513 results on '"Waszak, Sebastian M'
Search Results
2. Somatic CpG hypermutation is associated with mismatch repair deficiency in cancer
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Aidan Flynn, Sebastian M Waszak, and Joachim Weischenfeldt
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Pan-Cancer ,CpG Hypermutator ,MMR ,TMB ,Immunotherapy ,Biology (General) ,QH301-705.5 ,Medicine (General) ,R5-920 - Abstract
Abstract Somatic hypermutation in cancer has gained momentum with the increased use of tumour mutation burden as a biomarker for immune checkpoint inhibitors. Spontaneous deamination of 5-methylcytosine to thymine at CpG dinucleotides is one of the most ubiquitous endogenous mutational processes in normal and cancer cells. Here, we performed a systematic investigation of somatic CpG hypermutation at a pan-cancer level. We studied 30,191 cancer patients and 103 cancer types and developed an algorithm to identify somatic CpG hypermutation. Across cancer types, we observed the highest prevalence in paediatric leukaemia (3.5%), paediatric high-grade glioma (1.7%), and colorectal cancer (1%). We discovered germline variants and somatic mutations in the mismatch repair complex MutSα (MSH2-MSH6) as genetic drivers of somatic CpG hypermutation in cancer, which frequently converged on CpG sites and TP53 driver mutations. We further observe an association between somatic CpG hypermutation and response to immune checkpoint inhibitors. Overall, our study identified novel cancer types that display somatic CpG hypermutation, strong association with MutSα-deficiency, and potential utility in cancer immunotherapy.
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- 2024
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3. A polygenic two-hit hypothesis for prostate cancer
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Houlahan, Kathleen E, Livingstone, Julie, Fox, Natalie S, Kurganovs, Natalie, Zhu, Helen, Sietsma Penington, Jocelyn, Jung, Chol-Hee, Yamaguchi, Takafumi N, Heisler, Lawrence E, Jovelin, Richard, Costello, Anthony J, Pope, Bernard J, Kishan, Amar U, Corcoran, Niall M, Bristow, Robert G, Waszak, Sebastian M, Weischenfeldt, Joachim, He, Housheng H, Hung, Rayjean J, Hovens, Christopher M, and Boutros, Paul C
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Genetics ,Aging ,Prostate Cancer ,Urologic Diseases ,Prevention ,Genetic Testing ,Human Genome ,Good Health and Well Being ,Male ,Humans ,Prostatic Neoplasms ,Risk Factors ,Prognosis ,Genetic Predisposition to Disease ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.
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- 2023
4. Clinical, genomic, and epigenomic analyses of H3K27M-mutant diffuse midline glioma long-term survivors reveal a distinct group of tumors with MAPK pathway alterations
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Roberts, Holly J., Ji, Sunjong, Picca, Alberto, Sanson, Marc, Garcia, Mekka, Snuderl, Matija, Schüller, Ulrich, Picart, Thiébaud, Ducray, François, Green, Adam L., Nakano, Yoshiko, Sturm, Dominik, Abdullaev, Zied, Aldape, Kenneth, Dang, Derek, Kumar-Sinha, Chandan, Wu, Yi-Mi, Robinson, Dan, Vo, Josh N., Chinnaiyan, Arul M., Cartaxo, Rodrigo, Upadhyaya, Santhosh A., Mody, Rajen, Chiang, Jason, Baker, Suzanne, Solomon, David, Venneti, Sriram, Pratt, Drew, Waszak, Sebastian M., and Koschmann, Carl
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- 2023
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5. Upfront biology-guided therapy in diffuse intrinsic pontine glioma: therapeutic, molecular, and biomarker outcomes from PNOC003
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Kline, Cassie, Jain, Payal, Kilburn, Lindsay, Bonner, Erin R, Gupta, Nalin, Crawford, John R, Banerjee, Anu, Packer, Roger J, Villanueva-Meyer, Javier, Luks, Tracy, Zhang, Yalan, Kambhampati, Madhuri, Zhang, Jie, Yadavilli, Sridevi, Zhang, Bo, Gaonkar, Krutika S, Rokita, Jo Lynne, Kraya, Adam, Kuhn, John, Liang, Winnie, Byron, Sara, Berens, Michael, Molinaro, Annette, Prados, Michael, Resnick, Adam, Waszak, Sebastian M, Nazarian, Javad, and Mueller, Sabine
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Neurosciences ,Cancer ,Genetics ,Brain Disorders ,Pediatric ,Human Genome ,Rare Diseases ,Clinical Research ,Clinical Trials and Supportive Activities ,Brain Cancer ,Orphan Drug ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,Good Health and Well Being ,Astrocytoma ,Biology ,Biomarkers ,Brain Stem Neoplasms ,Child ,Circulating Tumor DNA ,Diffuse Intrinsic Pontine Glioma ,Female ,Genomic Instability ,Glioma ,Humans ,Young Adult ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposePNOC003 is a multicenter precision medicine trial for children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG).Patients and methodsPatients (3-25 years) were enrolled on the basis of imaging consistent with DIPG. Biopsy tissue was collected for whole-exome and mRNA sequencing. After radiotherapy (RT), patients were assigned up to four FDA-approved drugs based on molecular tumor board recommendations. H3K27M-mutant circulating tumor DNA (ctDNA) was longitudinally measured. Tumor tissue and matched primary cell lines were characterized using whole-genome sequencing and DNA methylation profiling. When applicable, results were verified in an independent cohort from the Children's Brain Tumor Network (CBTN).ResultsOf 38 patients enrolled, 28 patients (median 6 years, 10 females) were reviewed by the molecular tumor board. Of those, 19 followed treatment recommendations. Median overall survival (OS) was 13.1 months [95% confidence interval (CI), 11.2-18.4] with no difference between patients who followed recommendations and those who did not. H3K27M-mutant ctDNA was detected at baseline in 60% of cases tested and associated with response to RT and survival. Eleven cell lines were established, showing 100% fidelity of key somatic driver gene alterations in the primary tumor. In H3K27-altered DIPGs, TP53 mutations were associated with worse OS (TP53mut 11.1 mo; 95% CI, 8.7-14; TP53wt 13.3 mo; 95% CI, 11.8-NA; P = 3.4e-2), genome instability (P = 3.1e-3), and RT resistance (P = 6.4e-4). The CBTN cohort confirmed an association between TP53 mutation status, genome instability, and clinical outcome.ConclusionsUpfront treatment-naïve biopsy provides insight into clinically relevant molecular alterations and prognostic biomarkers for H3K27-altered DIPGs.
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- 2022
6. Pan-cancer atlas of somatic core and linker histone mutations
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Bonner, Erin R., Dawood, Adam, Gordish-Dressman, Heather, Eze, Augustine, Bhattacharya, Surajit, Yadavilli, Sridevi, Mueller, Sabine, Waszak, Sebastian M., and Nazarian, Javad
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- 2023
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7. Pan-cancer atlas of somatic core and linker histone mutations
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Erin R. Bonner, Adam Dawood, Heather Gordish-Dressman, Augustine Eze, Surajit Bhattacharya, Sridevi Yadavilli, Sabine Mueller, Sebastian M. Waszak, and Javad Nazarian
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Medicine ,Genetics ,QH426-470 - Abstract
Abstract Recent genomic data points to a growing role for somatic mutations altering core histone and linker histone-encoding genes in cancer. However, the prevalence and the clinical and biological implications of histone gene mutations in malignant tumors remain incompletely defined. To address these knowledge gaps, we analyzed somatic mutations in 88 linker and core histone genes across 12,743 tumors from pediatric, adolescent and young adult (AYA), and adult cancer patients. We established a pan-cancer histone mutation atlas contextualized by patient age, survival outcome, and tumor location. Overall, 11% of tumors harbored somatic histone mutations, with the highest rates observed among chondrosarcoma (67%), pediatric high-grade glioma (pHGG, >60%), and lymphoma (>30%). Previously unreported histone mutations were discovered in pHGG and other pediatric brain tumors, extending the spectrum of histone gene alterations associated with these cancers. Histone mutation status predicted patient survival outcome in tumor entities including adrenocortical carcinoma. Recurrent pan-cancer histone mutation hotspots were defined and shown to converge on evolutionarily conserved and functional residues. Moreover, we studied histone gene mutations in 1700 pan-cancer cell lines to validate the prevalence and spectrum of histone mutations seen in primary tumors and derived histone-associated drug response profiles, revealing candidate drugs targeting histone mutant cancer cells. This study presents the first-of-its-kind atlas of both core and linker histone mutations across pediatric, AYA, and adult cancers, providing a framework by which specific cancers may be redefined in the context of histone and chromatin alterations.
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- 2023
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8. Copy-number dosage regulates telomere maintenance and disease-associated pathways in neuroblastoma
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Burkert, Martin, Blanc, Eric, Thiessen, Nina, Weber, Christiane, Toedling, Joern, Monti, Remo, Dombrowe, Victoria M., Stella de Biase, Maria, Kaufmann, Tom L., Haase, Kerstin, Waszak, Sebastian M., Eggert, Angelika, Beule, Dieter, Schulte, Johannes H., Ohler, Uwe, and Schwarz, Roland F.
