@article{MTMT:3232913, title = {Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution}, url = {https://m2.mtmt.hu/api/publication/3232913}, author = {Abbosh, C and Birkbak, NJ and Wilson, GA and Jamal-Hanjani, M and Constantin, T and Salari, R and Le Quesne, J and Moore, DA and Veeriah, S and Rosenthal, R and Marafioti, T and Kirkizlar, E and Watkins, TBK and McGranahan, N and Ward, S and Martinson, L and Riley, J and Fraioli, F and Al, Bakir M and Gronroos, E and Zambrana, F and Endozo, R and Bi, WL and Fennessy, FM and Sponer, N and Johnson, D and Laycock, J and Shafi, S and Czyzewska-Khan, J and Rowan, A and Chambers, T and Matthews, N and Turajlic, S and Hiley, C and Lee, SM and Forster, MD and Ahmad, T and Falzon, M and Borg, E and Lawrence, D and Hayward, M and Kolvekar, S and Panagiotopoulos, N and Janes, SM and Thakrar, R and Ahmed, A and Blackhall, F and Summers, Y and Hafez, D and Naik, A and Ganguly, A and Kareht, S and Shah, R and Joseph, L and Marie, Quinn A and Crosbie, PA and Naidu, B and Middleton, G and Langman, G and Trotter, S and Nicolson, M and Remmen, H and Kerr, K and Chetty, M and Gomersall, L and Fennell, DA and Nakas, A and Rathinam, S and Anand, G and Khan, S and Russell, P and Ezhil, V and Ismail, B and Irvin-Sellers, M and Prakash, V and Lester, JF and Kornaszewska, M and Attanoos, R and Adams, H and Davies, H and Oukrif, D and Akarca, AU and Hartley, JA and Lowe, HL and Lock, S and Iles, N and Bell, H and Ngai, Y and Elgar, G and Szállási, Zoltán and Schwarz, RF and Herrero, J and Stewart, A and Quezada, SA and Peggs, KS and Van, Loo P and Dive, C and Lin, CJ and Rabinowitz, M and Aerts, HJWL and Hackshaw, A and Shaw, JA and Zimmermann, BG and Swanton, C}, doi = {10.1038/nature22364}, journal-iso = {NATURE}, journal = {NATURE}, volume = {545}, unique-id = {3232913}, issn = {0028-0836}, abstract = {The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.}, year = {2017}, eissn = {1476-4687}, pages = {446-451}, orcid-numbers = {Szállási, Zoltán/0000-0001-5395-7509} } @article{MTMT:3232911, title = {Tracking the Evolution of Non-Small-Cell Lung Cancer}, url = {https://m2.mtmt.hu/api/publication/3232911}, author = {Jamal-Hanjani, M and Wilson, GA and McGranahan, N and Birkbak, NJ and Watkins, TBK and Veeriah, S and Shafi, S and Johnson, DH and Mitter, R and Rosenthal, R and Salm, M and Horswell, S and Escudero, M and Matthews, N and Rowan, A and Chambers, T and Moore, DA and Turajlic, S and Xu, H and Lee, SM and Forster, MD and Ahmad, T and Hiley, CT and Abbosh, C and Falzon, M and Borg, E and Marafioti, T and Lawrence, D and Hayward, M and Kolvekar, S and Panagiotopoulos, N and Janes, SM and Thakrar, R and Ahmed, A and Blackhall, F and Summers, Y and Shah, R and Joseph, L and Quinn, AM and Crosbie, PA and Naidu, B and Middleton, G and Langman, G and Trotter, S and Nicolson, M and Remmen, H and Kerr, K and Chetty, M and Gomersall, L and Fennell, DA and Nakas, A and Rathinam, S and Anand, G and Khan, S and Russell, P and Ezhil, V and Ismail, B and Irvin-Sellers, M and Prakash, V and Lester, JF and Kornaszewska, M and Attanoos, R and Adams, H and Davies, H and Dentro, S and Taniere, P and O'Sullivan, B and Lowe, HL and Hartley, JA and Iles, N and Bell, H and Ngai, Y and Shaw, JA and Herrero, J and Szállási, Zoltán and Schwarz, RF and Stewart, A and Quezada, SA and Le Quesne, J and Van, Loo P and Dive, C and Hackshaw, A and Swanton, C}, doi = {10.1056/NEJMoa1616288}, journal-iso = {NEW ENGL J MED}, journal = {NEW ENGLAND JOURNAL OF MEDICINE}, volume = {376}, unique-id = {3232911}, issn = {0028-4793}, abstract = {Background Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. Methods In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. Results We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P=4.4x10-4), which remained significant in multivariate analysis. Conclusions Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).