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Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensitivity to 265 drugs. We find that cell lines faithfully recapitulate oncogenic alterations identified in tumors, find that many of these associate with drug sensitivity/resistance, and highlight the importance of tissue lineage in mediating drug response. Logic-based modeling uncovers combinations of alterations that sensitize to drugs, while machine learning demonstrates the relative importance of different data types in predicting drug response. Our analysis and datasets are rich resources to link genotypes with cellular phenotypes and to identify therapeutic options for selected cancer sub-populations. ; This work was funded by the Wellcome Trust (086375 and 102696). F.I. was supported by the European Bioinformatics Institute and Wellcome Trust Sanger Institute post-doctoral (ESPOD) program. T.A.K. was supported by the National Cancer Institute (U24CA143835) and the Netherlands Organization for Scientific Research. D.T. was supported by the People Programme (Marie Curie Actions) of the 7th Framework Programme of the European Union (FP7/2007-2013; 600388) and the Agency of Competitiveness for Companies of the Government of Catalonia (ACCIO´ ). N.L.-B. was supported by La Fundacio ´ la Marato´ de TV3. M.E. was funded by the European Research Council (268626), the Ministerio de Ciencia e Innovacion (SAF2011-22803), the Institute of Health Carlos III (ISCIII) under the Integrated Project of Excellence (PIE13/00022), the Spanish Cancer Research Network (RD12/0036/0039), the Health and Science Departments of the Catalan Government Generalitat de Catalunya 2014-SGR 633, and the Cellex Foundation. U.M. was supported by a Cancer Research UK Clinician Scientist Fellowship. We thank Aiqing He for expression data and Ilya Shmulevich for assistance with the LOBICO framework. We thank P. Campbell, M. Ranzani, J. Brammeld, M. Petljak, F. Behan, C. Alsinet Armengol, H. Francies, V. Grinkevich, and A. ''Lilla'' Mupo for useful comments. P.R.-M., H.C., and H.d.S. are employees and shareholders of Bristol-Myers Squibb. Research in the M.J.G. lab is supported in part with funding from AstraZeneca.

Somatic epigenetic inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) is frequent in colorectal cancer (CRC); however, its involvement in CRC predisposition remains unexplored. We assessed the role and relevance of MGMT germline mutations and epimutations in familial and early-onset CRC. Mutation and promoter methylation screenings were performed in 473 familial and/or early-onset mismatch repair-proficient nonpolyposis CRC cases. No constitutional MGMT inactivation by promoter methylation was observed. Of six rare heterozygous germline variants identified, c.346C > T (p.H116Y) and c.476G > A (p.R159Q), detected in three and one families respectively, affected highly conserved residues and showed segregation with cancer in available family members. In vitro, neither p.H116Y nor p.R159Q caused statistically significant reduction of MGMT repair activity. No evidence of somatic second hits was found in the studied tumors. Case-control data showed over-representation of c.346C > T (p.H116Y) in familial CRC compared to controls, but no overall association of MGMT mutations with CRC predisposition. In conclusion, germline mutations and constitutional epimutations in MGMT are not major players in hereditary CRC. Nevertheless, the over-representation of c.346C > T (p.H116Y) in our familial CRC cohort warrants further research ; This work was funded by the Spanish Ministry of Science, Innovation and Universities, co-funded by FEDER funds -a way to build Europe- [SAF2016-80888-R (LV), SAF2014-55000-R (ME), SAF2015- 68016-R (GC/MP), Juan de la Cierva and Sara Borrell postdoctoral contracts (PM)]; Instituto de Salud Carlos III [DTS16/00153 (ME) and CIBERONC CB16/12/00234]; the Government of Catalonia [Pla Estratègic de Recerca i Innovació en Salut SLT002/16/0037, 2017SGR1282, 2017SGR1080, 2014SGR633 and 2009SGR1315]; and Fundación Olga Torres. We thank the CERCA/Generalitat de Catalunya Program for institutional support. This study has been enabled by COST Action CA17118