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- 2024
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9. Mutation-Attention (MuAt): deep representation learning of somatic mutations for tumour typing and subtyping
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Prima Sanjaya, Katri Maljanen, Riku Katainen, Sebastian M. Waszak, Genomics England Research Consortium, Lauri A. Aaltonen, Oliver Stegle, Jan O. Korbel, and Esa Pitkänen
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Cancer genomics ,Precision cancer medicine ,Machine learning ,Deep learning ,Tumour type prediction ,Molecular tumour subtyping ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Cancer genome sequencing enables accurate classification of tumours and tumour subtypes. However, prediction performance is still limited using exome-only sequencing and for tumour types with low somatic mutation burden such as many paediatric tumours. Moreover, the ability to leverage deep representation learning in discovery of tumour entities remains unknown. Methods We introduce here Mutation-Attention (MuAt), a deep neural network to learn representations of simple and complex somatic alterations for prediction of tumour types and subtypes. In contrast to many previous methods, MuAt utilizes the attention mechanism on individual mutations instead of aggregated mutation counts. Results We trained MuAt models on 2587 whole cancer genomes (24 tumour types) from the Pan-Cancer Analysis of Whole Genomes (PCAWG) and 7352 cancer exomes (20 types) from the Cancer Genome Atlas (TCGA). MuAt achieved prediction accuracy of 89% for whole genomes and 64% for whole exomes, and a top-5 accuracy of 97% and 90%, respectively. MuAt models were found to be well-calibrated and perform well in three independent whole cancer genome cohorts with 10,361 tumours in total. We show MuAt to be able to learn clinically and biologically relevant tumour entities including acral melanoma, SHH-activated medulloblastoma, SPOP-associated prostate cancer, microsatellite instability, POLE proofreading deficiency, and MUTYH-associated pancreatic endocrine tumours without these tumour subtypes and subgroups being provided as training labels. Finally, scrunity of MuAt attention matrices revealed both ubiquitous and tumour-type specific patterns of simple and complex somatic mutations. Conclusions Integrated representations of somatic alterations learnt by MuAt were able to accurately identify histological tumour types and identify tumour entities, with potential to impact precision cancer medicine.
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- 2023
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10. Enterosignatures define common bacterial guilds in the human gut microbiome
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Frioux, Clémence, Ansorge, Rebecca, Özkurt, Ezgi, Ghassemi Nedjad, Chabname, Fritscher, Joachim, Quince, Christopher, Waszak, Sebastian M., and Hildebrand, Falk
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- 2023
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11. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.
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Rodriguez-Martin, Bernardo, Alvarez, Eva G, Baez-Ortega, Adrian, Zamora, Jorge, Supek, Fran, Demeulemeester, Jonas, Santamarina, Martin, Ju, Young Seok, Temes, Javier, Garcia-Souto, Daniel, Detering, Harald, Li, Yilong, Rodriguez-Castro, Jorge, Dueso-Barroso, Ana, Bruzos, Alicia L, Dentro, Stefan C, Blanco, Miguel G, Contino, Gianmarco, Ardeljan, Daniel, Tojo, Marta, Roberts, Nicola D, Zumalave, Sonia, Edwards, Paul A, Weischenfeldt, Joachim, Puiggròs, Montserrat, Chong, Zechen, Chen, Ken, Lee, Eunjung Alice, Wala, Jeremiah A, Raine, Keiran M, Butler, Adam, Waszak, Sebastian M, Navarro, Fabio CP, Schumacher, Steven E, Monlong, Jean, Maura, Francesco, Bolli, Niccolo, Bourque, Guillaume, Gerstein, Mark, Park, Peter J, Wedge, David C, Beroukhim, Rameen, Torrents, David, Korbel, Jan O, Martincorena, Iñigo, Fitzgerald, Rebecca C, Van Loo, Peter, Kazazian, Haig H, Burns, Kathleen H, PCAWG Structural Variation Working Group, Campbell, Peter J, Tubio, Jose MC, and PCAWG Consortium
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PCAWG Structural Variation Working Group ,PCAWG Consortium ,Humans ,Neoplasms ,Retroelements ,Gene Rearrangement ,Long Interspersed Nucleotide Elements ,Genome ,Human ,Carcinogenesis ,Genetics ,Digestive Diseases ,Human Genome ,Cancer ,Rare Diseases ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.
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- 2020
12. Butler enables rapid cloud-based analysis of thousands of human genomes
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Yakneen, Sergei, Waszak, Sebastian M, Gertz, Michael, and Korbel, Jan O
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Genetics ,Human Genome ,Cancer ,Cloud Computing ,Computational Biology ,Genome ,Human ,Humans ,Neoplasms ,Software ,PCAWG Technical Working Group ,PCAWG Consortium - Abstract
We present Butler, a computational tool that facilitates large-scale genomic analyses on public and academic clouds. Butler includes innovative anomaly detection and self-healing functions that improve the efficiency of data processing and analysis by 43% compared with current approaches. Butler enabled processing of a 725-terabyte cancer genome dataset from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project in a time-efficient and uniform manner.
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- 2020
13. Pan-cancer analysis of whole genomes
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Campbell, Peter J, Getz, Gad, Korbel, Jan O, Stuart, Joshua M, Jennings, Jennifer L, Stein, Lincoln D, Perry, Marc D, Nahal-Bose, Hardeep K, Ouellette, BF Francis, Li, Constance H, Rheinbay, Esther, Nielsen, G Petur, Sgroi, Dennis C, Wu, Chin-Lee, Faquin, William C, Deshpande, Vikram, Boutros, Paul C, Lazar, Alexander J, Hoadley, Katherine A, Louis, David N, Dursi, L Jonathan, Yung, Christina K, Bailey, Matthew H, Saksena, Gordon, Raine, Keiran M, Buchhalter, Ivo, Kleinheinz, Kortine, Schlesner, Matthias, Zhang, Junjun, Wang, Wenyi, Wheeler, David A, Ding, Li, Simpson, Jared T, O'Connor, Brian D, Yakneen, Sergei, Ellrott, Kyle, Miyoshi, Naoki, Butler, Adam P, Royo, Romina, Shorser, Solomon I, Vazquez, Miguel, Rausch, Tobias, Tiao, Grace, Waszak, Sebastian M, Rodriguez-Martin, Bernardo, Shringarpure, Suyash, Wu, Dai-Ying, Demidov, German M, Delaneau, Olivier, Hayashi, Shuto, Imoto, Seiya, Habermann, Nina, Segre, Ayellet V, Garrison, Erik, Cafferkey, Andy, Alvarez, Eva G, Maria Heredia-Genestar, Jose, Muyas, Francesc, Drechsel, Oliver, Bruzos, Alicia L, Temes, Javier, Zamora, Jorge, Baez-Ortega, Adrian, Kim, Hyung-Lae, Mashl, R Jay, Ye, Kai, DiBiase, Anthony, Huang, Kuan-lin, Letunic, Ivica, McLellan, Michael D, Newhouse, Steven J, Shmaya, Tal, Kumar, Sushant, Wedge, David C, Wright, Mark H, Yellapantula, Venkata D, Gerstein, Mark, Khurana, Ekta, Marques-Bonet, Tomas, Navarro, Arcadi, Bustamante, Carlos D, Siebert, Reiner, Nakagawa, Hidewaki, Easton, Douglas F, Ossowski, Stephan, Tubio, Jose MC, De La Vega, Francisco M, Estivill, Xavier, Yuen, Denis, Mihaiescu, George L, Omberg, Larsson, Ferretti, Vincent, Sabarinathan, Radhakrishnan, Pich, Oriol, Gonzalez-Perez, Abel, Weiner, Amaro Taylor, Fittall, Matthew W, Demeulemeester, Jonas, Tarabichi, Maxime, and Roberts, Nicola D
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Biological Sciences ,Biomedical and Clinical Sciences ,Bioinformatics and Computational Biology ,Genetics ,Oncology and Carcinogenesis ,Cancer Genomics ,Biotechnology ,Human Genome ,Cancer ,Prevention ,2.1 Biological and endogenous factors ,Cell Proliferation ,Cellular Senescence ,Chromothripsis ,Cloud Computing ,DNA Mutational Analysis ,Evolution ,Molecular ,Female ,Genome ,Human ,Genomics ,Germ-Line Mutation ,High-Throughput Nucleotide Sequencing ,Humans ,Information Dissemination ,Male ,Mutagenesis ,Mutation ,Neoplasms ,Oncogenes ,Promoter Regions ,Genetic ,RNA Splicing ,Reproducibility of Results ,Telomerase ,Telomere ,ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium ,General Science & Technology - Abstract
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1-3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10-18.
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- 2020
14. Genomic basis for RNA alterations in cancer.
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PCAWG Transcriptome Core Group, Calabrese, Claudia, Davidson, Natalie R, Demircioğlu, Deniz, Fonseca, Nuno A, He, Yao, Kahles, André, Lehmann, Kjong-Van, Liu, Fenglin, Shiraishi, Yuichi, Soulette, Cameron M, Urban, Lara, Greger, Liliana, Li, Siliang, Liu, Dongbing, Perry, Marc D, Xiang, Qian, Zhang, Fan, Zhang, Junjun, Bailey, Peter, Erkek, Serap, Hoadley, Katherine A, Hou, Yong, Huska, Matthew R, Kilpinen, Helena, Korbel, Jan O, Marin, Maximillian G, Markowski, Julia, Nandi, Tannistha, Pan-Hammarström, Qiang, Pedamallu, Chandra Sekhar, Siebert, Reiner, Stark, Stefan G, Su, Hong, Tan, Patrick, Waszak, Sebastian M, Yung, Christina, Zhu, Shida, Awadalla, Philip, Creighton, Chad J, Meyerson, Matthew, Ouellette, BF Francis, Wu, Kui, Yang, Huanming, PCAWG Transcriptome Working Group, Brazma, Alvis, Brooks, Angela N, Göke, Jonathan, Rätsch, Gunnar, Schwarz, Roland F, Stegle, Oliver, Zhang, Zemin, and PCAWG Consortium
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PCAWG Transcriptome Core Group ,PCAWG Transcriptome Working Group ,PCAWG Consortium ,Humans ,Neoplasms ,DNA ,Neoplasm ,RNA ,Genomics ,Gene Expression Regulation ,Neoplastic ,Genome ,Human ,DNA Copy Number Variations ,Transcriptome ,DNA ,Neoplasm ,Gene Expression Regulation ,Neoplastic ,Genome ,Human ,General Science & Technology - Abstract
Transcript alterations often result from somatic changes in cancer genomes1. Various forms of RNA alterations have been described in cancer, including overexpression2, altered splicing3 and gene fusions4; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)5. Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed 'bridged' fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.
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- 2020
15. Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.
