Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer

Nature Genetics, Journal Year: 2017, Volume and Issue: 49(3), P. 358 - 366

Published: Jan. 16, 2017

Language: Английский

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Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution

Proceedings of the National Academy of Sciences, Journal Year: 2015, Volume and Issue: 112(47)

Published: Nov. 11, 2015

Significance A tumor comprising many cells can be compared to a natural population with individuals. The amount of genetic diversity reflects how it has evolved and influence its future evolution. We evaluated single by sequencing or genotyping nearly 300 regions from the tumor. When data were analyzed modern theory, we estimated more than 100 million coding region mutations in this unexceptional extreme implies evolution under non-Darwinian mode. In contrast, prevailing view Darwinian selection, would orders magnitude lower. Because accrues rapidly, high probability drug resistance should heeded, even treatment microscopic tumors.

Language: Английский

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Tumor evolution: Linear, branching, neutral or punctuated?

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2017, Volume and Issue: 1867(2), P. 151 - 161

Published: Jan. 19, 2017

Language: Английский

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stLearn: integrating spatial location, tissue morphology and gene expression to find cell types, cell-cell interactions and spatial trajectories within undissociated tissues

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2020, Volume and Issue: unknown

Published: May 31, 2020

ABSTRACT Spatial Transcriptomics is an emerging technology that adds spatial dimensionality and tissue morphology to the genome-wide transcriptional profile of cells in undissociated tissue. Integrating these three types data creates a vast potential for deciphering novel biology cell their native morphological context. Here we developed innovative integrative analysis approaches utilise all first find types, then reconstruct type evolution within tissue, search regions with high cell-to-cell interactions. First, normalisation gene expression, compute distance measure using similarity neighbourhood smoothing. The normalised used clusters represent profiles specific cellular phenotypes. Clusters are further sub-clustered if spatially separated. Analysing anatomical mouse brain sections 12 human datasets, found clustering method more accurate sensitive than other methods. Second, introduce calculate states by pseudo-space-time (PST) distance. PST function physical (spatial distance) expression (pseudotime estimate pairwise between among We transition gradients connected locally cluster, or globally clusters, directed minimum spanning tree optimisation approach algorithm could model from non-invasive invasive breast cancer dataset. Third, information identify locations where there both ligand-receptor interaction activity diverse co-localisation. These predicted be hotspots cell-cell interactions likely occur. detected pairs significantly enriched compared background distribution across Together, algorithms, implemented comprehensive Python software stLearn, allow elucidation biological processes healthy diseased tissues.

Language: Английский

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Integrating genetic and non-genetic determinants of cancer evolution by single-cell multi-omics

Nature Reviews Genetics, Journal Year: 2020, Volume and Issue: 22(1), P. 3 - 18

Published: Aug. 17, 2020

Language: Английский

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Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival

Oncotarget, Journal Year: 2016, Volume and Issue: 7(9), P. 10051 - 10063

Published: Jan. 28, 2016

// Luc G.T. Morris 1,2,* , Nadeem Riaz 1,3* Alexis Desrichard 1 Yasin Şenbabaoğlu 4 A. Ari Hakimi 2 Vladimir Makarov Jorge S. Reis-Filho 1,5 and Timothy Chan 1,3 Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA Department of Surgery, 3 Radiation Oncology, Computational Biology 5 Pathology, * These authors have contributed equally to this work Correspondence to: Morris, email: Chan, Keywords : heterogeneity, evolution, survival, cancer, immune surveillance Received January 14, 2016 Accepted 21, Published 28, Abstract As tumors accumulate genetic alterations, an evolutionary process occurs in which genetically distinct subclonal populations cells co-exist, resulting intratumor heterogeneity (ITH). The clinical implications ITH remain poorly defined. Data are limited with respect whether is independent determinant patient survival outcomes, across different cancer types. Here, we report the results a pan-cancer analysis over 3300 tumors, showing varied landscape 9 While some gene mutations subclonal, majority driver clonal events, present nearly all cells. Strikingly, high levels associated poorer diverse types cancer. adverse impact other clinical, pathologic molecular factors. High tends be lower tumor-infiltrating cells, but association not able explain observed differences. Together, these data show that prognostic marker multiple cancers. illuminate natural history indicating tumor represents significant obstacle control.