Oxidation of H3 at lysine 4 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) generates an H3 modification with an unknown physiological function. We find that LOXL2 and H3K4ox are higher in triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs) than those from other breast cancer subtypes. ChIP-seq revealed that H3K4ox is located primarily in heterochromatin, where it is involved in chromatin compaction. Knocking down LOXL2 reduces H3K4ox levels and causes chromatin decompaction, resulting in a sustained activation of the DNA damage response (DDR) and increased susceptibility to anticancer agents. This critical role that LOXL2 and oxidized H3 play in chromatin compaction and DDR suggests that functionally targeting LOXL2 could be a way to sensitize TNBC cells to conventional therapy. ; This work was supported by grants from Instituto de Salud Carlos III (ISCIII) FIS/FEDER (PI12/01250; CP08/00223; PI16/00253; and CB16/12/00449), MINECO (SAF2013-48849-C2-1-R) to SP, BFU2015-68354 to THS, Breast Cancer Research Foundation (BCRF-17-008) to JA, AGL2014-52395-C2-2-R to DA, Worldwide Cancer Research, Red Temática de Investigación Cooperativa en Cáncer (RD012/0036/005), Fundación Científica de la Asociación Española contra el Cáncer, and Fundació La Marató TV3.THS was supported by institutional funding (MINECO) through theCentres of Excellence Severo Ochoa award and the CERCA Pro-gramme of the Catalan Government, and SS-B, by a Fundació LaCaixa fellowship. We thank La Caixa Foundation and Cellex Foun-dation for provide research facilities and equipment. GV has received f unding from the MINECO (a "Juan de la Cierva Incorporation " fellowship; IJCI-2014-20723). SP was a recipient of a Miguel Servet contract (ISCIII/FIS), and AI, JPC-C, LP-G, and GS-B are supported by contracts from Worldwide Cancer Research, Fundació La MaratóTV3, Fundació FERO, and a FI Fellowship from the Generalitat de Catalunya, respectively.

The costs of systemic treatment of lung cancer are rising rapidly due to the use of new and targeted substances. Increases in survival will further add to this development. This explains the exemplary health economic relevance of the treatment of lung cancer, which can be analyzed using various economic methods and instruments. From epidemiologic and economic perspectives, prevention should be given highest priority but the formation of health political and social opinion is not yet completed. Valid evidence on the roles of screening interventions can be expected in the next years. In this article legal, institutional and cooperative approaches within the health care system to address this problem are discussed.

Lung carcinoma is the main cause of cancer related deaths among the male population in The Netherlands. In females this carcinoma is only surpassed by breast and colon cancer. In The Netherlands in 1987, 8.500 persons died due to lung carcinoma (1). It is anticipated that despite government-installed preventive measures -including stop-smoking programs- the number of persons suffering from lung cancer will continue to rise in the near future (2,3). The results of all therapeutic modalities for lung cancer have reached a plateau for many years with about 10% overall cure (4). For therapeutic reasons, lung cancer is generally divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). For NSCLC surgery is the only curative modality for patients without demonstrable metastatic disease (5). For SCLC, which comprises 20-25% of all cases, combination chemotherapy forms the cornerstone of therapy with the vast majority of patients responding to therapy with prolonged survival and a small percentage of cures. While SCLC is responsive to chemotherapy, NSCLC is only moderately responsive to such therapy (6). Although much knowledge has been gathered on the biology of lung cancer, this basic research did not, however, result in improved survival of patients treated by chemotherapy for lung cancer (7). The failure of chemotherapy to cure lung cancer patients is basically a problem of drug resistance. Several resistance mechanisms have been discovered in the recent years. The most widely studied form is the so called pleiotropic drug resistance (PDR) (8). PDR has emerged as a consistent mechanism of resistance for several structurally unrelated cytotoxic agents in cancer cells. Resistance seems to be caused by a decreased intracellular drug concentration, caused by an increased efflux pump. This efflux pump can be antagonated in vitro by calcium antagonists. It has become clear that reversal of resistance mediated by the PDR-phenotype is in some cases possible in the clinic (9,lO). PDR however, seems to play little or no role in lung cancer (1 1). Resistance mechanisms which have been identified in vitro in lung cancer cell lines include enhanced DNA repair capacity and altered drug-topoisomerase interactions (12). For these and other drug resistance mechanisms it has by no means been elucidated whether they can be circumvented by sophisticated measures in the near future.