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Gerhauser, Clarissa, Favero, Francesco, Risch, Thomas, Simon, Ronald, Feuerbach, Lars, Assenov, Yassen, Heckmann, Doreen, Sidiropoulos, Nikos, Waszak, Sebastian M, Hübschmann, Daniel, Urbanucci, Alfonso, Girma, Etsehiwot G, Kuryshev, Vladimir, Klimczak, Leszek J, Saini, Natalie, Stütz, Adrian M, Weichenhan, Dieter, Böttcher, Lisa-Marie, Toth, Reka, Hendriksen, Josephine D, Koop, Christina, Lutsik, Pavlo, Matzk, Sören, Warnatz, Hans-Jörg, Amstislavskiy, Vyacheslav, Feuerstein, Clarissa, Raeder, Benjamin, Bogatyrova, Olga, Schmitz, Eva-Maria, Hube-Magg, Claudia, Kluth, Martina, Huland, Hartwig, Graefen, Markus, Lawerenz, Chris, Henry, Gervaise H, Yamaguchi, Takafumi N, Malewska, Alicia, Meiners, Jan, Schilling, Daniela, Reisinger, Eva, Eils, Roland, Schlesner, Matthias, Strand, Douglas W, Bristow, Robert G, Boutros, Paul C, von Kalle, Christof, Gordenin, Dmitry, Sültmann, Holger, Brors, Benedikt, Sauter, Guido, Plass, Christoph, Yaspo, Marie-Laure, Korbel, Jan O, Schlomm, Thorsten, and Weischenfeldt, Joachim
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Humans ,Prostatic Neoplasms ,RNA-Binding Proteins ,Risk Factors ,Evolution ,Molecular ,DNA Methylation ,Gene Expression Regulation ,Neoplastic ,Mutation ,Adult ,Middle Aged ,Male ,Transcriptome ,Biomarkers ,Tumor ,Whole Genome Sequencing ,APOBEC ,cancer genomics ,early-onset cancer ,epigenetic risk-score ,mutational processes ,prostate cancer ,structural variants ,tumor evolution ,tumor evolution prediction ,Human Genome ,Aging ,Prevention ,Cancer ,Urologic Diseases ,Prostate Cancer ,Genetics ,4.1 Discovery and preclinical testing of markers and technologies ,Aetiology ,2.1 Biological and endogenous factors ,Detection ,screening and diagnosis ,Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples.
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- 2018
16. Rare Germline Variants Are Associated with Rapid Biochemical Recurrence After Radical Prostate Cancer Treatment: A Pan Prostate Cancer Group Study
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Burns, Daniel, Anokian, Ezequiel, Saunders, Edward J., Bristow, Robert G., Fraser, Michael, Reimand, Jüri, Schlomm, Thorsten, Sauter, Guido, Brors, Benedikt, Korbel, Jan, Weischenfeldt, Joachim, Waszak, Sebastian M., Corcoran, Niall M., Jung, Chol-Hee, Pope, Bernard J., Hovens, Chris M., Cancel-Tassin, Géraldine, Cussenot, Olivier, Loda, Massimo, Sander, Chris, Hayes, Vanessa M., Dalsgaard Sorensen, Karina, Lu, Yong-Jie, Hamdy, Freddie C., Foster, Christopher S., Gnanapragasam, Vincent, Butler, Adam, Lynch, Andy G., Massie, Charlie E., Woodcock, Dan J., Cooper, Colin S., Wedge, David C., Brewer, Daniel S., Kote-Jarai, Zsofia, and Eeles, Rosalind A.
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- 2022
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17. A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation
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Llimos, Gerard, Gardeux, Vincent, Koch, Ute, Kribelbauer, Judith F., Hafner, Antonina, Alpern, Daniel, Pezoldt, Joern, Litovchenko, Maria, Russeil, Julie, Dainese, Riccardo, Moia, Riccardo, Mahmoud, Abdurraouf Mokhtar, Rossi, Davide, Gaidano, Gianluca, Plass, Christoph, Lutsik, Pavlo, Gerhauser, Clarissa, Waszak, Sebastian M., Boettiger, Alistair, Radtke, Freddy, and Deplancke, Bart
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- 2022
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18. A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation
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Gerard Llimos, Vincent Gardeux, Ute Koch, Judith F. Kribelbauer, Antonina Hafner, Daniel Alpern, Joern Pezoldt, Maria Litovchenko, Julie Russeil, Riccardo Dainese, Riccardo Moia, Abdurraouf Mokhtar Mahmoud, Davide Rossi, Gianluca Gaidano, Christoph Plass, Pavlo Lutsik, Clarissa Gerhauser, Sebastian M. Waszak, Alistair Boettiger, Freddy Radtke, and Bart Deplancke
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Science - Abstract
Non-coding variants can regulate transcription factor binding and gene expression at variable chromatin modules. Here, the authors show that a germline variant induces transcription factor nucleation through chromatin compaction leading to AXIN2 up-regulation and is associated to better prognosis in chronic lymphocytic leukaemia.
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- 2022
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19. Author Correction: Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition
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Rodriguez-Martin, Bernardo, Alvarez, Eva G., Baez-Ortega, Adrian, Zamora, Jorge, Supek, Fran, Demeulemeester, Jonas, Santamarina, Martin, Ju, Young Seok, Temes, Javier, Garcia-Souto, Daniel, Detering, Harald, Li, Yilong, Rodriguez-Castro, Jorge, Dueso-Barroso, Ana, Bruzos, Alicia L., Dentro, Stefan C., Blanco, Miguel G., Contino, Gianmarco, Ardeljan, Daniel, Tojo, Marta, Roberts, Nicola D., Zumalave, Sonia, Edwards, Paul A., Weischenfeldt, Joachim, Puiggròs, Montserrat, Chong, Zechen, Chen, Ken, Lee, Eunjung Alice, Wala, Jeremiah A., Raine, Keiran M., Butler, Adam, Waszak, Sebastian M., Navarro, Fabio C. P., Schumacher, Steven E., Monlong, Jean, Maura, Francesco, Bolli, Niccolo, Bourque, Guillaume, Gerstein, Mark, Park, Peter J., Wedge, David C., Beroukhim, Rameen, Torrents, David, Korbel, Jan O., Martincorena, Iñigo, Fitzgerald, Rebecca C., Van Loo, Peter, Kazazian, Haig H., Burns, Kathleen H., Campbell, Peter J., and Tubio, Jose M. C.
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- 2023
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20. Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies
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Findlay, Izac J., De Iuliis, Geoffry N., Duchatel, Ryan J., Jackson, Evangeline R., Vitanza, Nicholas A., Cain, Jason E., Waszak, Sebastian M., and Dun, Matthew D.
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- 2022
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21. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.
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Waszak, Sebastian M, Northcott, Paul A, Buchhalter, Ivo, Robinson, Giles W, Sutter, Christian, Groebner, Susanne, Grund, Kerstin B, Brugières, Laurence, Jones, David TW, Pajtler, Kristian W, Morrissy, A Sorana, Kool, Marcel, Sturm, Dominik, Chavez, Lukas, Ernst, Aurelie, Brabetz, Sebastian, Hain, Michael, Zichner, Thomas, Segura-Wang, Maia, Weischenfeldt, Joachim, Rausch, Tobias, Mardin, Balca R, Zhou, Xin, Baciu, Cristina, Lawerenz, Christian, Chan, Jennifer A, Varlet, Pascale, Guerrini-Rousseau, Lea, Fults, Daniel W, Grajkowska, Wiesława, Hauser, Peter, Jabado, Nada, Ra, Young-Shin, Zitterbart, Karel, Shringarpure, Suyash S, De La Vega, Francisco M, Bustamante, Carlos D, Ng, Ho-Keung, Perry, Arie, MacDonald, Tobey J, Hernáiz Driever, Pablo, Bendel, Anne E, Bowers, Daniel C, McCowage, Geoffrey, Chintagumpala, Murali M, Cohn, Richard, Hassall, Timothy, Fleischhack, Gudrun, Eggen, Tone, Wesenberg, Finn, Feychting, Maria, Lannering, Birgitta, Schüz, Joachim, Johansen, Christoffer, Andersen, Tina V, Röösli, Martin, Kuehni, Claudia E, Grotzer, Michael, Kjaerheim, Kristina, Monoranu, Camelia M, Archer, Tenley C, Duke, Elizabeth, Pomeroy, Scott L, Shelagh, Redmond, Frank, Stephan, Sumerauer, David, Scheurlen, Wolfram, Ryzhova, Marina V, Milde, Till, Kratz, Christian P, Samuel, David, Zhang, Jinghui, Solomon, David A, Marra, Marco, Eils, Roland, Bartram, Claus R, von Hoff, Katja, Rutkowski, Stefan, Ramaswamy, Vijay, Gilbertson, Richard J, Korshunov, Andrey, Taylor, Michael D, Lichter, Peter, Malkin, David, Gajjar, Amar, Korbel, Jan O, and Pfister, Stefan M
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Humans ,Medulloblastoma ,Cerebellar Neoplasms ,Genetic Predisposition to Disease ,Risk Factors ,Retrospective Studies ,Prospective Studies ,Reproducibility of Results ,Predictive Value of Tests ,Gene Expression Profiling ,Pedigree ,DNA Mutational Analysis ,DNA Methylation ,Heredity ,Phenotype ,Germ-Line Mutation ,Models ,Genetic ,Adolescent ,Adult ,Child ,Child ,Preschool ,Infant ,Female ,Male ,Young Adult ,Genetic Testing ,Transcriptome ,Biomarkers ,Tumor ,Progression-Free Survival ,Exome Sequencing ,Brain Cancer ,Genetics ,Cancer ,Human Genome ,Pediatric ,Pediatric Cancer ,Rare Diseases ,Brain Disorders ,Aetiology ,2.1 Biological and endogenous factors ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundMedulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.MethodsIn this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma.FindingsWe included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.InterpretationGenetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.FundingGerman Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.
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- 2018
22. Everolimus for Children With Recurrent or Progressive Low-Grade Glioma: Results From the Phase II PNOC001 Trial
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Haas-Kogan, Daphne A., primary, Aboian, Mariam S., additional, Minturn, Jane E., additional, Leary, Sarah E.S., additional, Abdelbaki, Mohamed S., additional, Goldman, Stewart, additional, Elster, Jennifer D., additional, Kraya, Adam, additional, Lueder, Matthew R., additional, Ramakrishnan, Divya, additional, von Reppert, Marc, additional, Liu, Kevin X., additional, Rokita, Jo Lynne, additional, Resnick, Adam C., additional, Solomon, David A., additional, Phillips, Joanna J., additional, Prados, Michael, additional, Molinaro, Annette M., additional, Waszak, Sebastian M., additional, and Mueller, Sabine, additional
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- 2024
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23. Publisher Correction: Butler enables rapid cloud-based analysis of thousands of human genomes
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Yakneen, Sergei, Waszak, Sebastian M., Gertz, Michael, and Korbel, Jan O.
