403
Cancer across the tree of life: cooperation and cheating in multicellularity
Aktipis, C. A., Boddy, A. M., Jansen, G., Hibner, U., Hochberg, M. E., Maley, C. C., & Wilkinson, G. S. (2015) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2014.0219 · Cited by 466
“In advanced disease, metastases can form a metapopulation with genetically diverse colonies of cells [223], leading to the kinds of population structure that could favour cooperation within the cell colonies [224].”
BackgroundTumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer
Russo, M., Siravegna, G., Blaszkowsky, L. S., Corti, G., Crisafulli, G., Ahronian, L. G., Mussolin, B., Kwak, E. L., Buscarino, M., Lazzari, L., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1283 · Cited by 411
“However, tumors can display high levels of molecular heterogeneity(2-7).”
BackgroundGenomic alterations in lung adenocarcinoma
Devarakonda, S. H. K., Morgensztern, D., & Govindan, R. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00077-7 · Cited by 423
Predicting outcomes in radiation oncology—multifactorial decision support systems
Lambin, P., van Stiphout, R. G. P. M., Starmans, M. H. W., Velazquez, E. R., Nalbantov, G. I., Aerts, H. J. W. L., Roelofs, E., van Elmpt, W., Boutros, P. C., Granone, P. M., et al. (2012) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2012.196 · Cited by 396
Spatial and Temporal Heterogeneity in High-Grade Serous Ovarian Cancer: A Phylogenetic Analysis
Schwarz, R. F., Ng, C. K. Y., Cooke, S. L., Newman, S., Temple, J., Piskorz, A., Gale, D. G., Sayal, K., Murtaza, M., Baldwin, P., et al. (2015) · PLoS Medicine · doi:10.1371/journal.pmed.1001789 · Cited by 403
Enderle, D., Spiel, A., Coticchia, C. M., Berghoff, E. G., Mueller, R., Schlumpberger, M., Sprenger‐Haussels, M., Shaffer, J. M., Lader, E., Skog, J., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0136133 · Cited by 406
“In Oncology, biofluids might also provide a more accurate representation of a tumor’s genetic makeup than a spatially restricted fine needle biopsy, including the heterogeneity of the primary tumor and of metastatic lesions [35,36].”
BackgroundABC Transporters in Cancer Stem Cells: Beyond Chemoresistance
Begicevic, R.-R., & Falasca, M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18112362 · Cited by 424
“These mutations include passenger mutations, such as mammalian target of rapamycin (mTOR) or KDMSC, but also metastasis-specific driver mutations, such as those in the SETD2 gene [166].”
BackgroundQuantifying tumour heterogeneity with CT
Ganeshan, B., & Miles, K. A. (2013) · Cancer Imaging · doi:10.1102/1470-7330.2013.0015 · Cited by 395
Functional Heterogeneity of Genetically Defined Subclones in Acute Myeloid Leukemia
Klco, J. M., Spencer, D. H., Miller, C. A., Griffith, M., Westover, T., O’Laughlin, M. D., Fronick, C. C., Magrini, V. J., Demeter, R., Fulton, R. S., et al. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.01.031 · Cited by 410
A role for cancer stem cells in therapy resistance: Cellular and molecular mechanisms
Cojoc, M., Mäbert, K., Muders, M. H., & Dubrovska, A. (2014) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2014.06.004 · Cited by 410
Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis
Ramaswamy, V., Remke, M., Bouffet, É., Faria, C. C., Perreault, S., Cho, Y., Shih, D. J. H., Luu, B., Dubuc, A. M., Northcott, P. A., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70449-2 · Cited by 394
Self-citationMutational Profile of Metastatic Breast Cancers: A Retrospective Analysis
Lefèbvre, C., Bachelot, T., Filleron, T., Pedrero, M., Campone, M., Soria, J., Massard, C., Lévy, C., Arnedos, M., Lacroix‐Triki, M., et al. (2016) · PLoS Medicine · doi:10.1371/journal.pmed.1002201 · Cited by 398
Zill, O. A., Banks, K. C., Fairclough, S. R., Mortimer, S. A., Vowles, J. V., Mokhtari, R., Gandara, D. R., Mack, P. C., Odegaard, J. I., Nagy, R. J., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3837 · Cited by 391
Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics
Morita, K., Wang, F., Jahn, K., Hu, T., Tanaka, T. N., Sasaki, Y., Kuipers, J., Loghavi, S., Wang, S. A., Yan, Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19119-8 · Cited by 411
Self-citationSomatic Mutations Drive Distinct Imaging Phenotypes in Lung Cancer
Velazquez, E. R., Parmar, C., Liu, Y., Coroller, T. P., Cruz, G., Stringfield, O., Ye, Z., Makrigiorgos, M. G., Fennessy, F., Mak, R. H., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0122 · Cited by 391
“We believe that a detailed analysis of the intratumoral tumor heterogeneity, by compartment mappings, particularly if paired with multiple biopsies at distinct geographical locations, such as investigated in renal cell carcinomas (7, 51), may allow us to further elucidate intratumoral genotype–phenotype relationships.”
BackgroundImmunotherapy in ovarian cancer
Odunsi, K. O. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx444 · Cited by 396
“tumor in a single biopsy [37, 38], it is evident that the vast majority of neoantigens occur within exonic sequence and do not lead to the formation of neoantigens that are recognized by autologous T cells [38, 39].”
BackgroundTreatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer
Tan, C., Gilligan, D., & Pacey, S. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00246-6 · Cited by 393
Single Cell Isolation and Analysis
Hu, P., Zhang, W., Xin, H., & Deng, G. Y. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2016.00116 · Cited by 401
“Exome sequencing of single cells isolated from primary renal carcinomas showed that only 31–37% of the genetic lesions within a tumor are identical to the rest of the tumor cells (Gerlinger et al., 2012; Xu et al., 2012).”
BackgroundWhole-genome sequencing in health care
van El, C. G., Cornel, M. C., Borry, P., Hastings, R. J., Fellmann, F., Hodgson, S. V., Howard, H. C., Cambon‐Thomsen, A., Knoppers, B. M., Meijers-Heijboer, H. E. J., et al. (2013) · European Journal of Human Genetics · doi:10.1038/ejhg.2013.46 · Cited by 399
Mattos‐Arruda, L. D., Weigelt, B., Cortés, J., Won, H. H., Ng, C. K. Y., Nuciforo, P. G., Bidard, F., Aura, C. M., Saura, C., Peg, V., et al. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu239 · Cited by 387
Tumor neoantigens: from basic research to clinical applications
Jiang, T., Shi, T., Zhang, H., Hu, J., Song, Y., Wei, J., Ren, S., & Zhou, C. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0787-5 · Cited by 401
“Platinum resistant” ovarian cancer: What is it, who to treat and how to measure benefit?
Davis, A., Tinker, A. V., & Friedlander, M. (2014) · Gynecologic Oncology · doi:10.1016/j.ygyno.2014.02.038 · Cited by 433
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
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