Language: Английский

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Quantification of subclonal selection in cancer from bulk sequencing data

Nature Genetics, Journal Year: 2018, Volume and Issue: 50(6), P. 895 - 903

Published: May 24, 2018

Language: Английский

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Cancer Evolution and the Limits of Predictability in Precision Cancer Medicine

Trends in cancer, Journal Year: 2016, Volume and Issue: 2(1), P. 49 - 63

Published: Jan. 1, 2016

Large-scale genomic cancer medicine initiatives are under way in several countries across the globe. However, it remains a major challenge to use information make accurate predictions for individual patients. Multiple studies substantiated notion of as an evolutionary process that can readily adapt within lifetime patient. Evolutionary adaptation results from interplay mutation generation and genetic drift, which both stochastic processes, clonal selection, is deterministic nature. The influence factors fundamentally limits predictability evolution. Understanding development more prediction algorithms using models key improving outcomes through medicine. ability predict future behavior crucial precision discovery extensive intratumor heterogeneity ongoing human tumors process. Random events inherent evolution tumor spatial structures hinder efficacy only force. This review outlines how interaction these have been extensively studied biology, develops strategies improve predictions. advancing horizon outcomes. precisely clinical course patient's would be highly beneficial oncological care. For example, patients whose cancers will never progress point affecting their health may not require any treatment those who need systemic therapy should treated with drugs realistic chance being effective. Genomic aberrations differ between same histological type, extent no two thought show identical somatic aberration profile [1Stratton M.R. et al.The genome.Nature. 2009; 458: 719-724Crossref PubMed Scopus (1414) Google Scholar]. specific combination epigenetic tumor, context germline variants present patient, determinant biology hence cancer. Recognition this intertumor led concept personalized medicine: deciphering profiles provide precise insights into disease allow targeting genetically encoded susceptibilities therapeutic benefit. Next-generation sequencing technologies enable routine interrogation (epi)genomic landscapes [2Meyerson M. al.Advances understanding genomes second-generation sequencing.Nat. Rev. Genet. 2010; 11: 685-696Crossref (674) Scholar, 3Reuter J.A. al.High-throughput technologies.Mol. Cell. 2015; 58: 586-597Abstract Full Text PDF In parallel, increasing number expand options target alterations. Yet, despite noticeable advances approaches some types, whether long respond what genotype eventually evolve drive resistance remain suboptimal [4Dienstmann R. al.Genomic frontier solid tumors: prospects challenges.J. Clin. Oncol. 2013; 31: 1874-1884Crossref (67) Precisely forecasting recur after potentially curative even elusive, resulting dramatic overtreatment oncology [5Gnant Steger G.G. Fighting adjuvant breast therapy.Lancet. 374: 2029-2030Abstract (0) Forty years ago, Peter Nowell first formally described [6Nowell P.C. cell populations.Science. 1976; 194: 23-28Crossref hypothesis has since by subclonal selection multiple types [7Anderson K. al.Genetic variegation architecture propagating cells leukaemia.Nature. 2011; 469: 356-361Crossref (486) 8Diaz L.A. molecular acquired targeted EGFR blockade colorectal cancers.Nature. 2012; 486: 537-540Crossref (799) 9Gerlinger al.Intratumor branched revealed multiregion sequencing.N. Engl. J. Med. 366: 883-892Crossref (3265) 10Awad M.M. al.Acquired crizotinib CD74-ROS1.N. 368: 2395-2401Crossref (149) 11Gerlinger clear renal carcinomas defined 2014; 46: 225-233Crossref (421) 12Bettegowda C. al.Detection circulating DNA early- late-stage malignancies.Sci. Transl. 6: 224ra24Crossref (904) 13Gundem G. history lethal metastatic prostate cancer.Nature. 