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- 2023
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24. Author Correction: Butler enables rapid cloud-based analysis of thousands of human genomes
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Yakneen, Sergei, Waszak, Sebastian M., Gertz, Michael, and Korbel, Jan O.
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- 2023
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25. Author Correction: Genomic basis for RNA alterations in cancer
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Calabrese, Claudia, Davidson, Natalie R., Demircioğlu, Deniz, Fonseca, Nuno A., He, Yao, Kahles, André, Lehmann, Kjong-Van, Liu, Fenglin, Shiraishi, Yuichi, Soulette, Cameron M., Urban, Lara, Greger, Liliana, Li, Siliang, Liu, Dongbing, Perry, Marc D., Xiang, Qian, Zhang, Fan, Zhang, Junjun, Bailey, Peter, Erkek, Serap, Hoadley, Katherine A., Hou, Yong, Huska, Matthew R., Kilpinen, Helena, Korbel, Jan O., Marin, Maximillian G., Markowski, Julia, Nandi, Tannistha, Pan-Hammarström, Qiang, Pedamallu, Chandra Sekhar, Siebert, Reiner, Stark, Stefan G., Su, Hong, Tan, Patrick, Waszak, Sebastian M., Yung, Christina, Zhu, Shida, Awadalla, Philip, Creighton, Chad J., Meyerson, Matthew, Ouellette, B. F. Francis, Wu, Kui, Yang, Huanming, Brazma, Alvis, Brooks, Angela N., Göke, Jonathan, Rätsch, Gunnar, Schwarz, Roland F., Stegle, Oliver, and Zhang, Zemin
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- 2023
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26. The whole-genome landscape of medulloblastoma subtypes
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Northcott, Paul A, Buchhalter, Ivo, Morrissy, A Sorana, Hovestadt, Volker, Weischenfeldt, Joachim, Ehrenberger, Tobias, Gröbner, Susanne, Segura-Wang, Maia, Zichner, Thomas, Rudneva, Vasilisa A, Warnatz, Hans-Jörg, Sidiropoulos, Nikos, Phillips, Aaron H, Schumacher, Steven, Kleinheinz, Kortine, Waszak, Sebastian M, Erkek, Serap, Jones, David TW, Worst, Barbara C, Kool, Marcel, Zapatka, Marc, Jäger, Natalie, Chavez, Lukas, Hutter, Barbara, Bieg, Matthias, Paramasivam, Nagarajan, Heinold, Michael, Gu, Zuguang, Ishaque, Naveed, Jäger-Schmidt, Christina, Imbusch, Charles D, Jugold, Alke, Hübschmann, Daniel, Risch, Thomas, Amstislavskiy, Vyacheslav, Gonzalez, Francisco German Rodriguez, Weber, Ursula D, Wolf, Stephan, Robinson, Giles W, Zhou, Xin, Wu, Gang, Finkelstein, David, Liu, Yanling, Cavalli, Florence MG, Luu, Betty, Ramaswamy, Vijay, Wu, Xiaochong, Koster, Jan, Ryzhova, Marina, Cho, Yoon-Jae, Pomeroy, Scott L, Herold-Mende, Christel, Schuhmann, Martin, Ebinger, Martin, Liau, Linda M, Mora, Jaume, McLendon, Roger E, Jabado, Nada, Kumabe, Toshihiro, Chuah, Eric, Ma, Yussanne, Moore, Richard A, Mungall, Andrew J, Mungall, Karen L, Thiessen, Nina, Tse, Kane, Wong, Tina, Jones, Steven JM, Witt, Olaf, Milde, Till, Von Deimling, Andreas, Capper, David, Korshunov, Andrey, Yaspo, Marie-Laure, Kriwacki, Richard, Gajjar, Amar, Zhang, Jinghui, Beroukhim, Rameen, Fraenkel, Ernest, Korbel, Jan O, Brors, Benedikt, Schlesner, Matthias, Eils, Roland, Marra, Marco A, Pfister, Stefan M, Taylor, Michael D, and Lichter, Peter
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Cancer ,Human Genome ,Brain Disorders ,Pediatric Cancer ,Brain Cancer ,Genetics ,Biotechnology ,Rare Diseases ,Neurosciences ,Pediatric ,Aetiology ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Carcinogenesis ,Carrier Proteins ,Cohort Studies ,DNA Methylation ,DNA Mutational Analysis ,Datasets as Topic ,Epistasis ,Genetic ,Genome ,Human ,Genomics ,Humans ,Medulloblastoma ,Molecular Targeted Therapy ,Muscle Proteins ,Mutation ,Oncogenes ,Transcription Factors ,Whole Genome Sequencing ,Wnt Proteins ,General Science & Technology - Abstract
Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analysed cases, and identify subgroup-specific driver alterations that include previously undiscovered actionable targets. Driver mutations were confidently assigned to most patients belonging to Group 3 and Group 4 medulloblastoma subgroups, greatly enhancing previous knowledge. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and 'enhancer hijacking' events that activate PRDM6. Thus, the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.
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- 2017
27. Mutational mechanisms shaping the coding and noncoding genome of germinal center derived B-cell lymphomas
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Hübschmann, Daniel, Kleinheinz, Kortine, Wagener, Rabea, Bernhart, Stephan H., López, Cristina, Toprak, Umut H., Sungalee, Stephanie, Ishaque, Naveed, Kretzmer, Helene, Kreuz, Markus, Waszak, Sebastian M., Paramasivam, Nagarajan, Ammerpohl, Ole, Aukema, Sietse M., Beekman, Renée, Bergmann, Anke K., Bieg, Matthias, Binder, Hans, Borkhardt, Arndt, Borst, Christoph, Brors, Benedikt, Bruns, Philipp, Carrillo de Santa Pau, Enrique, Claviez, Alexander, Doose, Gero, Haake, Andrea, Karsch, Dennis, Haas, Siegfried, Hansmann, Martin-Leo, Hoell, Jessica I., Hovestadt, Volker, Huang, Bingding, Hummel, Michael, Jäger-Schmidt, Christina, Kerssemakers, Jules N. A., Korbel, Jan O., Kube, Dieter, Lawerenz, Chris, Lenze, Dido, Martens, Joost H. A., Ott, German, Radlwimmer, Bernhard, Reisinger, Eva, Richter, Julia, Rico, Daniel, Rosenstiel, Philip, Rosenwald, Andreas, Schillhabel, Markus, Stilgenbauer, Stephan, Stadler, Peter F., Martín-Subero, José I., Szczepanowski, Monika, Warsow, Gregor, Weniger, Marc A., Zapatka, Marc, Valencia, Alfonso, Stunnenberg, Hendrik G., Lichter, Peter, Möller, Peter, Loeffler, Markus, Eils, Roland, Klapper, Wolfram, Hoffmann, Steve, Trümper, Lorenz, Küppers, Ralf, Schlesner, Matthias, and Siebert, Reiner
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- 2021
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28. Genomic basis for RNA alterations in cancer.
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Claudia Calabrese, Natalie R. Davidson, Deniz Demircioglu, Nuno A. Fonseca, Yao He, André Kahles, Kjong-Van Lehmann, Fenglin Liu, Yuichi Shiraishi, Cameron M. Soulette, Lara Urban, Liliana Greger, Siliang Li, Dongbing Liu, Marc D. Perry, Qian Xiang, Fan Zhang, Junjun Zhang, Peter Bailey, Serap Erkek, Katherine A. Hoadley, Yong Hou, Matthew R. Huska, Helena Kilpinen, Jan O. Korbel, Maximillian G. Marin, Julia Markowski, Tannistha Nandi, Qiang Pan-Hammarström, Chandra Sekhar Pedamallu, Reiner Siebert, Stefan G. Stark, Hong Su, Patrick Tan, Sebastian M. Waszak, Christina K. Yung, Shida Zhu, Philip Awadalla, Matthew Meyerson, B. F. Francis Ouellette, Kui Wu 0005, Huanming Yang, Samirkumar B. Amin, Aurélien Chateigner, Isidro Cortés-Ciriano, Brian Craft, Milana Frenkel-Morgenstern, Mary Goldman, Ekta Khurana, Fabien C. Lamaze, Chang Li, Xiaobo Li, Xinyue Li, Xingmin Liu, Morten Muhlig Nielsen, Akinyemi I. Ojesina, Peter J. Park, Jakob Skou Pedersen, Bin Tean Teh, Jian Wang 0065, Heng Xiong, Sergei Yakneen, Chen Ye, Xiuqing Zhang, Liangtao Zheng, Jingchun Zhu, Chad Creighton, Jonathan Göke, Roland F. Schwarz, Oliver Stegle, Zemin Zhang, Alvis Brazma, Gunnar Rätsch, and Angela N. Brooks
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- 2020
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29. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.
