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1,055 results on '"Ladanyi M"'

1. Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers

Author

Shukla, N., Levine, M. F., Gundem, G., Domenico, D., Spitzer, B., Bouvier, N., Arango-Ossa, J. E., Glodzik, D., Medina-Martínez, J. S., Bhanot, U., Gutiérrez-Abril, J., Zhou, Y., Fiala, E., Stockfisch, E., Li, S., Rodriguez-Sanchez, M. I., O’Donohue, T., Cobbs, C., Roehrl, M. H. A., Benhamida, J., Iglesias Cardenas, F., Ortiz, M., Kinnaman, M., Roberts, S., Ladanyi, M., Modak, S., Farouk-Sait, S., Slotkin, E., Karajannis, M. A., Dela Cruz, F., Glade Bender, J., Zehir, A., Viale, A., Walsh, M. F., Kung, A. L., and Papaemmanuil, E.

Published
2022
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2. Local characteristics of the standing genetic diversity of European beech with high within-region differentiation at the eastern part of the range

Author

Hohn, M., Major, E., Avdagic, A., Bielak, K., Bosela, M., Coll, L., Dinca, L., Giammarchi, F., Ibrahimspahic, A., Mataruga, M., Pach, M., Uhl, E., Zlatanov, T., Cseke, K., Kovacs, Zs., Palla, B., Ladanyi, M., and Heinze, B.

Subjects
Beech -- Genetic aspects -- Distribution, Forests and forestry -- Natural history -- Europe, Company distribution practices, Earth sciences
Abstract

Developing 'climate smart forestry' (CSF) indicators in mountain forest regions requires collection and evaluation of local data and their attributes. Genetic resources are listed among the core indicators for forest biological diversity. This study is a report on the evaluation of the standing genetic diversity within and across 12 pure beech stands (Fagus sylvatica L.) established within the CLIMO (CLImate Smart Forestry in Mountain Regions) project, using nuclear microsatellite markers. The sampling sites were set along the species' distribution range, including the Balkan region and extending towards the Iberian Peninsula. Cores or leaves from 20 to 23 old, mature trees per plot were sampled for DNA analysis. Genetic diversity indices were high across the range ([H.sub.E] = 0.74-0.81) with the highest in the Bosnian Mountains. Genetic divergence increased significantly with the geographical distance (Mantel test: r = 0.81, p < 0.001). Most of the stands exhibited an excess of heterozygotes, with the highest value at the Hungarian site ([H.sub.O]/[H.sub.E] = 1.177), where beech persists close to the eastern xeric limit of the species' distribution. STRUCTURE revealed within-region differentiation in the Balkan Peninsula, where the Bulgarian stand was the most outstanding. The genetic parameters of each stand could be assessed as a resource for CSF indicators interpreted especially at the local level. Key words: Fagus sylvatica, heterozygosity, F statistics, geographical groups, environmental variables. Le developpement d'indicateurs de foresterie intelligente face au climat (FIFC) dans les regions forestieres montagneuses exige la collecte et revaluation de donnees locales et de leurs attributs. Les ressources genetiques sont considerees comme des indicateurs de base pour la diversite biologique de la foret. Cette etude est un rapport sur revaluation de la diversite genetique actuelle dans et parmi 12 peuplements purs de hetre commun (Fagus sylvatica L.) etablis dans le cadre du projet CLIMO (CLIMO (<>) a l'aide de marqueurs microsatellites nucleaires. Les sites d'echantillonnage ont ete etablis le long de l'aire de repartition de l'espece, incluant la region des Balkans et se prolongeant vers la peninsule iberique. Des carottes ou des feuilles prelevees sur 20 a 23 vieux arbres matures par place echantillon ont ete echantillonnees pour l'analyse de l'ADN. Les indices de diversite genetique etaient eleves ([H.sub.E] = 0,74-0,81) a travers l'aire de repartition; les plus eleves ont ete observes dans les montagnes de Bosnie. La divergence genetique augmentait significativement avec la distance geographique (test de Mantel : r = 0,81, p < 0,001). La plupart des peuplements avaient un exces d'heterozygotes : le site hongrois, ou le hetre persiste pres de la limite xerique orientale de l'aire de repartition de 1'espece, avait la valeur la plus elevee ([H.sub.O]/[H.sub.E] = 1,177). STRUCTURE a revele une differenciation au sein de la region dans la peninsule des Balkans, ou un peuplement bulgare etait le plus remarquable. Les parametres genetiques de chaque peuplement pouvaient etre evalues en tant ressource pour les indicateurs de FIFC interpretes particulierement a l'echelle locale. [Traduit par la Redaction] Mots-cles: Fagus sylvatica, heterozygotie, statistique F, groupes geographiques, variables environnementales., 1. Introduction Forests play an important role in the mitigation of the effects of climate change. Therefore, climate smart forestry (CSF) may significantly invigorate the positive effects of forests and [...]

Published
2021
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7. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer

Author

Hastings, K., Yu, H.A., Wei, W., Sanchez-Vega, F., DeVeaux, M., Choi, J., Rizvi, H., Lisberg, A., Truini, A., Lydon, C.A., Liu, Z., Henick, B.S., Wurtz, A., Cai, G., Plodkowski, A.J., Long, N.M., Halpenny, D.F., Killam, J., Oliva, I., Schultz, N., Riely, G.J., Arcila, M.E., Ladanyi, M., Zelterman, D., Herbst, R.S., Goldberg, S.B., Awad, M.M., Garon, E.B., Gettinger, S., Hellmann, M.D., and Politi, K.

Published
2019
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9. Ultra-deep next-generation sequencing of plasma cell-free DNA in patients with advanced lung cancers: results from the Actionable Genome Consortium

Author

Li, B.T., Janku, F., Jung, B., Hou, C., Madwani, K., Alden, R., Razavi, P., Reis-Filho, J.S., Shen, R., Isbell, J.M., Blocker, A.W., Eattock, N., Gnerre, S., Satya, R.V., Xu, H., Zhao, C., Hall, M.P., Hu, Y., Sehnert, A.J., Brown, D., Ladanyi, M., Rudin, C.M., Hunkapiller, N., Feeney, N., Mills, G.B., Paweletz, C.P., Janne, P.A., Solit, D.B., Riely, G.J., Aravanis, A., and Oxnard, G.R.