Background One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized. Results Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles with impact on transforming processes during carcinogenesis. Conclusions We develop an extensive catalogue of human DNA methylomes at base resolution to better understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes. ; The research leading to these results received funding from: the European Research Council (ERC), grant EPINORC, under agreement number 268626; MICINN Projects–SAF2011-22803 and BFU2011-28549; Ministerio de Economía y Competitividad (MINECO), co-financed by the European Development Regional Fund, 'A way to achieve Europe' ERDF, under grant number SAF2014-55000-R; the Cellex Foundation; AGAUR Catalan Government Project #2009SGR1315; the Institute of Health Carlos III (ISCIII), under the Spanish Cancer Research Network (RTICC) number RD12/0036/0039, the Integrated Project of Excellence number PIE13/00022 (ONCOPROFILE) and the research grant PI11/00321; the Sandra Ibarra Foundation, under IV ghd Grants for breast cancer research; the Olga Torres Foundation; the European Community's Seventh Framework Programme (FP7/2007-2013), grant HEALTH-F5-2011-282510 – BLUEPRINT, and the Health and Science Departments of the Generalitat de Catalunya. H.H. is a Miguel Servet (CP14/00229) researcher funded by the Spanish Institute of Health Carlos III (ISCIII). D.T. and M.E. are ICREA Research Professors. ; Peer Reviewed ; Postprint (author's final draft)

Background One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized. Results Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles with impact on transforming processes during carcinogenesis. Conclusions We develop an extensive catalogue of human DNA methylomes at base resolution to better understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes. ; The research leading to these results received funding from: the European Research Council (ERC), grant EPINORC, under agreement number 268626; MICINN Projects–SAF2011-22803 and BFU2011-28549; Ministerio de Economía y Competitividad (MINECO), co-financed by the European Development Regional Fund, 'A way to achieve Europe' ERDF, under grant number SAF2014-55000-R; the Cellex Foundation; AGAUR Catalan Government Project #2009SGR1315; the Institute of Health Carlos III (ISCIII), under the Spanish Cancer Research Network (RTICC) number RD12/0036/0039, the Integrated Project of Excellence number PIE13/00022 (ONCOPROFILE) and the research grant PI11/00321; the Sandra Ibarra Foundation, under IV ghd Grants for breast cancer research; the Olga Torres Foundation; the European Community's Seventh Framework Programme (FP7/2007-2013), grant HEALTH-F5-2011-282510 – BLUEPRINT, and the Health and Science Departments of the Generalitat de Catalunya. H.H. is a Miguel Servet (CP14/00229) researcher funded by the Spanish Institute of Health Carlos III (ISCIII). D.T. and M.E. are ICREA Research Professors. ; Peer Reviewed ; Postprint (author's final draft)

Active immunotherapy products (widely known as "cancer vaccines") are products intended to stimulate an immune response to mediate tumor destruction or reduce the progression of disease in patients where cancer has been diagnosed. Some quality attributes of these products are very difficult to characterize or present a high variability (especially if they are for autologous use), further complicating the interpretation of some of the clinical data. Furthermore, questions arise in the evaluation of efficacy and safety data in comparison with current chemical or biological treatments for the same indications. Some of these aspects are discussed in this paper in relationship with the regulatory requirements in the European Union and as applied to two recently assessed medicinal products, Oncophage and Provenge, both considered therapeutic "cancer vaccines" for renal cell carcinoma and prostate cancer, respectively.