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Esther Rheinbay, Morten Muhlig Nielsen, Federico Abascal, Jeremiah Wala, Ofer Shapira, Grace Tiao, Henrik Hornshøj, Julian M. Hess, Randi Istrup Juul, Ziao Lin, Lars Feuerbach, Radhakrishnan Sabarinathan, Tobias Madsen, Jaegil Kim, Loris Mularoni, Shimin Shuai, Andrés Lanzós, Carl Herrmann, Yosef E. Maruvka, Ciyue Shen, Samirkumar B. Amin, Pratiti Bandopadhayay, Johanna Bertl, Keith A. Boroevich, John Busanovich, Joana Carlevaro-Fita, Dimple Chakravarty, Calvin Wing Yiu Chan, David Craft, Priyanka Dhingra, Klev Diamanti, Nuno A. Fonseca, Abel Gonzalez-Perez, Qianyun Guo, Mark P. Hamilton, Nicholas J. Haradhvala, Chen Hong, Keren Isaev, Todd A. Johnson, Malene Juul, André Kahles, Abdullah Kahraman, Youngwook Kim, Jan Komorowski, Kiran Kumar, Sushant Kumar, Donghoon Lee 0006, Kjong-Van Lehmann, Yilong Li, Eric Minwei Liu, Lucas Lochovsky, Keunchil Park, Oriol Pich, Nicola D. Roberts, Gordon Saksena, Steven E. Schumacher, Nikos Sidiropoulos, Lina Sieverling, Nasa Sinnott-Armstrong, Chip Stewart, David Tamborero, Jose M. C. Tubio, Husen M. Umer, Liis Uusküla-Reimand, Claes Wadelius, Lina Wadi, Xiaotong Yao, Cheng-Zhong Zhang, Jing Zhang 0062, James E. Haber, Asger Hobolth, Marcin Imielinski, Manolis Kellis, Michael S. Lawrence, Christian von Mering, Hidewaki Nakagawa, Benjamin J. Raphael, Mark A. Rubin, Chris Sander, Lincoln D. Stein, Joshua M. Stuart, Tatsuhiko Tsunoda, David A. Wheeler, Rory Johnson, Jüri Reimand, Mark Gerstein, Ekta Khurana, Peter J. Campbell, Núria López-Bigas, Gary D. Bader, Jonathan Barenboim, Rameen Beroukhim, Søren Brunak, Ken Chen, Jung Kyoon Choi, Jordi Deu-Pons, J. Lynn Fink, Joan Frigola, Carlo Gambacorti Passerini, Dale W. Garsed, Gad Getz, Ivo Glynne Gut, David Haan, Arif Ozgun Harmanci, Mohamed Helmy, Ermin Hodzic, José M. G. Izarzugaza, Jong K. Kim, Jan O. Korbel, Erik Larsson, Shantao Li, Xiaotong Li, Shaoke Lou, Kathleen Marchal, Iñigo Martincorena, Alexander Martínez-Fundichely, Patrick D. McGillivray, William Meyerson, Ferran Muiños, Marta Paczkowska, Kiejung Park, Jakob Skou Pedersen, Tirso Pons, Sergio Pulido-Tamayo, Iker Reyes-Salazar, Matthew A. Reyna, Carlota Rubio-Perez, Süleyman Cenk Sahinalp, Leonidas Salichos, Mark Shackleton, Raunak Shrestha, Alfonso Valencia, Miguel Vazquez, Lieven P. C. Verbeke, Jiayin Wang, Jonathan Warrell, Sebastian M. Waszak, Joachim Weischenfeldt, Guanming Wu, Jun Yu, Xuanping Zhang, Yan Zhang 0032, Zhongming Zhao, Lihua Zou, Kadir C. Akdemir, Eva G. Alvarez, Adrian Baez-Ortega, Paul C. Boutros, David D. L. Bowtell, Benedikt Brors, Kathleen H. Burns, Kin Chan, Isidro Cortés-Ciriano, Ana Dueso-Barroso, Andrew J. Dunford, Paul A. Edwards, Xavier Estivill, Dariush Etemadmoghadam, Milana Frenkel-Morgenstern, Dmitry A. Gordenin, Barbara Hutter, David T. W. Jones, Young Seok Ju, Marat D. Kazanov, Leszek J. Klimczak, Youngil Koh, Eunjung Alice Lee, Jake June-Koo Lee, Andy G. Lynch, Geoff MacIntyre, Florian Markowetz, Matthew Meyerson, Satoru Miyano, Fabio C. P. Navarro, Stephan Ossowski, Peter J. Park, John V. Pearson, Montserrat Puiggròs, Karsten Rippe, Steven A. Roberts, Bernardo Rodriguez-Martin, Ralph Scully, David Torrents, Izar Villasante, Nicola Waddell, Jeremiah A. Wala, Lixing Yang, Sung-Soo Yoon, and Jorge Zamora
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- 2020
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30. Rational combination platform trial design for children and young adults with Diffuse Midline Glioma: a report from PNOC
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Mueller, Sabine, primary, Kline, Cassie, additional, Franson, Andrea, additional, van der Lugt, Jasper, additional, Prados, Michael, additional, Waszak, Sebastian M, additional, Plasschaert, Sabine, additional, Molinaro, Annette M, additional, Koschmann, Carl, additional, and Nazarian, Javad, additional
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- 2023
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31. Table S4 from Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
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Venneti, Sriram, primary, Kawakibi, Abed Rahman, primary, Ji, Sunjong, primary, Waszak, Sebastian M., primary, Sweha, Stefan R., primary, Mota, Mateus, primary, Pun, Matthew, primary, Deogharkar, Akash, primary, Chung, Chan, primary, Tarapore, Rohinton S., primary, Ramage, Samuel, primary, Chi, Andrew, primary, Wen, Patrick Y., primary, Arrillaga-Romany, Isabel, primary, Batchelor, Tracy T., primary, Butowski, Nicholas A., primary, Sumrall, Ashley, primary, Shonka, Nicole, primary, Harrison, Rebecca A., primary, de Groot, John, primary, Mehta, Minesh, primary, Hall, Matthew D., primary, Daghistani, Doured, primary, Cloughesy, Timothy F., primary, Ellingson, Benjamin M., primary, Beccaria, Kevin, primary, Varlet, Pascale, primary, Kim, Michelle M., primary, Umemura, Yoshie, primary, Garton, Hugh, primary, Franson, Andrea, primary, Schwartz, Jonathan, primary, Jain, Rajan, primary, Kachman, Maureen, primary, Baum, Heidi, primary, Burant, Charles F., primary, Mottl, Sophie L., primary, Cartaxo, Rodrigo T., primary, John, Vishal, primary, Messinger, Dana, primary, Qin, Tingting, primary, Peterson, Erik, primary, Sajjakulnukit, Peter, primary, Ravi, Karthik, primary, Waugh, Alyssa, primary, Walling, Dustin, primary, Ding, Yujie, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Hawes, Debra, primary, Yang, Fusheng, primary, Judkins, Alexander R., primary, Wahl, Daniel, primary, Lyssiotis, Costas A., primary, de la Nava, Daniel, primary, Alonso, Marta M., primary, Eze, Augustine, primary, Spitzer, Jasper, primary, Schmidt, Susanne V., primary, Duchatel, Ryan J., primary, Dun, Matthew D., primary, Cain, Jason E., primary, Jiang, Li, primary, Stopka, Sylwia A., primary, Baquer, Gerard, primary, Regan, Michael S., primary, Filbin, Mariella G., primary, Agar, Nathalie Y.R., primary, Zhao, Lili, primary, Kumar-Sinha, Chandan, primary, Mody, Rajen, primary, Chinnaiyan, Arul, primary, Kurokawa, Ryo, primary, Pratt, Drew, primary, Yadav, Viveka N., primary, Grill, Jacques, primary, Kline, Cassie, primary, Mueller, Sabine, primary, Resnick, Adam, primary, Nazarian, Javad, primary, Allen, Joshua E., primary, Odia, Yazmin, primary, Gardner, Sharon L., primary, and Koschmann, Carl, primary
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- 2023
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32. Supplementary Figures 1-15 from Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
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Venneti, Sriram, primary, Kawakibi, Abed Rahman, primary, Ji, Sunjong, primary, Waszak, Sebastian M., primary, Sweha, Stefan R., primary, Mota, Mateus, primary, Pun, Matthew, primary, Deogharkar, Akash, primary, Chung, Chan, primary, Tarapore, Rohinton S., primary, Ramage, Samuel, primary, Chi, Andrew, primary, Wen, Patrick Y., primary, Arrillaga-Romany, Isabel, primary, Batchelor, Tracy T., primary, Butowski, Nicholas A., primary, Sumrall, Ashley, primary, Shonka, Nicole, primary, Harrison, Rebecca A., primary, de Groot, John, primary, Mehta, Minesh, primary, Hall, Matthew D., primary, Daghistani, Doured, primary, Cloughesy, Timothy F., primary, Ellingson, Benjamin M., primary, Beccaria, Kevin, primary, Varlet, Pascale, primary, Kim, Michelle M., primary, Umemura, Yoshie, primary, Garton, Hugh, primary, Franson, Andrea, primary, Schwartz, Jonathan, primary, Jain, Rajan, primary, Kachman, Maureen, primary, Baum, Heidi, primary, Burant, Charles F., primary, Mottl, Sophie L., primary, Cartaxo, Rodrigo T., primary, John, Vishal, primary, Messinger, Dana, primary, Qin, Tingting, primary, Peterson, Erik, primary, Sajjakulnukit, Peter, primary, Ravi, Karthik, primary, Waugh, Alyssa, primary, Walling, Dustin, primary, Ding, Yujie, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Hawes, Debra, primary, Yang, Fusheng, primary, Judkins, Alexander R., primary, Wahl, Daniel, primary, Lyssiotis, Costas A., primary, de la Nava, Daniel, primary, Alonso, Marta M., primary, Eze, Augustine, primary, Spitzer, Jasper, primary, Schmidt, Susanne V., primary, Duchatel, Ryan J., primary, Dun, Matthew D., primary, Cain, Jason E., primary, Jiang, Li, primary, Stopka, Sylwia A., primary, Baquer, Gerard, primary, Regan, Michael S., primary, Filbin, Mariella G., primary, Agar, Nathalie Y.R., primary, Zhao, Lili, primary, Kumar-Sinha, Chandan, primary, Mody, Rajen, primary, Chinnaiyan, Arul, primary, Kurokawa, Ryo, primary, Pratt, Drew, primary, Yadav, Viveka N., primary, Grill, Jacques, primary, Kline, Cassie, primary, Mueller, Sabine, primary, Resnick, Adam, primary, Nazarian, Javad, primary, Allen, Joshua E., primary, Odia, Yazmin, primary, Gardner, Sharon L., primary, and Koschmann, Carl, primary
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- 2023
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33. Supplementary Data S2 from Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