Published
2019
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10. P1.21-12 Microsatellite Instability Defines a Subset of Lung Cancers with Smoking Exposure, High Tumor Mutational Burden and MLH1 Inactivation

Author

Yang, S.-R., primary, Gedvilaite, E., additional, Ptashkin, R., additional, Chang, J., additional, Ziegler, J., additional, Mata, D., additional, Villafania, L.B., additional, Nafa, K., additional, Hechtman, J.F., additional, Benhamida, J., additional, Benayed, R., additional, Arcila, M.E., additional, Mandelker, D., additional, Rudin, C.M., additional, Paik, P.K., additional, Drilon, A., additional, Hellmann, M.D., additional, and Ladanyi, M., additional

Published
2023
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12. DOK2 inhibits EGFR-mutated lung adenocarcinoma

Author

Taylor, Barry, Berger, AH, Chen, M, Morotti, A, Janas, JA, Niki, M, Bronson, RT, Taylor, BS, Ladanyi, M, Van, L, and Politi, K

Abstract

Somatic mutations in the EGFR proto-oncogene occur in ∼15% of human lung adenocarcinomas and the importance of EGFR mutations for the initiation and maintenance of lung cancer is well established from mouse models and cancer therapy trials in human lung ca

Published
2013

13. An integrated genomic analysis of lung cancer reveals loss of DUSP4 in EGFR-mutant tumors

Author

Chitale, D, Gong, Y, Taylor, BS, Broderick, S, Brennan, C, Somwar, R, Golas, B, Wang, L, Motoi, N, Szoke, J, Reinersman, JM, Major, J, Sander, C, Seshan, VE, Zakowski, MF, Rusch, V, Pao, W, Gerald, W, and Ladanyi, M

Subjects
Biotechnology, Lung Cancer, Rare Diseases, Genetics, Human Genome, Lung, Cancer, 2.1 Biological and endogenous factors, Aetiology, Adenocarcinoma, Cell Line, Tumor, Cell Proliferation, Chromosome Aberrations, Cluster Analysis, Cyclin-Dependent Kinase Inhibitor p16, Dual-Specificity Phosphatases, ErbB Receptors, Female, Gene Dosage, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genes, ras, Genome-Wide Association Study, Humans, In Situ Hybridization, Fluorescence, Kaplan-Meier Estimate, Lung Neoplasms, Male, Mitogen-Activated Protein Kinase Phosphatases, Mutation, Nucleic Acid Hybridization, RNA Interference, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

To address the biological heterogeneity of lung cancer, we studied 199 lung adenocarcinomas by integrating genome-wide data on copy number alterations and gene expression with full annotation for major known somatic mutations in this cancer. This showed non-random patterns of copy number alterations significantly linked to EGFR and KRAS mutation status and to distinct clinical outcomes, and led to the discovery of a striking association of EGFR mutations with underexpression of DUSP4, a gene within a broad region of frequent single-copy loss on 8p. DUSP4 is involved in negative feedback control of EGFR signaling, and we provide functional validation for its role as a growth suppressor in EGFR-mutant lung adenocarcinoma. DUSP4 loss also associates with p16/CDKN2A deletion and defines a distinct clinical subset of lung cancer patients. Another novel observation is that of a reciprocal relationship between EGFR and LKB1 mutations. These results highlight the power of integrated genomics to identify candidate driver genes within recurrent broad regions of copy number alteration and to delineate distinct oncogenetic pathways in genetically complex common epithelial cancers.

Published
2009

15. What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC)

Author

Drilon, A., Li, G., Dogan, S., Gounder, M., Shen, R., Arcila, M., Wang, L., Hyman, D.M., Hechtman, J., Wei, G., Cam, N.R., Christiansen, J., Luo, D., Maneval, E.C., Bauer, T., Patel, M., Liu, S.V., Ou, S.H.I., Farago, A., Shaw, A., Shoemaker, R.F., Lim, J., Hornby, Z., Multani, P., Ladanyi, M., Berger, M., Katabi, N., Ghossein, R., and Ho, A.L.

Published
2016
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17. APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas

Author

Selenica, P., primary, Marra, A., additional, Choudhury, N.J., additional, Gazzo, A., additional, Falcon, C.J., additional, Patel, J., additional, Pei, X., additional, Zhu, Y., additional, Ng, C.K.Y., additional, Curry, M., additional, Heller, G., additional, Zhang, Y.-K., additional, Berger, M.F., additional, Ladanyi, M., additional, Rudin, C.M., additional, Chandarlapaty, S., additional, Lovly, C.M., additional, Reis-Filho, J.S., additional, and Yu, H.A., additional

Published
2022
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20. MA13.05 TA0953/HM06, a Novel RET-specific Inhibitor Effective in Extracranial and CNS Disease Models of NSCLC with RETfusions

Author

Odintsov, I., primary, Lui, A.J.W., additional, Delasos, L., additional, Khodos, I., additional, Chang, Q., additional, Mattar, M.S., additional, Vojnic, M., additional, Lu, Y.C., additional, Kunte, S., additional, Bonifacio, A., additional, Giuliano, C., additional, de Stanchina, E., additional, Lovati, E., additional, Ladanyi, M., additional, and Somwar, R., additional

Published
2022
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27. Comprehensive assessment of germline pathogenic variant detection in tumor-only sequencing

Author

Terraf, P., primary, Pareja, F., additional, Brown, D.N., additional, Ceyhan-Birsoy, O., additional, Misyura, M., additional, Rana, S., additional, O’Reilly, E., additional, Carlo, M.I., additional, Aghajanian, C., additional, Liu, Y., additional, Derakhshan, F., additional, Jayakumaran, G., additional, Weigelt, B., additional, Walsh, M., additional, Stadler, Z., additional, Offit, K., additional, Ladanyi, M., additional, Robson, M., additional, Zehir, A., additional, Reis-Filho, J.S., additional, and Mandelker, D., additional

Published
2022
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28. Frost hardiness of flower buds of 16 apricot cultivars during dormancy

Author

Bakos József L., Ladányi Márta, and Szalay László

Subjects
artificial freezing tests, dehardening, hardening, lt50, prunus armeniaca, Plant culture, SB1-1110
Abstract

The effectiveness of apricot cultivation is greatly threatened by frost damage to flower buds during the dormancy period. One of the most important aspects of the evaluation of cultivars is therefore the determination of their frost tolerance. In this paper, the frost hardiness of flower buds of 16 apricot cultivars was investigated in three dormancy periods, applying a standardised artificial freezing test protocol and determining LT50 values. The results showed that both the genotypes and the yearly climatic conditions had a significant effect on frost tolerance. A genotype generally determines the potential maximum of its frost tolerance (‘Sweet Red’ and ‘Primaya’ were very sensitive to frost every year, while ‘Harlayne’ and ‘Rózskajszi C.1406’ could be considered as frost hardy). Flower buds can reach different levels of frost resistance each year depending on the temperature conditions during the hardening and dehardening periods. From the point of view of yield security, it is essential when planning an orchard, to take into account and harmonise the frost hardiness of the cultivars selected and the growing site conditions. Therefore, it is very important to have adequate information about the frost hardiness of different apricot cultivars, which should be included in cultivar descriptions. This paper is intended to contribute to this goal.

Published
2024
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29. Erratum to ‘Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group’: [Annals of Oncology 30 (2019) 1221–1231]

Author

Mandelker, D., Donoghue, M., Talukdar, S., Bandlamudi, C., Srinivasan, P., Vivek, M., Jezdic, S., Hanson, H., Snape, K., Kulkarni, A., Hawkes, L., Douillard, J.-Y., Wallace, S.E., Rial-Sebbag, E., Meric-Bersntam, F., George, A., Chubb, D., Loveday, C., Ladanyi, M., Berger, M.F., Taylor, B.S., and Turnbull, C.