B cells have the unique property to somatically alter their immunoglobulin (IG) genes by V(D)J recombination, somatic hypermutation (SHM) and class-switch recombination (CSR). Aberrant targeting of these mechanisms is implicated in lymphomagenesis, but the mutational processes are poorly understood. By performing whole genome and transcriptome sequencing of 181 germinal center derived B-cell lymphomas (gcBCL) we identified distinct mutational signatures linked to SHM and CSR. We show that not only SHM, but presumably also CSR causes off-target mutations in non-IG genes. Kataegis clusters with high mutational density mainly affected early replicating regions and were enriched for SHM- and CSR-mediated off-target mutations. Moreover, they often co-occurred in loci physically interacting in the nucleus, suggesting that mutation hotspots promote increased mutation targeting of spatially co-localized loci (termed hypermutation by proxy). Only around 1% of somatic small variants were in protein coding sequences, but in about half of the driver genes, a contribution of B-cell specific mutational processes to their mutations was found. The B-cell-specific mutational processes contribute to both lymphoma initiation and intratumoral heterogeneity. Overall, we demonstrate that mutational processes involved in the development of gcBCL are more complex than previously appreciated, and that B cell-specific mutational processes contribute via diverse mechanisms to lymphomagenesis. ; This study has been supported by the German Ministry of Science and Education (BMBF) in the framework of the ICGC MMML-Seq project (01KU1002A-J) the MMML-MYC-SYS project (036166B) and the project ICGC DE-MINING (01KU1505E), the European Union in the framework of the BLUEPRINT Project (HEALTH-F5-2011-282510) and the KinderKrebsInitiative Buchholz/Holm-Seppensen. This work was supported by the BMBF-funded Heidelberg Center for Human Bioinformatics (HD-HuB) within the German Network for Bioinformatics Infrastructure (de.NBI) (#031A537A, #031A537C). Former grant support of MMML by the Deutsche Krebshilfe (2003–2011) is gratefully acknowledged. We acknowledge COSMIC and use of Cancer Gene Census. Part of the work was performed in association with SFB1074 (particularly subproject B1) funded by DFG. We wish to thank Barbara Hutter, Ivo Buchhalter, Zuguang Gu, and Natalie Jäger for skillful technical assistance. We thank the High-Throughput Sequencing Unit of the Genome and Proteome Core Facility and the Omics IT and Data Management Core Facility of the German Cancer Research Center (DKFZ, Heidelberg) as well as the Institute of Clinical Molecular Biology (IKMB, Christian-Albrechts-University Kiel) for excellent technical support and expertise. DH is a member of the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS) and of the MD/PhD-program of the University of Heidelberg. KK and UHT are funded by the Helmholtz International Graduate School for Cancer Research at the German Cancer Research Center. SHB, HK, and SH acknowledge support by LIFE (Leipzig Research Center for Civilization Diseases), Leipzig University. LIFE is funded by the European Union, the European Regional Development Fund (ERDF), the European Social Fund (ESF), and the Free State of Saxony. This work has been carried out with the help of the Interdisciplinary Bank of Biomaterials and Data of the University Hospital of Würzburg and the Julius Maximilian University of Würzburg (idbw). ; Peer Reviewed ; "Article signat per 70 autors/es:Daniel Hübschmann, Kortine Kleinheinz, Rabea Wagener, Stephan H. Bernhart, Cristina López, Umut H. Toprak, Stephanie Sungalee, Naveed Ishaque, Helene Kretzmer, Markus Kreuz, Sebastian M. Waszak, Nagarajan Paramasivam, Ole Ammerpohl, Sietse M. Aukema, Renée Beekman, Anke K. Bergmann, Matthias Bieg, Hans Binder, Arndt Borkhardt, Christoph Borst, Benedikt Brors, Philipp Bruns, Enrique Carrillo de Santa Pau, Alexander Claviez, Gero Doose, Andrea Haake, Dennis Karsch, Siegfried Haas, Martin-Leo Hansmann, Jessica I. Hoell, Volker Hovestadt, Bingding Huang, Michael Hummel, Christina Jäger-Schmidt, Jules N. A. Kerssemakers, Jan O. Korbel, Dieter Kube, Chris Lawerenz, Dido Lenze, Joost H. A. Martens, German Ott, Bernhard Radlwimmer, Eva Reisinger, Julia Richter, Daniel Rico, Philip Rosenstiel, Andreas Rosenwald, Markus Schillhabel, Stephan Stilgenbauer, Peter F. Stadler, José I. Martín-Subero, Monika Szczepanowski, Gregor Warsow, Marc A. Weniger, Marc Zapatka, Alfonso Valencia, Hendrik G. Stunnenberg, Peter Lichter, Peter Möller, Markus Loeffler, Roland Eils, Wolfram Klapper, Steve Hoffmann, Lorenz Trümper, ICGC MMML-Seq consortium, ICGC DE-Mining consortium, BLUEPRINT consortium, Ralf Küppers, Matthias Schlesner & Reiner Siebert" ; Postprint (published version)