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Venneti, Sriram, primary, Kawakibi, Abed Rahman, primary, Ji, Sunjong, primary, Waszak, Sebastian M., primary, Sweha, Stefan R., primary, Mota, Mateus, primary, Pun, Matthew, primary, Deogharkar, Akash, primary, Chung, Chan, primary, Tarapore, Rohinton S., primary, Ramage, Samuel, primary, Chi, Andrew, primary, Wen, Patrick Y., primary, Arrillaga-Romany, Isabel, primary, Batchelor, Tracy T., primary, Butowski, Nicholas A., primary, Sumrall, Ashley, primary, Shonka, Nicole, primary, Harrison, Rebecca A., primary, de Groot, John, primary, Mehta, Minesh, primary, Hall, Matthew D., primary, Daghistani, Doured, primary, Cloughesy, Timothy F., primary, Ellingson, Benjamin M., primary, Beccaria, Kevin, primary, Varlet, Pascale, primary, Kim, Michelle M., primary, Umemura, Yoshie, primary, Garton, Hugh, primary, Franson, Andrea, primary, Schwartz, Jonathan, primary, Jain, Rajan, primary, Kachman, Maureen, primary, Baum, Heidi, primary, Burant, Charles F., primary, Mottl, Sophie L., primary, Cartaxo, Rodrigo T., primary, John, Vishal, primary, Messinger, Dana, primary, Qin, Tingting, primary, Peterson, Erik, primary, Sajjakulnukit, Peter, primary, Ravi, Karthik, primary, Waugh, Alyssa, primary, Walling, Dustin, primary, Ding, Yujie, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Hawes, Debra, primary, Yang, Fusheng, primary, Judkins, Alexander R., primary, Wahl, Daniel, primary, Lyssiotis, Costas A., primary, de la Nava, Daniel, primary, Alonso, Marta M., primary, Eze, Augustine, primary, Spitzer, Jasper, primary, Schmidt, Susanne V., primary, Duchatel, Ryan J., primary, Dun, Matthew D., primary, Cain, Jason E., primary, Jiang, Li, primary, Stopka, Sylwia A., primary, Baquer, Gerard, primary, Regan, Michael S., primary, Filbin, Mariella G., primary, Agar, Nathalie Y.R., primary, Zhao, Lili, primary, Kumar-Sinha, Chandan, primary, Mody, Rajen, primary, Chinnaiyan, Arul, primary, Kurokawa, Ryo, primary, Pratt, Drew, primary, Yadav, Viveka N., primary, Grill, Jacques, primary, Kline, Cassie, primary, Mueller, Sabine, primary, Resnick, Adam, primary, Nazarian, Javad, primary, Allen, Joshua E., primary, Odia, Yazmin, primary, Gardner, Sharon L., primary, and Koschmann, Carl, primary
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- 2023
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34. Data from Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
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Venneti, Sriram, primary, Kawakibi, Abed Rahman, primary, Ji, Sunjong, primary, Waszak, Sebastian M., primary, Sweha, Stefan R., primary, Mota, Mateus, primary, Pun, Matthew, primary, Deogharkar, Akash, primary, Chung, Chan, primary, Tarapore, Rohinton S., primary, Ramage, Samuel, primary, Chi, Andrew, primary, Wen, Patrick Y., primary, Arrillaga-Romany, Isabel, primary, Batchelor, Tracy T., primary, Butowski, Nicholas A., primary, Sumrall, Ashley, primary, Shonka, Nicole, primary, Harrison, Rebecca A., primary, de Groot, John, primary, Mehta, Minesh, primary, Hall, Matthew D., primary, Daghistani, Doured, primary, Cloughesy, Timothy F., primary, Ellingson, Benjamin M., primary, Beccaria, Kevin, primary, Varlet, Pascale, primary, Kim, Michelle M., primary, Umemura, Yoshie, primary, Garton, Hugh, primary, Franson, Andrea, primary, Schwartz, Jonathan, primary, Jain, Rajan, primary, Kachman, Maureen, primary, Baum, Heidi, primary, Burant, Charles F., primary, Mottl, Sophie L., primary, Cartaxo, Rodrigo T., primary, John, Vishal, primary, Messinger, Dana, primary, Qin, Tingting, primary, Peterson, Erik, primary, Sajjakulnukit, Peter, primary, Ravi, Karthik, primary, Waugh, Alyssa, primary, Walling, Dustin, primary, Ding, Yujie, primary, Xia, Ziyun, primary, Schwendeman, Anna, primary, Hawes, Debra, primary, Yang, Fusheng, primary, Judkins, Alexander R., primary, Wahl, Daniel, primary, Lyssiotis, Costas A., primary, de la Nava, Daniel, primary, Alonso, Marta M., primary, Eze, Augustine, primary, Spitzer, Jasper, primary, Schmidt, Susanne V., primary, Duchatel, Ryan J., primary, Dun, Matthew D., primary, Cain, Jason E., primary, Jiang, Li, primary, Stopka, Sylwia A., primary, Baquer, Gerard, primary, Regan, Michael S., primary, Filbin, Mariella G., primary, Agar, Nathalie Y.R., primary, Zhao, Lili, primary, Kumar-Sinha, Chandan, primary, Mody, Rajen, primary, Chinnaiyan, Arul, primary, Kurokawa, Ryo, primary, Pratt, Drew, primary, Yadav, Viveka N., primary, Grill, Jacques, primary, Kline, Cassie, primary, Mueller, Sabine, primary, Resnick, Adam, primary, Nazarian, Javad, primary, Allen, Joshua E., primary, Odia, Yazmin, primary, Gardner, Sharon L., primary, and Koschmann, Carl, primary
- Published
- 2023
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35. Germline Elongator mutations in Sonic Hedgehog medulloblastoma
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Waszak, Sebastian M., Robinson, Giles W, Gudenas, Brian L., Smith, Kyle S., Forget, Antoine, Kojic, Marija, and Garcia-Lopez, Jesus
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Gene mutations -- Physiological aspects -- Genetic aspects ,Medulloblastoma -- Development and progression -- Genetic aspects -- Physiological aspects ,Translation elongation factors -- Genetic aspects -- Physiological aspects ,Tumors in children -- Development and progression -- Genetic aspects -- Physiological aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children.sup.1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma.sup.3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MB.sub.SHH).sub..ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MB.sub.SHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHH[alpha] subtype.sup.4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U.sub.34) position.sup.5,6. Tumours from patients with ELP1-associated MB.sub.SHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems.sup.7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference. Germline mutations in the Elongator complex gene ELP1 predispose individuals to the development of childhood medulloblastoma., Author(s): Sebastian M. Waszak [sup.1] , Giles W Robinson [sup.2] , Brian L. Gudenas [sup.3] , Kyle S. Smith [sup.3] , Antoine Forget [sup.4] , Marija Kojic [sup.5] , Jesus [...]
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- 2020
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36. The molecular landscape of ETMR at diagnosis and relapse
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Lambo, Sander, Gröbner, Susanne N., Rausch, Tobias, Waszak, Sebastian M., Schmidt, Christin, Gorthi, Aparna, and Romero, July Carolina
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Molecular genetics -- Analysis ,Tumors, Embryonal -- Identification and classification -- Diagnosis -- Genetic aspects ,Cancer -- Relapse ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis.sup.1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC.sup.2-4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease. Analyses of primary and relapse samples of embryonal tumours with multilayered rosettes provide insights into the molecular mechanisms that underlie the development and opportunities for the treatment of this deadly disease., Author(s): Sander Lambo [sup.1] [sup.2] [sup.3] , Susanne N. Gröbner [sup.1] [sup.2] [sup.3] , Tobias Rausch [sup.4] , Sebastian M. Waszak [sup.4] , Christin Schmidt [sup.1] [sup.2] [sup.3] , Aparna [...]
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- 2019
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37. Genomic basis for RNA alterations in cancer
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Calabrese, Claudia, Davidson, Natalie R., Demircioğlu, Deniz, Fonseca, Nuno A., He, Yao, Kahles, André, Lehmann, Kjong-Van, Liu, Fenglin, Shiraishi, Yuichi, Soulette, Cameron M., Urban, Lara, Greger, Liliana, Li, Siliang, Liu, Dongbing, Perry, Marc D., Xiang, Qian, Zhang, Fan, Zhang, Junjun, Bailey, Peter, Erkek, Serap, Hoadley, Katherine A., Hou, Yong, Huska, Matthew R., Kilpinen, Helena, Korbel, Jan O., Marin, Maximillian G., Markowski, Julia, Nandi, Tannistha, Pan-Hammarström, Qiang, Pedamallu, Chandra Sekhar, Siebert, Reiner, Stark, Stefan G., Su, Hong, Tan, Patrick, Waszak, Sebastian M., Yung, Christina, Zhu, Shida, Awadalla, Philip, Creighton, Chad J., Meyerson, Matthew, Ouellette, B. F. Francis, Wu, Kui, Yang, Huanming, Brazma, Alvis, Brooks, Angela N., Göke, Jonathan, Rätsch, Gunnar, Schwarz, Roland F., Stegle, Oliver, and Zhang, Zemin
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- 2020
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38. ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma
- Author
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Evangeline R. Jackson, Ryan J. Duchatel, Dilana E. Staudt, Mika L. Persson, Abdul Mannan, Sridevi Yadavilli, Sarah Parackal, Shaye Game, Wai Chin Chong, W. Samantha N. Jayasekara, Marion Le Grand, Padraic S. Kearney, Alicia M. Douglas, Izac J. Findlay, Zacary P. Germon, Holly P. McEwen, Tyrone S. Beitaki, Adjanie Patabendige, David A. Skerrett-Byrne, Brett Nixon, Nathan D. Smith, Bryan Day, Neevika Manoharan, Sumanth Nagabushan, Jordan R. Hansford, Dinisha Govender, Geoff B. McCowage, Ron Firestein, Meegan Howlett, Raelene Endersby, Nicholas G. Gottardo, Frank Alvaro, Sebastian M. Waszak, Martin R. Larsen, Yolanda Colino-Sanguino, Fatima Valdes-Mora, Andria Rakotomalala, Samuel Meignan, Eddy Pasquier, Nicolas André, Esther Hulleman, David D. Eisenstat, Nicholas A. Vitanza, Javad Nazarian, Carl Koschmann, Sabine Mueller, Jason E. Cain, and Matthew D. Dun
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Cancer Research ,Oncology - Abstract
Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA mutations showed increased sensitivity to ONC201, whereas those harboring TP53 mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992. Significance: PI3K/Akt signaling promotes metabolic adaptation to ONC201-mediated disruption of mitochondrial energy homeostasis in diffuse intrinsic pontine glioma, highlighting the utility of a combination treatment strategy using ONC201 and the PI3K/Akt inhibitor paxalisib.