Published
2021
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30. Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature

Author

Koelsche, C., Benhamida, J.K., Kommoss, F.K.F., Stichel, D., Jones, D.T.W., Pfister, S.M., Heilig, C.E., Fröhling, S., Stenzinger, A., Buslei, R., Mentzel, T., Baumhoer, D., Ladanyi, M., Antonescu, C.R., Flucke, U.E., Gorp, J.V., Bode-Lesniewska, B., Deimling, A.V., Mechtersheimer, G., Koelsche, C., Benhamida, J.K., Kommoss, F.K.F., Stichel, D., Jones, D.T.W., Pfister, S.M., Heilig, C.E., Fröhling, S., Stenzinger, A., Buslei, R., Mentzel, T., Baumhoer, D., Ladanyi, M., Antonescu, C.R., Flucke, U.E., Gorp, J.V., Bode-Lesniewska, B., Deimling, A.V., and Mechtersheimer, G.

Abstract

Item does not contain fulltext, Undifferentiated mesenchymal tumors arising from the inner lining (intima) of large arteries are classified as intimal sarcomas (ISA) with MDM2 amplification as their molecular hallmark. Interestingly, undifferentiated pleomorphic sarcomas (UPS) of the heart have recently been suggested to represent the cardiac analog of ISA due to morphological overlap and high prevalence of MDM2 amplifications in both neoplasms. However, little is known about ISAs and cardiac UPS without MDM2 amplifications and molecular data supporting their common classification is sparse. Here, we report a series of 35 cases comprising 25 ISAs of the pulmonary artery, one ISA of the renal artery and 9 UPS of the left atrium. Tumors were analyzed utilizing the Illumina Infinium MethylationEPIC BeadChip array, enabling copy number profile generation and unsupervised DNA methylation analysis. DNA methylation patterns were investigated using t-distributed stochastic neighbor embedding (t-SNE) analysis. Histologically, all ISAs and UPS of the left atrium resembled extra-cardiac UPS. All cases exhibited highly complex karyotypes with overlapping patterns between ISA and UPS. 29/35 cases showed mutually exclusive amplifications in the cell-cycle associated oncogenes MDM2 (25/35), MDM4 (2/35), and CDK6 (2/35). We further observed recurrent co-amplifications in PDGFRA (21/35), CDK4 (15/35), TERT (11/35), HDAC9 (9/35), and CCND1 (4/35). Sporadic co-amplifications occurred in MYC, MYCN, and MET (each 1/35). The tumor suppressor CDKN2A/B was frequently deleted (10/35). Interestingly, DNA methylation profiling (t-SNE) revealed an overlap of ISA and cardiac UPS. This "ISA" methylation signature was distinct from potential histologic and molecular mimics. In conclusion, our data reveal MDM4 and CDK6 amplifications in ISAs and UPS of the left atrium, lacking MDM2 amplification. We further report novel co-amplifications of various oncogenes, which may have therapeutic implications. Finally, the genetic and epig

Published
2021

31. Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

Author

Brohl, AS, Sindiri, S, Wei, JS, Milewski, D, Chou, H-C, Song, YK, Wen, X, Kumar, J, Reardon, HV, Mudunuri, US, Collins, JR, Nagaraj, S, Gangalapudi, V, Tyagi, M, Zhu, YJ, Masih, KE, Yohe, ME, Shern, JF, Qi, Y, Guha, U, Catchpoole, D, Orentas, RJ, Kuznetsov, IB, Llosa, NJ, Ligon, JA, Turpin, BK, Leino, DG, Iwata, S, Andrulis, IL, Wunder, JS, Toledo, SRC, Meltzer, PS, Lau, C, Teicher, BA, Magnan, H, Ladanyi, M, Khan, J, Brohl, AS, Sindiri, S, Wei, JS, Milewski, D, Chou, H-C, Song, YK, Wen, X, Kumar, J, Reardon, HV, Mudunuri, US, Collins, JR, Nagaraj, S, Gangalapudi, V, Tyagi, M, Zhu, YJ, Masih, KE, Yohe, ME, Shern, JF, Qi, Y, Guha, U, Catchpoole, D, Orentas, RJ, Kuznetsov, IB, Llosa, NJ, Ligon, JA, Turpin, BK, Leino, DG, Iwata, S, Andrulis, IL, Wunder, JS, Toledo, SRC, Meltzer, PS, Lau, C, Teicher, BA, Magnan, H, Ladanyi, M, and Khan, J

Abstract

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.

Published
2021

32. Sarcoma classification by DNA methylation profiling

Author

Koelsche, C, Schrimpf, D, Stichel, D, Sill, M, Sahm, F, Reuss, DE, Blattner, M, Worst, B, Heilig, CE, Beck, K, Horak, P, Kreutzfeldt, S, Paff, E, Stark, S, Johann, P, Selt, F, Ecker, J, Sturm, D, Pajtler, K W, Reinhardt, A, Wefers, AK, Sievers, P, Ebrahimi, A, Suwala, A, Fernandez-Klett, F, Casalini, B, Korshunov, A, Hovestadt, V, Kommoss, FKF, Kriegsmann, M, Schick, M, Bewerunge-Hudler, M, Milde, T, Witt, O, Kulozik, AE, Kool, M, Romero-Perez, L, Grunewald, TGP, Kirchner, T, Wick, W, Platten, M, Unterberg, A, Uhl, M, Abdollahi, A, Debus, J, Lehner, B, Thomas, C, Hasselblatt, M, Paulus, W, Hartmann, C, Staszewski, O, Prinz, M, Hench, J, Frank, S, Versleijen-Jonkers, YMH, Weidema, ME, Mentzel, T, Griewank, K, Alava, E, Martin, JD, Gastearena, MAI, Chang, KTE, Low, SYY, Cuevas-Bourdier, A, Mittelbronn, M, Mynarek, M, Rutkowski, S, Schuller, U, Mautner, VF, Schittenhelm, J, Serrano, J, Snuderl, M, Buttner, R, Klingebiel, T, Buslei, R, Gessler, M, Wesseling, P, Dinjens, Winand, Brandner, S, Jaunmuktane, Z, Lyskjaer, I, Schirmacher, P, Stenzinger, A, Brors, B, Glimm, H, Heining, C, Tirado, OM, Sainz-Jaspeado, M, Mora, J, Alonso, J, del Muro, XG, Moran, S, Esteller, M, Benhamida, JK, Ladanyi, M, Wardelmann, E, Antonescu, C, Flanagan, A, Dirksen, U, Hohenberger, P, Baumhoer, D, Hartmann, W, Vokuhl, C, Flucke, U, Petersen, I, Mechtersheimer, G, Capper, D, Jones, DT, Frohling, S, Pfister, SM, von Deimling, A, Koelsche, C, Schrimpf, D, Stichel, D, Sill, M, Sahm, F, Reuss, DE, Blattner, M, Worst, B, Heilig, CE, Beck, K, Horak, P, Kreutzfeldt, S, Paff, E, Stark, S, Johann, P, Selt, F, Ecker, J, Sturm, D, Pajtler, K W, Reinhardt, A, Wefers, AK, Sievers, P, Ebrahimi, A, Suwala, A, Fernandez-Klett, F, Casalini, B, Korshunov, A, Hovestadt, V, Kommoss, FKF, Kriegsmann, M, Schick, M, Bewerunge-Hudler, M, Milde, T, Witt, O, Kulozik, AE, Kool, M, Romero-Perez, L, Grunewald, TGP, Kirchner, T, Wick, W, Platten, M, Unterberg, A, Uhl, M, Abdollahi, A, Debus, J, Lehner, B, Thomas, C, Hasselblatt, M, Paulus, W, Hartmann, C, Staszewski, O, Prinz, M, Hench, J, Frank, S, Versleijen-Jonkers, YMH, Weidema, ME, Mentzel, T, Griewank, K, Alava, E, Martin, JD, Gastearena, MAI, Chang, KTE, Low, SYY, Cuevas-Bourdier, A, Mittelbronn, M, Mynarek, M, Rutkowski, S, Schuller, U, Mautner, VF, Schittenhelm, J, Serrano, J, Snuderl, M, Buttner, R, Klingebiel, T, Buslei, R, Gessler, M, Wesseling, P, Dinjens, Winand, Brandner, S, Jaunmuktane, Z, Lyskjaer, I, Schirmacher, P, Stenzinger, A, Brors, B, Glimm, H, Heining, C, Tirado, OM, Sainz-Jaspeado, M, Mora, J, Alonso, J, del Muro, XG, Moran, S, Esteller, M, Benhamida, JK, Ladanyi, M, Wardelmann, E, Antonescu, C, Flanagan, A, Dirksen, U, Hohenberger, P, Baumhoer, D, Hartmann, W, Vokuhl, C, Flucke, U, Petersen, I, Mechtersheimer, G, Capper, D, Jones, DT, Frohling, S, Pfister, SM, and von Deimling, A