}, year = {2017}, eissn = {1533-4406}, pages = {2109-2121}, orcid-numbers = {Szállási, Zoltán/0000-0001-5395-7509} } @article{MTMT:2992681, title = {Utilization of Benchtop Next Generation Sequencing Platforms Ion Torrent PGM and MiSeq in Noninvasive Prenatal Testing for Chromosome 21 Trisomy and Testing of Impact of In Silico and Physical Size Selection on Its Analytical Performance}, url = {https://m2.mtmt.hu/api/publication/2992681}, author = {Minarik, G and Repiska, G and Hyblova, M and Nagyova, E and Soltys, K and Budis, J and Duris, F and Sysak, R and Gerykova, Bujalkova M and Vlkova-Izrael, B and Biró, Orsolya and Nagy, Bálint and Szemes, T}, doi = {10.1371/journal.pone.0144811}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {10}, unique-id = {2992681}, issn = {1932-6203}, abstract = {OBJECTIVES: The aims of this study were to test the utility of benchtop NGS platforms for NIPT for trisomy 21 using previously published z score calculation methods and to optimize the sample preparation and data analysis with use of in silico and physical size selection methods. METHODS: Samples from 130 pregnant women were analyzed by whole genome sequencing on benchtop NGS systems Ion Torrent PGM and MiSeq. The targeted yield of 3 million raw reads on each platform was used for z score calculation. The impact of in silico and physical size selection on analytical performance of the test was studied. RESULTS: Using a z score value of 3 as the cut-off, 98.11% - 100% (104-106/106) specificity and 100% (24/24) sensitivity and 99.06% - 100% (105-106/106) specificity and 100% (24/24) sensitivity were observed for Ion Torrent PGM and MiSeq, respectively. After in silico based size selection both platforms reached 100% specificity and sensitivity. Following the physical size selection z scores of tested trisomic samples increased significantly-p = 0.0141 and p = 0.025 for Ion Torrent PGM and MiSeq, respectively. CONCLUSIONS: Noninvasive prenatal testing for chromosome 21 trisomy with the utilization of benchtop NGS systems led to results equivalent to previously published studies performed on high-to-ultrahigh throughput NGS systems. The in silico size selection led to higher specificity of the test. Physical size selection performed on isolated DNA led to significant increase in z scores. The observed results could represent a basis for increasing of cost effectiveness of the test and thus help with its penetration worldwide.}, year = {2015}, eissn = {1932-6203}, orcid-numbers = {Biró, Orsolya/0000-0002-4300-3602; Nagy, Bálint/0000-0002-0295-185X} } @article{MTMT:32695715, title = {Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.}, url = {https://m2.mtmt.hu/api/publication/32695715}, author = {Gerlinger, Marco and Rowan, Andrew J and Horswell, Stuart and Math, M and Larkin, James and Endesfelder, David and Gronroos, Eva and Martinez, Pierre and Matthews, Nicholas and Stewart, Aengus and Tarpey, Patrick and Varela, Ignacio and Phillimore, Benjamin and Begum, Sharmin and McDonald, Neil Q and Butler, Adam and Jones, David and Raine, Keiran and Latimer, Calli and Santos, Claudio R and Nohadani, Mahrokh and Eklund, Aron C and Spencer-Dene, Bradley and Clark, Graham and Pickering, Lisa and Stamp, Gordon and Gore, Martin and Szállási, Zoltán and Downward, Julian and Futreal, P Andrew and Swanton, Charles}, doi = {10.1056/NEJMoa1113205}, journal-iso = {NEW ENGL J MED}, journal = {NEW ENGLAND JOURNAL OF MEDICINE}, volume = {366}, unique-id = {32695715}, issn = {0028-4793}, abstract = {Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples.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.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.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.).}, year = {2012}, eissn = {1533-4406}, pages = {883-892}, orcid-numbers = {Szállási, Zoltán/0000-0001-5395-7509} }