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- 2023
39. Rational combination platform trial design for children and young adults with diffuse midline glioma: A report from PNOC.
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Mueller, Sabine, Kline, Cassie, Franson, Andrea, van der Lugt, Jasper, Prados, Michael, Waszak, Sebastian M, Plasschaert, Sabine L A, Molinaro, Annette M, Koschmann, Carl, and Nazarian, Javad
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- 2024
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40. Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
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Venneti, Sriram, primary, Kawakibi, Abed Rahman, additional, Ji, Sunjong, additional, Waszak, Sebastian M., additional, Sweha, Stefan R., additional, Mota, Mateus, additional, Pun, Matthew, additional, Deogharkar, Akash, additional, Chung, Chan, additional, Tarapore, Rohinton S., additional, Ramage, Samuel, additional, Chi, Andrew, additional, Wen, Patrick Y., additional, Arrillaga-Romany, Isabel, additional, Batchelor, Tracy T., additional, Butowski, Nicholas A., additional, Sumrall, Ashley, additional, Shonka, Nicole, additional, Harrison, Rebecca A., additional, de Groot, John, additional, Mehta, Minesh, additional, Hall, Matthew D., additional, Daghistani, Doured, additional, Cloughesy, Timothy F., additional, Ellingson, Benjamin M., additional, Beccaria, Kevin, additional, Varlet, Pascale, additional, Kim, Michelle M., additional, Umemura, Yoshie, additional, Garton, Hugh, additional, Franson, Andrea, additional, Schwartz, Jonathan, additional, Jain, Rajan, additional, Kachman, Maureen, additional, Baum, Heidi, additional, Burant, Charles F., additional, Mottl, Sophie L., additional, Cartaxo, Rodrigo T., additional, John, Vishal, additional, Messinger, Dana, additional, Qin, Tingting, additional, Peterson, Erik, additional, Sajjakulnukit, Peter, additional, Ravi, Karthik, additional, Waugh, Alyssa, additional, Walling, Dustin, additional, Ding, Yujie, additional, Xia, Ziyun, additional, Schwendeman, Anna, additional, Hawes, Debra, additional, Yang, Fusheng, additional, Judkins, Alexander R., additional, Wahl, Daniel, additional, Lyssiotis, Costas A., additional, de la Nava, Daniel, additional, Alonso, Marta M., additional, Eze, Augustine, additional, Spitzer, Jasper, additional, Schmidt, Susanne V., additional, Duchatel, Ryan J., additional, Dun, Matthew D., additional, Cain, Jason E., additional, Jiang, Li, additional, Stopka, Sylwia A., additional, Baquer, Gerard, additional, Regan, Michael S., additional, Filbin, Mariella G., additional, Agar, Nathalie Y.R., additional, Zhao, Lili, additional, Kumar-Sinha, Chandan, additional, Mody, Rajen, additional, Chinnaiyan, Arul, additional, Kurokawa, Ryo, additional, Pratt, Drew, additional, Yadav, Viveka N., additional, Grill, Jacques, additional, Kline, Cassie, additional, Mueller, Sabine, additional, Resnick, Adam, additional, Nazarian, Javad, additional, Allen, Joshua E., additional, Odia, Yazmin, additional, Gardner, Sharon L., additional, and Koschmann, Carl, additional
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- 2023
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41. Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma
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Cristina López, Kortine Kleinheinz, Sietse M. Aukema, Marius Rohde, Stephan H. Bernhart, Daniel Hübschmann, Rabea Wagener, Umut H. Toprak, Francesco Raimondi, Markus Kreuz, Sebastian M. Waszak, Zhiqin Huang, Lina Sieverling, Nagarajan Paramasivam, Julian Seufert, Stephanie Sungalee, Robert B. Russell, Julia Bausinger, Helene Kretzmer, Ole Ammerpohl, Anke K. Bergmann, Hans Binder, Arndt Borkhardt, Benedikt Brors, Alexander Claviez, Gero Doose, Lars Feuerbach, Andrea Haake, Martin-Leo Hansmann, Jessica Hoell, Michael Hummel, Jan O. Korbel, Chris Lawerenz, Dido Lenze, Bernhard Radlwimmer, Julia Richter, Philip Rosenstiel, Andreas Rosenwald, Markus B. Schilhabel, Harald Stein, Stephan Stilgenbauer, Peter F. Stadler, Monika Szczepanowski, Marc A. Weniger, Marc Zapatka, Roland Eils, Peter Lichter, Markus Loeffler, Peter Möller, Lorenz Trümper, Wolfram Klapper, ICGC MMML-Seq Consortium, Steve Hoffmann, Ralf Küppers, Birgit Burkhardt, Matthias Schlesner, and Reiner Siebert
- Subjects
Science - Abstract
Burkitt lymphoma (BL) is the most common pediatric B-cell lymphoma. Here, within the International Cancer Genome Consortium, the authors performed whole genome and transcriptome sequencing of 39 sporadic BL, describing the landscape of mutations, structural variants, and mutational processes that underpin this disease how alterations on different cellular levels cooperate in deregulating key pathways and complexes.
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- 2019
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42. Versatile workflow for cell type–resolved transcriptional and epigenetic profiles from cryopreserved human lung
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Maria Llamazares-Prada, Elisa Espinet, Vedrana Mijošek, Uwe Schwartz, Pavlo Lutsik, Raluca Tamas, Mandy Richter, Annika Behrendt, Stephanie T. Pohl, Naja P. Benz, Thomas Muley, Arne Warth, Claus Peter Heußel, Hauke Winter, Jonathan J. M. Landry, Felix J.F. Herth, Tinne C.J. Mertens, Harry Karmouty-Quintana, Ina Koch, Vladimir Benes, Jan O. Korbel, Sebastian M. Waszak, Andreas Trumpp, David M. Wyatt, Heiko F. Stahl, Christoph Plass, and Renata Z. Jurkowska
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Pulmonology ,Medicine - Abstract
Complexity of lung microenvironment and changes in cellular composition during disease make it exceptionally hard to understand molecular mechanisms driving development of chronic lung diseases. Although recent advances in cell type–resolved approaches hold great promise for studying complex diseases, their implementation relies on local access to fresh tissue, as traditional tissue storage methods do not allow viable cell isolation. To overcome these hurdles, we developed a versatile workflow that allows storage of lung tissue with high viability, permits thorough sample quality check before cell isolation, and befits sequencing-based profiling. We demonstrate that cryopreservation enables isolation of multiple cell types from both healthy and diseased lungs. Basal cells from cryopreserved airways retain their differentiation ability, indicating that cellular identity is not altered by cryopreservation. Importantly, using RNA sequencing and EPIC Array, we show that gene expression and DNA methylation signatures are preserved upon cryopreservation, emphasizing the suitability of our workflow for omics profiling of lung cells. Moreover, we obtained high-quality single-cell RNA-sequencing data of cells from cryopreserved human lungs, demonstrating that cryopreservation empowers single-cell approaches. Overall, thanks to its simplicity, our workflow is well suited for prospective tissue collection by academic collaborators and biobanks, opening worldwide access to viable human tissue.
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- 2021
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43. A polygenic two-hit hypothesis for prostate cancer
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Kathleen E Houlahan, Julie Livingstone, Natalie S Fox, Natalie Kurganovs, Helen Zhu, Jocelyn Sietsma Penington, Chol-Hee Jung, Takafumi N Yamaguchi, Lawrence E Heisler, Richard Jovelin, Anthony J Costello, Bernard J Pope, Amar U Kishan, Niall M Corcoran, Robert G Bristow, Sebastian M Waszak, Joachim Weischenfeldt, Housheng H He, Rayjean J Hung, Christopher M Hovens, and Paul C Boutros
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Cancer Research ,Oncology - Abstract
Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic “two-hit” model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.
- Published
- 2023
44. Chromatin accessibility landscape of pediatric T‐lymphoblastic leukemia and human T‐cell precursors
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Büşra Erarslan‐Uysal, Joachim B Kunz, Tobias Rausch, Paulina Richter‐Pechańska, Ianthe AEM vanBelzen, Viktoras Frismantas, Beat Bornhauser, Diana Ordoñez‐Rueada, Malte Paulsen, Vladimir Benes, Martin Stanulla, Martin Schrappe, Gunnar Cario, Gabriele Escherich, Kseniya Bakharevich, Renate Kirschner‐Schwabe, Cornelia Eckert, Tsvetomir Loukanov, Matthias Gorenflo, Sebastian M Waszak, Jean‐Pierre Bourquin, Martina U Muckenthaler, Jan O Korbel, and Andreas E Kulozik
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ATAC‐Seq ,chromatin accessibility ,T‐cell development ,T‐cell leukemia ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract We aimed at identifying the developmental stage at which leukemic cells of pediatric T‐ALLs are arrested and at defining leukemogenic mechanisms based on ATAC‐Seq. Chromatin accessibility maps of seven developmental stages of human healthy T cells revealed progressive chromatin condensation during T‐cell maturation. Developmental stages were distinguished by 2,823 signature chromatin regions with 95% accuracy. Open chromatin surrounding SAE1 was identified to best distinguish thymic developmental stages suggesting a potential role of SUMOylation in T‐cell development. Deconvolution using signature regions revealed that T‐ALLs, including those with mature immunophenotypes, resemble the most immature populations, which was confirmed by TF‐binding motif profiles. We integrated ATAC‐Seq and RNA‐Seq and found DAB1, a gene not related to leukemia previously, to be overexpressed, abnormally spliced and hyper‐accessible in T‐ALLs. DAB1‐negative patients formed a distinct subgroup with particularly immature chromatin profiles and hyper‐accessible binding sites for SPI1 (PU.1), a TF crucial for normal T‐cell maturation. In conclusion, our analyses of chromatin accessibility and TF‐binding motifs showed that pediatric T‐ALL cells are most similar to immature thymic precursors, indicating an early developmental arrest.