Abstract

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.

Published
2021

35. Oncogenic signaling pathways in the Cancer Genome Atlas

Author

Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., Chakravarty, D., Daian, F., Gao, Q., Bailey, M. H., Liang, W. -W., Foltz, S. M., Shmulevich, I., Ding, L., Heins, Z., Ochoa, A., Gross, B., Gao, J., Zhang, H., Kundra, R., Kandoth, C., Bahceci, I., Dervishi, L., Doğrusöz, Uğur, Zhou, W., Shen, H., Laird, P. W., Way, G. P., Greene, C. S., Liang, H., Xiao, Y., Wang, C., Iavarone, A., Berger, A. H., Bivona, T. G., Lazar, A. J., Hammer, G. D., Giordano, T., Kwong, L. N., McArthur, G., Huang, C., Tward, A. D., Frederick, M. J., McCormick, F., Meyerson, M., Caesar-Johnson, S. J., Demchok, J. A., Felau, I., Kasapi, M., Ferguson, M. L., Hutter, C. M., Sofia, H. J., Tarnuzzer, R., Wang, Z., Yang, L., Zenklusen, J. C., Zhang, J. J., Chudamani, S., Liu, J., Lolla, L., Naresh, R., Pihl, T., Sun, Q., Wan, Y., Wu, Y., Cho, J., DeFreitas, T., Frazer, S., Gehlenborg, N., Getz, G., Heiman, D. I., Kim, J., Lawrence, M. S., Lin, P., Meier, S., Noble, M. S., Saksena, G., Voet, D., Bernard, B., Chambwe, N., Dhankani, V., Knijnenburg, T., Kramer, R., Leinonen, K., Liu, Y., Miller, M., Reynolds, S., Thorsson, V., Zhang, W., Akbani, R., Broom, B. M., Hegde, A. M., Ju, Z., Kanchi, R. S., Korkut, A., Li, J., Ling, S., Liu W., Lu, Y., Mills, G. B., Ng, K. -S., Rao, A., Ryan, M., Wang, J., Weinstein, J. N., Zhang, J., Abeshouse, A., de, Bruijn, I., Gross, B. E., Heins, Z. J., La, K., Ladanyi, M., Nissan, M. G., Phillips, S. M., Reznik, E., Sander, C., Schultz, N., Sheridan, R., Sumer, S. O., Sun, Y., Taylor, B. S., Anur, P., Peto, M., Spellman, P., Benz, C., Stuart, J. M., Wong, C. K., Yau, C., Hayes, D. N., Parker, J. S., Wilkerson, M. D., Ally, A., Balasundaram, M., Bowlby, R., Brooks, D., Carlsen, R., Chuah, E., Dhalla, N., Holt, R., Jones, S. J. M., Kasaian, K., Lee, D., Ma, Y., Marra, M. A., Mayo, M., Moore, R. A., Mungall, A. J., Mungall, K., Robertson, A. 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Goparaju C., Melamed J., Pass H., Botnariuc N., Caraman I., Cernat M., Chemencedji I., Clipca A., Doruc S., Gorincioi G., Mura S., Pirtac M., Stancul I., Tcaciuc D., Albert M., Alexopoulou I., Arnaout A., Bartlett J., Engel J., Gilbert S., Parfitt J., Sekhon H., Thomas G., Rassl D.M., Rintoul R.C., Bifulco C., Tamakawa R., Urba W., Hayward N., Timmers H., Antenucci A., Facciolo F., Grazi G., Marino M., Merola R., de Krijger R., Gimenez-Roqueplo A.-P., Piche A., Chevalier S., McKercher G., Birsoy K., Barnett G., Brewer C., Farver C., Naska T., Pennell N.A., Raymond D., Schilero C., Smolenski K., Williams F., Morrison C., Borgia J.A., Liptay M.J., Pool M., Seder C.W., Junker K., Omberg L., Dinkin M., Manikhas G., Alvaro D., Bragazzi M.C., Cardinale V., Carpino G., Gaudio E., Chesla D., Cottingham S., Dubina M., Moiseenko F., Dhanasekaran R., Becker K.-F., Janssen K.-P., Slotta-Huspenina J., Abdel-Rahman M.H., Aziz D., Bell S., Cebulla C.M., Davis A., Duell R., Elder J.B., Hilty J., Kumar B., Lang J., Lehman N.L., Mandt R., Nguyen P., Pilarski R., Rai K., Schoenfield L., Senecal K., Wakely P., Hansen P., Lechan R., Powers J., Tischler A., Grizzle W.E., Sexton K.C., Kastl A., Henderson J., Porten S., Waldmann J., Fassnacht M., Asa S.L., Schadendorf D., Couce M., Graefen M., Huland H., Sauter G., Schlomm T., Simon R., Tennstedt P., Olabode O., Nelson M., Bathe O., Carroll P.R., Chan J.M., Disaia P., Glenn P., Kelley R.K., Landen C.N., Phillips J., Prados M., Simko J., Smith-McCune K., VandenBerg S., Roggin K., Fehrenbach A., Kendler A., Sifri S., Steele R., Jimeno A., Carey F., Forgie I., Mannelli M., Carney M., Hernandez B., Campos B., Herold-Mende C., Jungk C., Unterberg A., von Deimling A., Bossler A., Galbraith J., Jacobus L., Knudson M., Knutson T., Ma D., Milhem M., Sigmund R., Godwin A.K., Madan R., Rosenthal H.G., Adebamowo C., Adebamowo S.N., Boussioutas A., Beer D., Mes-Masson A.-M., Saad F., Bocklage T., Landrum L., Mannel R., Moore K., Moxley K., Postier R., Walker J., Zuna R., Feldman M., Valdivieso F., Dhir R., Luketich J., Pinero E.M.M., Quintero-Aguilo M., Carlotti C.G., Dos Santos J.S., Kemp R., Sankarankuty A., Tirapelli D., Catto J., Agnew K., Swisher E., Creaney J., Robinson B., Shelley C.S., Godwin E.M., Kendall S., Shipman C., Bradford C., Carey T., Haddad A., Moyer J., Peterson L., Prince M., Rozek L., Wolf G., Bowman R., Fong K.M., Yang I., Korst R., Rathmell W.K., Fantacone-Campbell J.L., Hooke J.A., Kovatich A.J., Shriver C.D., DiPersio J., Drake B., Govindan R., Heath S., Ley T., Van Tine B., Westervelt P., Rubin M.A., Lee J.I., Aredes N.D., Mariamidze A., Van Allen E.M., and Ciriello G.