520: 353-357Crossref (292) fundamental nature dynamically adapting 'organisms' requires reassessment opportunities limitations bestows on medicine.'Nothing makes sense except light evolution' – Theodosius Dobzhansky Cancer conceptually similar asexual microorganisms [14Sprouffske al.Cancer experimental evolution.Curr. Biol. 22: R762-R771Abstract Scholar] governed dynamic three basic processes [15Lynch Origins Genome Architecture. Sinauer Associates, 2007Google Scholar]: (i) heritable variation; (ii) random birth death fate new genotypes, referred drift; (iii) Darwinian changes frequency genotypes population based relative fitness advantage (Figure 1, Key Figure). acquisition alterations drift while (deterministic process; see Glossary) [16Szendro I.G. al.Predictability depends nonmonotonically size.Proc. Natl. Acad. Sci. U.S.A. 110: 571-576Crossref 17Blount Z.D. al.Historical contingency innovation Escherichia coli.Proc. 2008; 105: 7899-7906Crossref (349) questions patient predicted precision. integrates recent genomics concepts assess stochasticity (stochastic process) limit predictability. Based perspective cancer, we subsequently assemble novel such micro- macroheterogeneity profiling application empirical landscapes, efforts. Heritable variation encompasses mutations, insertions, deletions, chromosomal aberrations, well over generations. simplicity, term 'mutation' used all throughout review. A baseline rate detected mitotic tissue, but rates often elevated [18Roberts S.A. Gordenin D.A. Hypermutation genomes: footprints mechanisms.Nat. Cancer. 14: 786-800Crossref (115) Mutations result extrinsic (e.g., tobacco smoke exposure) or intrinsic oxidative damage defects repair). Many mutational preferentially strike sequence contexts, biasing mutations towards regions overrepresented. Distinct mechanisms leave signatures genome, shown pan-cancer analysis 20 different signatures, nine could linked known [19Alexandrov L.B. al.Signatures 500: 415-421Crossref (1889) preferential deamination cytosine 5′-TC-3′ dinucleotides regional hypermutation clusters caused aberrant activity apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) RNA-editing enzymes one example [20Nik-Zainal S. al.Mutational molding 21 cancers.Cell. 149: 979-993Abstract (685) Late-replicating prone acquire than early replicating [21Stamatoyannopoulos al.Human associated replication timing.Nat. 41: 393-395Crossref (178) Scholar], chromatin organization further influences [22Schuster-Bockler B. Lehner Chromatin cells.Nature. 488: 504-507Crossref (222) contributing variable regions. Structural also diverse mechanisms. Fusion chromosome ends fostering cycles breakage fusion during mitosis [23Gisselsson D. al.Generation trisomies multipolar incomplete cytokinesis.Proc. 107: 20489-20493Crossref (42) catastrophic 'chromothripsis' leading massive rearrangements single division [24Stephens P.J. al.Massive rearrangement event development.Cell. 144: 27-40Abstract (971) examples. fragments detached propagated so-called 'double minute chromosomes' abundance change rapidly, maintain optimal epidermal growth factor receptor (EGFR) signaling levels drug [25Nathanson al.Targeted mediated regulation extrachromosomal mutant DNA.Science. 343: 72-76Crossref (107) Different predominate at times. Clear (ccRCC) non-small lung (NSCLCs) exhibited distinct carcinogenesis compared progression subclones [9Gerlinger 26de Bruin E.C. al.Spatial temporal diversity instability defines evolution.Science. 346: 251-256Crossref (337) Ongoing exposure had minor NSCLC where were predominantly induced APOBEC [26de Single showed generated continuously progression, whereas copy [27Wang Y. al.Clonal nucleus genome sequencing.Nature. 512: 155-160Crossref (319) Whole doubling lead tetraploidy, permissive gains losses [28Dewhurst S.M. al.Tolerance whole-genome propagates accelerates evolution.Cancer Discov. 4: 175-185Crossref (99) occur late Extra gene copies buffer deleterious effects might therefore catalyze increase tolerance. originates diploid genome. encodes blueprint embryological adult homoeostasis complex multicellular organism structurally optimized undergo meiosis recombination sexual reproduction Such constraints structure many genes regulating tissue-specific functions likely irrelevant cells, permits survival genomes. robustness allows probe vast space phenotypes [29Garsed D.W. neochromosomes.Cancer 26: 653-667Abstract 30Shlien A. al.Combined hereditary error repair rapid onset ultra-hypermutated cancers.Nat. 47: 257-262Crossref (95) Taken together, prerequisite Mutation rates, mutagenesis, timing when particular mutagenic operate vary significantly cancers. accessibility evolution, APOBEC-driven generates activating phosphoinositide (PI)3-kinase active [31Henderson al.APOBEC-mediated links PIK3CA helical domain papillomavirus-driven development.Cell Rep. 7: 1833-1841Abstract (93) if operating measured exactly, still randomly regard exact location. Genetic refers allele due events: each newly subclone certain probability dying occasionally small die, clone harbors mutation. Drift bigger impact smaller populations eradicate yet expanded significantly. pronounced bottlenecks, few colonize niche reduction size cytotoxic treatment. As consequence expansion predictable certainty until exceeds escapes potential extinction [32Levy S.F. al.Quantitative dynamics high-resolution lineage tracking.Nature. 