Cohesin exists in two variants containing STAG1 or STAG2. STAG2 is one of the most mutated genes in cancer and a major bladder tumor suppressor. Little is known about how its inactivation contributes to tumorigenesis. Here, we analyze the genomic distribution of STAG1 and STAG2 and perform STAG2 loss-of-function experiments using RT112 bladder cancer cells; we then analyze the genomic effects by integrating gene expression and chromatin interaction data. Functional compartmentalization exists between the cohesin complexes: cohesin-STAG2 displays a distinctive genomic distribution and mediates short and mid-ranged interactions that engage genes at higher frequency than those established by cohesin-STAG1. STAG2 knockdown results in down-regulation of the luminal urothelial signature and up-regulation of the basal transcriptional program, mirroring differences between STAG2-high and STAG2-low human bladder tumors. This is accompanied by rewiring of DNA contacts within topological domains, while compartments and domain boundaries remain refractive. Contacts lost upon depletion of STAG2 are assortative, preferentially occur within silent chromatin domains, and are associated with de-repression of lineage-specifying genes. Our findings indicate that STAG2 participates in the DNA looping that keeps the basal transcriptional program silent and thus sustains the luminal program. This mechanism may contribute to the tumor suppressor function of STAG2 in the urothelium. ; Fundación Científica de la Asociación Española Contra el Cáncer (to F.X.R., E.L., in part); V.P. is supported by INSERM, the Fondation Toulouse Cancer Santé and Pierre Fabre Research Institute as part of the Chair of Bioinformatics in Oncology of the CRCT; Bioinfo4women programme at the Barcelona Supercomputing Center; European Union's H2020 Framework Programme through the ERC [609989 to M.A.M.-R., in part]; Spanish Ministerio de Ciencia, Innovación y Universidades [BFU2017-85926-P to M.A.M.-R.]; C.N.I.O. is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa [SEV-2015-0510]; C.R.G. acknowledges support from 'Centro de Excelencia Severo Ochoa 2013–2017' [SEV-2012-0208]; Spanish ministry of Science and Innovation to the EMBL partnership and the CERCA Programme/Generalitat de Catalunya (to C.R.G.); C.R.G. also acknowledges support of the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the Generalitat de Catalunya through Departament de Salut and Departament d'Empresa i Coneixement; Spanish Ministry of Science and Innovation with funds from the European Regional Development Fund (ERDF) corresponding to the 2014–2020 Smart Growth Operating Program (to C.N.A.G.). Funding for open access charge: Own funds. ; Peer Reviewed ; "Article signat per 15 autors/es: Laia Richart, Eleonora Lapi, Vera Pancaldi, Mirabai Cuenca-Ardura, Enrique Carrillo-de-Santa Pau, Miguel Madrid-Mencía, Hélène Neyret-Kahn, François Radvanyi, Juan Antonio Rodríguez, Yasmina Cuartero, François Serra, François Le Dily, Alfonso Valencia, Marc A Marti-Renom, Francisco X Real " ; Postprint (published version)