Subjects
0301 basic medicine, cancer genome atlas, cancer genomics, combination therapy, pan-cancer, PanCanAtlas, precision oncology, signaling pathways, TCGA, therapeutics, whole exome sequencing, Signaling pathways, Somatic cell, Wnt Protein, Cancer Genome Atlas Research Network, Biochemistry, Medical and Health Sciences, Phosphatidylinositol 3-Kinases, Transforming Growth Factor beta, Neoplasms, Databases, Genetic, LS2_1, Cancer genomics, LS4_6, 610 Medicine & health, 11 Medical and Health Sciences, Cancer, biology, Wnt signaling pathway, cancer genomic, Precision oncology, Biological Sciences, Cell cycle, DNA methylation, Signal transduction, CICLO CELULAR, Life Sciences & Biomedicine, Genes, Neoplasm, Humans, Neoplasms/genetics, Neoplasms/pathology, Phosphatidylinositol 3-Kinases/genetics, Phosphatidylinositol 3-Kinases/metabolism, Signal Transduction/genetics, Transforming Growth Factor beta/genetics, Transforming Growth Factor beta/metabolism, Tumor Suppressor Protein p53/genetics, Tumor Suppressor Protein p53/metabolism, Wnt Proteins/genetics, Wnt Proteins/metabolism, Biotechnology, Human, Signal Transduction, signaling pathway, EXPRESSION, Biochemistry & Molecular Biology, GENES, Pan-cancer, Therapeutics, General Biochemistry, Genetics and Molecular Biology, NO, Databases, 03 medical and health sciences, Genetic, Genetics, Combination therapy, Protein kinase B, Gene, SIGNATURES, Cancer genome atlas, Science & Technology, LANDSCAPE, MUTATIONS, Biochemistry, Genetics and Molecular Biology(all), Human Genome, Whole exome sequencing, Cell Biology, Transforming growth factor beta, cancer genome atla, 06 Biological Sciences, COMPREHENSIVE MOLECULAR CHARACTERIZATION, Wnt Proteins, therapeutic, Good Health and Well Being, 030104 developmental biology, Genes, PanCanAtla, biology.protein, Cancer research, Neoplasm, Phosphatidylinositol 3-Kinase, Tumor Suppressor Protein p53, Digestive Diseases, Genetics and Molecular Biology(all), Developmental Biology
Abstract

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies. Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals. Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck, Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD, NIH, and Astex Pharmaceuticals. Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc. and a shareholder and advisory board member of Tempus, Inc. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma. Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae.

Published
2018

36. Flower bud development of almond cultivars based on three different methods

Author

Keleta Belay Teweldemedhin, Szalay László, Ladányi Márta, and Békefi Zsuzsanna

Subjects
endodormancy, forcing, microsporogenesis, prunus amygdalus, pistil length, Plant culture, SB1-1110
Abstract

Flower bud development of fruit trees plays a key role in their climatic adaptation. It is closely related to dormancy release that determines winter frost susceptibility. Detailed characterisation of flower bud development of 25 almond (Prunus amygdalus L. Batsch) accessions representing wide range of flowering times have been performed by microsporogenesis and pistil growth studies for 3 years. Six developmental stages were distinguished in the process of microsporogenesis, while pistil development could be classified into four phases. The examined cultivars showed significant differences in the length and occurrence of microspore developmental stages and year effect was observed. On the basis of the length of microsporogenesis stages, cultivars were clustered into five main groups. The shortest periods of archesporium and microsporogenesis as a sum were detected in accessions ‘Eriane’, ‘5/15’ and ‘1/7’ (with an average of 20 and 138 days in all three), while the longest ones were determined in ‘Constanti’ and ‘Vairo’ (65 and 160 days in both), respectively. The increment of pistil length was suspended during the dormancy period and after dormancy release, it was accelerated first at a slow rate followed by a few days of rapid growth prior to blooming. In order to determine the date of endodormancy release, these three methods – microsporogenesis, pistil length studies, and forcing of shoots – were analysed. All methods revealed significant differences among accessions. The dormancy release estimated by microsporogenesis studies showed the highest variability among the three methods used.

Published
2023
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39. The anti-HER3 monoclonal antibody seribantumab effectively inhibits growth of patient-derived and isogenic cell line and xenograft models with NRG1 rearrangements

Author

Odintsov, I., primary, Gladstone, E., additional, Sisso, W.J., additional, Delasos, L., additional, Lui, A.J.W., additional, Sisso, E.M., additional, Vojnic, M., additional, Khodos, I., additional, Mattar, M.S., additional, de Stanchina, E., additional, Plessinger, D., additional, Leland, S.M., additional, Ladanyi, M., additional, and Somwar, R., additional

Published
2020
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40. A07 The Genomic Landscape of SMARCA4 Alterations and Association with Patient Outcomes in Lung Cancer

Author

Schoenfeld, A.J., primary, Montecalvo, J., additional, Namakydoust, A., additional, Lavery, J., additional, Bandlamudi, C., additional, Rizvi, H., additional, Paul, S., additional, Arcila, M., additional, Chang, J., additional, Sauter, J., additional, Beras, A., additional, Ladanyi, M., additional, Taylor, B., additional, Donoghue, M., additional, Heller, G., additional, Hellmann, M., additional, Rekhtman, N., additional, and Riely, G., additional

Published
2020
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42. Cross-Reactivity of EGFR-L858R Mutation-Specific Antibody With HER2 Overexpression in Lung Adenocarcinoma: Report of 2 Index Cases

Author

Leduc, C., Rekhtman, N., Travis, W., Moreira, A., Arcila, M., and Ladanyi, M.