519: 181-186Crossref (65) initiation [33Vermeulen L. al.Defining stem intestinal initiation.Science. 342: 995-998Crossref (131) 34Kozar al.Continuous labeling reveals numbers functional crypts adenomas.Cell Stem 13: 626-633Abstract (21) data demonstrating strength effect lacking. New assessing composition level tracing model systems 35Bhang H.E. al.Studying response high-complexity barcoding.Nat. 21: 440-448Crossref (170) insights. increases survive reproduce environmental conditions escaped gradually its population. arguably force 36Jain Krug Deterministic regimes rugged landscapes.Genetics. 2007; 175: 1275-1288Crossref time detail drafted chapters rulebooks. intratumoral harboring driver displaying phenotypes, evolving phylogenies identified 37Nik-Zainal life 994-1007Abstract (563) 38Landau al.Locally disordered methylation forms basis methylome chronic lymphocytic leukemia.Cancer 813-825Abstract (94) 39Yates L.R. al.Subclonal diversification primary 751-759Crossref (168) 40Sottoriva glioblastoma reflects dynamics.Proc. 4009-4014Crossref (474) 41Gulati al.Systematic evaluation prognostic intratumour carcinoma biomarkers.Eur. Urol. 66: 936-948Abstract (47) presence competition. then relation other competing clones [42Gerrish Lenski R.E. population.Genetica. 1998; 102–103: 127-144Crossref Hence, escape eradicated clones, complicating identification spatially separated suggests 3D hinders intermixing 43Zhang localized adenocarcinomas delineated sequencing.Science. 256-259Crossref (295) most competition immediately neighboring fit able rise 100% abundance, 'fixation' 'selective sweep' biology. Solid augment maintenance system behavior. supported microbial experiments found higher intrapopulation structured environments [44Korona al.Evidence adaptive peaks bacteria habitat.Proc. 1994; 91: 9037-9041Crossref Thus, ecological microcosms composed myriads populations, edges populations. Resistance almost invariably origins impressively illustrated plasticity majority NSCLCs inhibitors gefitinib erlotinib T790M [45Cortot A.B. Janne P.A. Molecular receptor-mutant adenocarcinomas.Eur. Respir. 23: 356-366Crossref (46) Alternative MET proto-oncogene erb-b2 tyrosine kinase 2 (ERBB2) amplification non-pathway-dependent transformation small-cell observed less frequently biopsies resistant [46Yu H.A. al.Analysis specimens EGFR-TKI 155 EGFR-mutant cancers.Clin. Res. 19: 2240-2247Crossref (676) high prevalence T790M-driven third rociletinib, against oncoprotein achieved 59% [47Sequist L.V. al.Rociletinib EGFR-mutated non-small-cell cancer.N. 372: 1700-1709Crossref (368) Rebiopsies rociletinib failure 6/13 T790 wild-type (wt) again. These already before probably harbored alternative drivers [48Piotrowska Z. al.Heterogeneity underlies emergence EGFRT790 following T790M-positive third-generation inhibitor.Cancer 5: 713-722Crossref (161) was failure. C797S mechanism [49Niederst M.J. allelic upon impacts sensitivity subsequent strategies.Clin. 3924-3933Crossref (106) Importantly, inhibited located trans ineffective cis allele. alleles, cannot occurred detected. compellingly demonstrates Somatic detection (ctDNA) comprehensive overview biopsies. ctDNA indeed up 12 subclones, RAS-type family GTPases (RAS) v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) genes, (CRC) they developed anti-EGFR [12Bettegowda Polyclonal drugs, hormones, chemotherapy [13Gundem 50Shi H. melanoma BRAF inhibitor therapy.Cancer 80-93Crossref (324) 51Juric al.Convergent loss PTEN leads PI(3)Kα inhibitor.Nature. 518: 240-244Crossref (125) 52Patch A.M. al.Whole-genome characterization chemoresistant ovarian 521: 489-494Crossref (264) 53Piotrowska al.Variation among 1 postresistant biopsy.Int. Radiat. 90: 2Abstract thus common phenomenon tumors, enormous adaptability Clonal analyses CRC suggested Kirsten rat (KRAS) [8Diaz standing recurrently reservoir permitting rescue changing environments. Overexpression V600E dependency xenografts [54Das Thakur al.