Subjects
Adenocarcinoma -- Genetic aspects, Antigen-antibody reactions, Immunohistochemistry, Gene mutation, Antibodies, Health
Abstract

The L858R point mutation of exon 21 of EGFR accounts for up to 45% of EGFR-mutated lung adenocarcinomas (LACs). EGFR (L858R) mutation-specific antibody has been shown to have high positive predictive value (99%-100%). HER2 amplification is known to be a mechanism of acquired resistance to erlotinib. False-positive staining of EGFR (L858R) by immunohistochemistry (IHC) has been reported in ER+, HER-amplified breast carcinomas, but not in LAC. We identified 2 LACs positive for both EGFR L858R (2-3+) and HER2 (3+) by IHC. Targeted gene sequencing was performed to confirm the underlying molecular abnormality and to uncover potential cross-reactivity. Patient 1 was a 57-year-old man with stage IV LAC. Staging node biopsy showed metastatic adenocarcinoma diffusely positive for EGFR L858R by IHC. Sequencing revealed no EGFR (L858R) mutation, but amplification of HER2. HER2 was also 3+ positive by IHC. Patient 2 was a 52-year-old man with progression while taking erlotinib for LAC with EGFR exon 19 deletion. Rebiopsy of the primary tumor showed focal strong positivity for EGFR (L858R) by IHC, despite lack of EGFR (L858R) mutation by sequencing. HER2 was 3+ by IHC in the same cells that were EGFR L858R positive by IHC. We demonstrate 2 examples of false positivity for EGFR L858R by IHC. Structural homology between HER2 and EGFR might partially explain the cross-reactivity; however, further studies are needed to elucidate the frequency and mechanism of this event., C. Leduc; N. Rekhtman; W. Travis; A. Moreira; M. Arcila; M. Ladanyi. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New [...]

Published
2016

43. Erratum: The Immune Landscape of Cancer (Immunity (2018) 48(4) (812–830.e14), (S1074761318301213), (10.1016/j.immuni.2018.03.023))

Author

Thorsson, V., Gibbs, D. L., Brown, S. D., Wolf, D., Bortone, D. S., Ou Yang, T. -H., Porta-Pardo, E., Gao, G. F., Plaisier, C. L., Eddy, J. A., Ziv, E., Culhane, A. C., Paull, E. O., Sivakumar, I. K. A., Gentles, A. J., Malhotra, R., Farshidfar, F., Colaprico, A., Parker, J. S., Mose, L. E., N. S., Vo, Liu, J., Liu, Y., Rader, J., Dhankani, V., Reynolds, S. M., Bowlby, R., Califano, A., Cherniack, A. D., Anastassiou, D., Bedognetti, D., Mokrab, Y., Newman, A. M., Rao, A., Chen, K., Krasnitz, A., Hu, H., Malta, T. M., Noushmehr, H., Pedamallu, C. S., Bullman, S., Ojesina, A. I., Lamb, A., Zhou, W., Shen, H., Choueiri, T. K., Weinstein, J. N., Guinney, J., Saltz, J., Holt, R. A., Rabkin, C. S., Caesar-Johnson, S. J., Demchok, J. A., Felau, I., Kasapi, M., Ferguson, M. L., Hutter, C. M., Sofia, H. J., Tarnuzzer, R., Wang, Z., Yang, L., Zenklusen, J. C., Zhang, J. J., Chudamani, S., Lolla, L., Naresh, R., Pihl, T., Sun, Q., Wan, Y., Wu, Y., Cho, J., Defreitas, T., Frazer, S., Gehlenborg, N., Getz, G., Heiman, D. I., Kim, J., Lawrence, M. S., Lin, P., Meier, S., Noble, M. S., Saksena, G., Voet, D., Zhang, H., Bernard, B., Chambwe, N., Knijnenburg, T., Kramer, R., Leinonen, K., Miller, M., Reynolds, S., Shmulevich, I., Zhang, W., Akbani, R., Broom, B. M., Hegde, A. M., Ju, Z., Kanchi, R. S., Korkut, A., Li, J., Liang, H., Ling, S., Liu, W., Lu, Y., Mills, G. B., K. -S., Ng, Ryan, M., Wang, J., Zhang, J., Abeshouse, A., Armenia, J., Chakravarty, D., Chatila, W. K., de Bruijn, I., Gao, J., Gross, B. E., Heins, Z. J., Kundra, R., La, K., Ladanyi, M., Luna, A., Nissan, M. G., Ochoa, A., Phillips, S. M., Reznik, E., Sanchez-Vega, F., Sander, C., Schultz, N., Sheridan, R., Sumer, S. O., Sun, Y., Taylor, B. S., Anur, P., Peto, M., Spellman, P., Benz, C., Stuart, J. M., Wong, C. K., Yau, C., Hayes, D. N., Wilkerson, M. D., Ally, A., Balasundaram, M., Brooks, D., Carlsen, R., Chuah, E., Dhalla, N., Holt, R., Jones, S. J. M., Kasaian, K., Lee, D., Ma, Y., Marra, M. A., Mayo, M., Moore, R. A., Mungall, A. J., Mungall, K., Robertson, A. G., Sadeghi, S., Schein, J. E., Sipahimalani, P., Tam, A., Thiessen, N., Tse, K., Wong, T., Berger, A. C., Beroukhim, R., Cibulskis, C., Gabriel, S. B., Ha, G., Meyerson, M., Schumacher, S. E., Shih, J., Kucherlapati, M. H., Kucherlapati, R. S., Baylin, S., Cope, L., Danilova, L., Bootwalla, M. S., Lai, P. H., Maglinte, D. T., Van Den Berg, D. J., Weisenberger, D. J., Auman, J. T., Balu, S., Bodenheimer, T., Fan, C., Hoadley, K. A., Hoyle, A. P., Jefferys, S. R., Jones, C. D., Meng, S., Mieczkowski, P. A., Perou, A. H., Perou, C. M., Roach, J., Shi, Y., Simons, J. V., Skelly, T., Soloway, M. G., Tan, D., Veluvolu, U., Fan, H., Hinoue, T., Laird, P. W., Bellair, M., Chang, K., Covington, K., Creighton, C. J., Dinh, H., Doddapaneni, H., Donehower, L. A., Drummond, J., Gibbs, R. A., Glenn, R., Hale, W., Han, Y., Hu, J., Korchina, V., Lee, S., Lewis, L., Li, W., Liu, X., Morgan, M., Morton, D., Muzny, D., Santibanez, J., Sheth, M., Shinbrot, E., Wang, L., Wang, M., Wheeler, D. A., Xi, L., Zhao, F., Hess, J., Appelbaum, E. L., Bailey, M., Cordes, M. G., Ding, L., Fronick, C. C., Fulton, L. A., Fulton, R. S., Kandoth, C., Mardis, E. R., Mclellan, M. D., Miller, C. A., Schmidt, H. K., Wilson, R. K., Crain, D., Curley, E., Gardner, J., Lau, K., Mallery, D., Morris, S., Paulauskis, J., Penny, R., Shelton, C., Shelton, T., Sherman, M., Thompson, E., Yena, P., Bowen, J., Gastier-Foster, J. M., Gerken, M., Leraas, K. M., Lichtenberg, T. M., Ramirez, N. C., Wise, L., Zmuda, E., Corcoran, N., Costello, T., Hovens, C., Carvalho, A. L., de Carvalho, A. C., Fregnani, J. H., Longatto-Filho, A., Reis, R. M., Scapulatempo-Neto, C., Silveira, H. C. S., Vidal, D. O., Burnette, A., Eschbacher, J., Hermes, B., Noss, A., Singh, R., Anderson, M. L., Castro, P. D., Ittmann, M., Huntsman, D., Kohl, B., Le, X., Thorp, R., Andry, C., Duffy, E. R., Lyadov, V., Paklina, O., Setdikova, G., Shabunin, A., Tavobilov, M., Mcpherson, C., Warnick, R., Berkowitz, R., Cramer, D., Feltmate, C., Horowitz, N., Kibel, A., Muto, M., Raut, C. P., Malykh, A., Barnholtz-Sloan, J. S., Barrett, W., Devine, K., Fulop, J., Ostrom, Q. T., Shimmel, K., Wolinsky, Y., Sloan, A. E., De Rose, A., Giuliante, F., Goodman, M., Karlan, B. Y., Hagedorn, C. H., Eckman, J., Harr, J., Myers, J., Tucker, K., Zach, L. A., Deyarmin, B., Kvecher, L., Larson, C., Mural, R. J., Somiari, S., Vicha, A., Zelinka, T., Bennett, J., Iacocca, M., Rabeno, B., Swanson, P., Latour, M., Lacombe, L., Tetu, B., Bergeron, A., Mcgraw, M., Staugaitis, S. M., Chabot, J., Hibshoosh, H., Sepulveda, A., Su, T., Wang, T., Potapova, O., Voronina, O., Desjardins, L., Mariani, O., Roman-Roman, S., Sastre, X., Stern, M. -H., Cheng, F., Signoretti, S., Berchuck, A., Bigner, D., Lipp, E., Marks, J., Mccall, S., Mclendon, R., Secord, A., Sharp, A., Behera, M., Brat, D. J., Chen, A., Delman, K., Force, S., Khuri, F., Magliocca, K., Maithel, S., Olson, J. J., Owonikoko, T., Pickens, A., Ramalingam, S., Shin, D. M., Sica, G., Van Meir, E. G., Eijckenboom, W., Gillis, A., Korpershoek, E., Looijenga, L., Oosterhuis, W., Stoop, H., van Kessel, K. E., Zwarthoff, E. C., Calatozzolo, C., Cuppini, L., Cuzzubbo, S., Dimeco, F., Finocchiaro, G., Mattei, L., Perin, A., Pollo, B., Chen, C., Houck, J., Lohavanichbutr, P., Hartmann, A., Stoehr, C., Stoehr, R., Taubert, H., Wach, S., Wullich, B., Kycler, W., Murawa, D., Wiznerowicz, M., Chung, K., Edenfield, W. J., Martin, J., Baudin, E., Bubley, G., Bueno, R., De Rienzo, A., Richards, W. G., Kalkanis, S., Mikkelsen, T., Scarpace, L., Girard, N., Aymerich, M., Campo, E., Gine, E., Guillermo, A. L., Van Bang, N., Hanh, P. T., Phu, B. D., Tang, Y., Colman, H., Evason, K., Dottino, P. R., Martignetti, J. A., Gabra, H., Juhl, H., Akeredolu, T., Stepa, S., Hoon, D., Ahn, K., Kang, K. J., Beuschlein, F., Breggia, A., Birrer, M., Bell, D., Borad, M., Bryce, A. H., Castle, E., Chandan, V., Cheville, J., Copland, J. A., Farnell, M., Flotte, T., Giama, N., Ho, T., Kendrick, M., Kocher, J. -P., Kopp, K., Moser, C., Nagorney, D., O'Brien, D., O'Neill, B. P., Patel, T., Petersen, G., Que, F., Rivera, M., Roberts, L., Smallridge, R., Smyrk, T., Stanton, M., Thompson, R. H., Torbenson, M., Yang, J. D., Zhang, L., Brimo, F., Ajani, J. A., Gonzalez, A. M. A., Behrens, C., Bondaruk, J., Broaddus, R., Czerniak, B., Esmaeli, B., Fujimoto, J., Gershenwald, J., Guo, C., Lazar, A. J., Logothetis, C., Meric-Bernstam, F., Moran, C., Ramondetta, L., Rice, D., Sood, A., Tamboli, P., Thompson, T., Troncoso, P., Tsao, A., Wistuba, I., Carter, C., Haydu, L., Hersey, P., Jakrot, V., Kakavand, H., Kefford, R., Lee, K., Long, G., Mann, G., Quinn, M., Saw, R., Scolyer, R., Shannon, K., Spillane, A., Stretch, O., Synott, M., Thompson, J., Wilmott, J., Al-Ahmadie, H., Chan, T. A., Ghossein, R., Gopalan, A., Levine, D. A., Reuter, V., Singer, S., Singh, B., Tien, N. V., Broudy, T., Mirsaidi, C., Nair, P., Drwiega, P., Miller, J., Smith, J., Zaren, H., Park, J. -W., Hung, N. P., Kebebew, E., Linehan, W. M., Metwalli, A. R., Pacak, K., Pinto, P. A., Schiffman, M., Schmidt, L. S., Vocke, C. D., Wentzensen, N., Worrell, R., Yang, H., Moncrieff, M., Goparaju, C., Melamed, J., Pass, H., Botnariuc, N., Caraman, I., Cernat, M., Chemencedji, I., Clipca, A., Doruc, S., Gorincioi, G., Mura, S., Pirtac, M., Stancul, I., Tcaciuc, D., Albert, M., Alexopoulou, I., Arnaout, A., Bartlett, J., Engel, J., Gilbert, S., Parfitt, J., Sekhon, H., Thomas, G., Rassl, D. M., Rintoul, R. C., Bifulco, C., Tamakawa, R., Urba, W., Hayward, N., Timmers, H., Antenucci, A., Facciolo, F., Grazi, G., Marino, M., Merola, R., de Krijger, R., Gimenez-Roqueplo, A. -P., Piche, A., Chevalier, S., Mckercher, G., Birsoy, K., Barnett, G., Brewer, C., Farver, C., Naska, T., Pennell, N. A., Raymond, D., Schilero, C., Smolenski, K., Williams, F., Morrison, C., Borgia, J. A., Liptay, M. J., Pool, M., Seder, C. W., Junker, K., Omberg, L., Dinkin, M., Manikhas, G., Alvaro, D., Bragazzi, M. C., Cardinale, V., Carpino, G., Gaudio, E., Chesla, D., Cottingham, S., Dubina, M., Moiseenko, F., Dhanasekaran, R., Becker, K. -F., Janssen, K. -P., Slotta-Huspenina, J., Abdel-Rahman, M. H., Aziz, D., Bell, S., Cebulla, C. M., Davis, A., Duell, R., Elder, J. B., Hilty, J., Kumar, B., Lang, J., Lehman, N. L., Mandt, R., Nguyen, P., Pilarski, R., Rai, K., Schoenfield, L., Senecal, K., Wakely, P., Hansen, P., Lechan, R., Powers, J., Tischler, A., Grizzle, W. E., Sexton, K. C., Kastl, A., Henderson, J., Porten, S., Waldmann, J., Fassnacht, M., Asa, S. L., Schadendorf, D., Couce, M., Graefen, M., Huland, H., Sauter, G., Schlomm, T., Simon, R., Tennstedt, P., Olabode, O., Nelson, M., Bathe, O., Carroll, P. R., Chan, J. M., Disaia, P., Glenn, P., Kelley, R. K., Landen, C. N., Phillips, J., Prados, M., Simko, J., Smith-McCune, K., Vandenberg, S., Roggin, K., Fehrenbach, A., Kendler, A., Sifri, S., Steele, R., Jimeno, A., Carey, F., Forgie, I., Mannelli, M., Carney, M., Hernandez, B., Campos, B., Herold-Mende, C., Jungk, C., Unterberg, A., von Deimling, A., Bossler, A., Galbraith, J., Jacobus, L., Knudson, M., Knutson, T., Ma, D., Milhem, M., Sigmund, R., Godwin, A. K., Madan, R., Rosenthal, H. G., Adebamowo, C., Adebamowo, S. N., Boussioutas, A., Beer, D., Giordano, T., Mes-Masson, A. -M., Saad, F., Bocklage, T., Landrum, L., Mannel, R., Moore, K., Moxley, K., Postier, R., Walker, J., Zuna, R., Feldman, M., Valdivieso, F., Dhir, R., Luketich, J., Pinero, E. M. M., Quintero-Aguilo, M., Carlotti, C. G., Dos Santos, J. S., Kemp, R., Sankarankuty, A., Tirapelli, D., Catto, J., Agnew, K., Swisher, E., Creaney, J., Robinson, B., Shelley, C. S., Godwin, E. M., Kendall, S., Shipman, C., Bradford, C., Carey, T., Haddad, A., Moyer, J., Peterson, L., Prince, M., Rozek, L., Wolf, G., Bowman, R., Fong, K. M., Yang, I., Korst, R., Rathmell, W. K., Fantacone-Campbell, J. L., Hooke, J. A., Kovatich, A. J., Shriver, C. D., Dipersio, J., Drake, B., Govindan, R., Heath, S., Ley, T., Van Tine, B., Westervelt, P., Rubin, M. A., Lee, J. I., Aredes, N. D., Mariamidze, A., Serody, J. S., Demicco, E. G., Disis, M. L., and Vincent, B. G.