Language: Английский

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Spatial Heterogeneity and Evolutionary Dynamics Modulate Time to Recurrence in Continuous and Adaptive Cancer Therapies

Cancer Research, Journal Year: 2018, Volume and Issue: 78(8), P. 2127 - 2139

Published: Jan. 30, 2018

Treatment of advanced cancers has benefited from new agents that supplement or bypass conventional therapies. However, even effective therapies fail as cancer cells deploy a wide range resistance strategies. We propose evolutionary dynamics ultimately determine survival and proliferation resistant cells. Therefore, strategies should be used with to delay prevent resistance. Using an agent-based framework model spatial competition among sensitive populations, we applied antiproliferative drug treatments varying ratios compared continuous maximum-tolerated dose schedule adaptive aimed at tumor control via between Continuous treatment cured mostly tumors, but any cells, recurrence was inevitable. identified two heterogeneous tumors: modulation controls most tumors less drug, while more vacation-oriented can invasive tumors. These findings offer potential modifications regimens may improve outcomes reduce recurrence.

Language: Английский

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WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Dec. 20, 2019

WNT/beta-catenin signaling is involved in many physiological processes. Its implication embryonic development, cell migration and polarization has been shown. Nevertheless, alterations this have also related with pathological events such as sustaining proliferating the cancer stem cells (CSCs) subset present tumor bulk. Related this, WNT associated maintenance, expansion epithelial-mesenchymal transition of cells, furthermore two distinctive features population: therapeutic resistance (MDR, multidrug resistance) immune escape. These mechanisms are developed maintained by activation through transcriptional control genes This review focuses on description best known pathways molecules them. Special attention given to cascade proteins deregulated tumors which a decisive role survival. Some these function extrusion pumps that, course chemotherapy, expel drugs outside cells; others help tumoral hide from effector mechanisms. Among targets drug resistance, pump MDR-1 (P-GP, ABCB1) adhesion CD44 family highlighted. The chemokine CCL4 checkpoint CD47 PD-L1 included list target immunity pathway should be main therapy since essential for progression survival, even presence anti-tumoral response and/or antineoplastic drugs. appropriate design combination strategies based modulation mediators protein could negatively affect growth improving efficacy type therapies.

Language: Английский

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