Subjects
immune, cancer, methods
Published
2019

50. Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study

Author

Shi, J, Hua, X, Zhu, B, Ravichandran, S, Wang, M, Nguyen, C, Brodie, SA, Palleschi, A, Alloisio, M, Pariscenti, G, Jones, K, Zhou, W, Bouk, AJ, Boland, J, Hicks, B, Risch, A, Bennett, H, Luke, BT, Song, L, Duan, J, Liu, P, Kohno, T, Chen, Q, Meerzaman, D, Marconett, C, Laird-Offringa, I, Mills, I, Caporaso, NE, Gail, MH, Pesatori, AC, Consonni, D, Bertazzi, PA, Chanock, SJ, Landi, MT, Ladanyi, M, and Ladanyi, M

Subjects
Male, 0301 basic medicine, Mutation rate, Lung Neoplasms, lcsh:Medicine, medicine.disease_cause, Biochemistry, Lung and Intrathoracic Tumors, Metastasis, 0302 clinical medicine, Risk Factors, Adenocarcinomas, Basic Cancer Research, Medicine and Health Sciences, Exome, Genetics, Mutation, DNA methylation, Adenocarcinoma of the Lung, Genomics, General Medicine, Middle Aged, Chromatin, 3. Good health, Nucleic acids, Italy, Oncology, 030220 oncology & carcinogenesis, Female, Epigenetics, KRAS, DNA modification, Chromatin modification, Research Article, Chromosome biology, Adult, Cell biology, Adenocarcinoma of Lung, Adenocarcinoma, Biology, Carcinomas, 03 medical and health sciences, Cancer Genomics, Germline mutation, SDG 3 - Good Health and Well-being, Genomic Medicine, medicine, Adenocarcinoma of the lung, Humans, Point Mutation, Aged, Retrospective Studies, lcsh:R, Biology and Life Sciences, Cancers and Neoplasms, DNA, medicine.disease, 030104 developmental biology, Somatic Mutation, Gene expression, Secondary Lung Tumors, Carcinogenesis
Abstract

Background Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression. Methods and Findings We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2) (mutated in 9 [8.9%] samples) and ZKSCAN1 (mutated in 6 [5.9%] samples), and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0078), suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p < 2.5×10−50). The total number of somatic mutations (p = 0.0039) and the fraction of transitions (p = 5.5×10−4) were associated with increased risk of distant metastasis. Our study’s limitations include a small number of LUAD patients for subgroup analyses and a single-sample design for investigation of subclonality. Conclusions These data provide a genomic characterization of LUAD pathogenesis and progression. The distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures, and may serve as a foundation for more effective treatments for this lethal disease. LUAD’s high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes., Maria Teresa Landi and colleagues report genomic tumor data for a cohort of patients with lung adenocarcinoma, focusing on implications for tumor initiation and distant metastasis., Author Summary Why Was This Study Done? Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and causes more than half a million deaths worldwide annually. Genomic studies of LUAD can shed light on tumor initiation and progression and identify potential targets for treatment. What Did the Researchers Do and Find? We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), DNA copy number and DNA methylation determination, and transcriptome sequencing in 101 LUAD samples. We replicated major findings using public genomic resources and combined all existing genomic data for an overall analysis of 825 LUAD samples. We identified two novel driver genes and characterized the driver events and types of mutations that have a stronger role in tumor initiation versus tumor progression. We found strong associations between DNA methylation and somatic mutation patterns. The total number of somatic mutations and the fraction of C→T transitions were associated with increased risk of distant metastasis. What Do These Findings Mean? We characterized LUAD genomic architecture and linked major genomic features with clinical outcomes. Tobacco smoking-related mutations appear to have a stronger role in tumor initiation, while mutations associated with endogenous processes are more prominent at a later stage of tumor development and are associated with tumor progression. Our findings highlight the complexity and heterogeneity of LUAD. In addition to new driver genes, we found some tumors with no exonic mutations in known lung cancer driver genes. This suggests that there are further drivers (genetic or epigenetic) to be identified, and larger numbers of samples need to be studied to fully capture LUAD genomic characteristics.

Published
2016

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