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- 2020
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45. Genome-wide Screens Implicate Loss of Cullin Ring Ligase 3 in Persistent Proliferation and Genome Instability in TP53-Deficient Cells
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Alexandros P. Drainas, Ruxandra A. Lambuta, Irina Ivanova, Özdemirhan Serçin, Ioannis Sarropoulos, Mike L. Smith, Theocharis Efthymiopoulos, Benjamin Raeder, Adrian M. Stütz, Sebastian M. Waszak, Balca R. Mardin, and Jan O. Korbel
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Summary: TP53 deficiency is the most common alteration in cancer; however, this alone is typically insufficient to drive tumorigenesis. To identify genes promoting tumorigenesis in combination with TP53 deficiency, we perform genome-wide CRISPR-Cas9 knockout screens coupled with proliferation and transformation assays in isogenic cell lines. Loss of several known tumor suppressors enhances cellular proliferation and transformation. Loss of neddylation pathway genes promotes uncontrolled proliferation exclusively in TP53-deficient cells. Combined loss of CUL3 and TP53 activates an oncogenic transcriptional program governed by the nuclear factor κB (NF-κB), AP-1, and transforming growth factor β (TGF-β) pathways. This program maintains persistent cellular proliferation, induces partial epithelial to mesenchymal transition, and increases DNA damage, genomic instability, and chromosomal rearrangements. Our findings reveal CUL3 loss as a key event stimulating persistent proliferation in TP53-deficient cells. These findings may be clinically relevant, since TP53-CUL3-deficient cells are highly sensitive to ataxia telangiectasia mutated (ATM) inhibition, exposing a vulnerability that could be exploited for cancer treatment. : Drainas et al. show that inactivation of genes in the neddylation pathway increases persistent proliferation in TP53-deficient cells. TP53- and CUL3-deficient cells induce an oncogenic transcriptional program, leading to partial EMT and heightened genomic instability. These cells show increased vulnerability to ATM inhibitors. Keywords: CUL3, neddylation, tumor suppressor, CRISPR screen, TP53, genome instability, ATM inhibitor, EMT
- Published
- 2020
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46. Supplementary Data from ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma
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Jackson, Evangeline R., primary, Duchatel, Ryan J., primary, Staudt, Dilana E., primary, Persson, Mika L., primary, Mannan, Abdul, primary, Yadavilli, Sridevi, primary, Parackal, Sarah, primary, Game, Shaye, primary, Chong, Wai Chin, primary, Jayasekara, W. Samantha N., primary, Grand, Marion Le, primary, Kearney, Padraic S., primary, Douglas, Alicia M., primary, Findlay, Izac J., primary, Germon, Zacary P., primary, McEwen, Holly P., primary, Beitaki, Tyrone S., primary, Patabendige, Adjanie, primary, Skerrett-Byrne, David A., primary, Nixon, Brett, primary, Smith, Nathan D., primary, Day, Bryan, primary, Manoharan, Neevika, primary, Nagabushan, Sumanth, primary, Hansford, Jordan R., primary, Govender, Dinisha, primary, McCowage, Geoff B., primary, Firestein, Ron, primary, Howlett, Meegan, primary, Endersby, Raelene, primary, Gottardo, Nicholas G., primary, Alvaro, Frank, primary, Waszak, Sebastian M., primary, Larsen, Martin R., primary, Colino-Sanguino, Yolanda, primary, Valdes-Mora, Fatima, primary, Rakotomalala, Andria, primary, Meignan, Samuel, primary, Pasquier, Eddy, primary, André, Nicolas, primary, Hulleman, Esther, primary, Eisenstat, David D., primary, Vitanza, Nicholas A., primary, Nazarian, Javad, primary, Koschmann, Carl, primary, Mueller, Sabine, primary, Cain, Jason E., primary, and Dun, Matthew D., primary
- Published
- 2023
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47. Data from ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma
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Jackson, Evangeline R., primary, Duchatel, Ryan J., primary, Staudt, Dilana E., primary, Persson, Mika L., primary, Mannan, Abdul, primary, Yadavilli, Sridevi, primary, Parackal, Sarah, primary, Game, Shaye, primary, Chong, Wai Chin, primary, Jayasekara, W. Samantha N., primary, Grand, Marion Le, primary, Kearney, Padraic S., primary, Douglas, Alicia M., primary, Findlay, Izac J., primary, Germon, Zacary P., primary, McEwen, Holly P., primary, Beitaki, Tyrone S., primary, Patabendige, Adjanie, primary, Skerrett-Byrne, David A., primary, Nixon, Brett, primary, Smith, Nathan D., primary, Day, Bryan, primary, Manoharan, Neevika, primary, Nagabushan, Sumanth, primary, Hansford, Jordan R., primary, Govender, Dinisha, primary, McCowage, Geoff B., primary, Firestein, Ron, primary, Howlett, Meegan, primary, Endersby, Raelene, primary, Gottardo, Nicholas G., primary, Alvaro, Frank, primary, Waszak, Sebastian M., primary, Larsen, Martin R., primary, Colino-Sanguino, Yolanda, primary, Valdes-Mora, Fatima, primary, Rakotomalala, Andria, primary, Meignan, Samuel, primary, Pasquier, Eddy, primary, André, Nicolas, primary, Hulleman, Esther, primary, Eisenstat, David D., primary, Vitanza, Nicholas A., primary, Nazarian, Javad, primary, Koschmann, Carl, primary, Mueller, Sabine, primary, Cain, Jason E., primary, and Dun, Matthew D., primary
- Published
- 2023
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48. Clinical outcome of pediatric medulloblastoma patients with Li–Fraumeni syndrome
- Author
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Kolodziejczak, Anna S, primary, Guerrini-Rousseau, Lea, additional, Planchon, Julien Masliah, additional, Ecker, Jonas, additional, Selt, Florian, additional, Mynarek, Martin, additional, Obrecht, Denise, additional, Sill, Martin, additional, Autry, Robert J, additional, Stutheit-Zhao, Eric, additional, Hirsch, Steffen, additional, Amouyal, Elsa, additional, Dufour, Christelle, additional, Ayrault, Olivier, additional, Torrejon, Jacob, additional, Waszak, Sebastian M, additional, Ramaswamy, Vijay, additional, Pentikainen, Virve, additional, Demir, Haci Ahmet, additional, Clifford, Steven C, additional, Schwalbe, Ed C, additional, Massimi, Luca, additional, Snuderl, Matija, additional, Galbraith, Kristyn, additional, Karajannis, Matthias A, additional, Hill, Katherine, additional, Li, Bryan K, additional, Walsh, Mike, additional, White, Christine L, additional, Redmond, Shelagh, additional, Loizos, Loizou, additional, Jakob, Marcus, additional, Kordes, Uwe R, additional, Schmid, Irene, additional, Hauer, Julia, additional, Blattmann, Claudia, additional, Filippidou, Maria, additional, Piccolo, Gianluca, additional, Scheurlen, Wolfram, additional, Farrag, Ahmed, additional, Grund, Kerstin, additional, Sutter, Christian, additional, Pietsch, Torsten, additional, Frank, Stephan, additional, Schewe, Denis M, additional, Malkin, David, additional, Ben-Arush, Myriam, additional, Sehested, Astrid, additional, Wong, Tai-Tong, additional, Wu, Kuo-Sheng, additional, Liu, Yen-Lin, additional, Carceller, Fernando, additional, Mueller, Sabine, additional, Stoller, Schuyler, additional, Taylor, Michael D, additional, Tabori, Uri, additional, Bouffet, Eric, additional, Kool, Marcel, additional, Sahm, Felix, additional, von Deimling, Andreas, additional, Korshunov, Andrey, additional, von Hoff, Katja, additional, Kratz, Christian P, additional, Sturm, Dominik, additional, Jones, David T W, additional, Rutkowski, Stefan, additional, van Tilburg, Cornelis M, additional, Witt, Olaf, additional, Bougeard, Gaëlle, additional, Pajtler, Kristian W, additional, Pfister, Stefan M, additional, Bourdeaut, Franck, additional, and Milde, Till, additional
- Published
- 2023
- Full Text
- View/download PDF
49. ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma
- Author
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Jackson, Evangeline R., primary, Duchatel, Ryan J., additional, Staudt, Dilana E., additional, Persson, Mika L., additional, Mannan, Abdul, additional, Yadavilli, Sridevi, additional, Parackal, Sarah, additional, Game, Shaye, additional, Chong, Wai Chin, additional, Jayasekara, W. Samantha N., additional, Grand, Marion Le, additional, Kearney, Padraic S., additional, Douglas, Alicia M., additional, Findlay, Izac J., additional, Germon, Zacary P., additional, McEwen, Holly P., additional, Beitaki, Tyrone S., additional, Patabendige, Adjanie, additional, Skerrett-Byrne, David A., additional, Nixon, Brett, additional, Smith, Nathan D., additional, Day, Bryan, additional, Manoharan, Neevika, additional, Nagabushan, Sumanth, additional, Hansford, Jordan R., additional, Govender, Dinisha, additional, McCowage, Geoff B., additional, Firestein, Ron, additional, Howlett, Meegan, additional, Endersby, Raelene, additional, Gottardo, Nicholas G., additional, Alvaro, Frank, additional, Waszak, Sebastian M., additional, Larsen, Martin R., additional, Colino-Sanguino, Yolanda, additional, Valdes-Mora, Fatima, additional, Rakotomalala, Andria, additional, Meignan, Samuel, additional, Pasquier, Eddy, additional, André, Nicolas, additional, Hulleman, Esther, additional, Eisenstat, David D., additional, Vitanza, Nicholas A., additional, Nazarian, Javad, additional, Koschmann, Carl, additional, Mueller, Sabine, additional, Cain, Jason E., additional, and Dun, Matthew D., additional
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- 2023
- Full Text
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50. Heterozygous BRCA1 and BRCA2 and Mismatch Repair Gene Pathogenic Variants in Children and Adolescents With Cancer
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Christian P Kratz, Dmitrii Smirnov, Robert Autry, Natalie Jäger, Sebastian M Waszak, Anika Großhennig, Riccardo Berutti, Mareike Wendorff, Pierre Hainaut, Stefan M Pfister, Holger Prokisch, Tim Ripperger, and David Malkin
- Subjects
Adult ,BRCA2 Protein ,Cancer Research ,Adolescent ,BRCA1 Protein ,Genes, BRCA2 ,Breast Neoplasms ,DNA Mismatch Repair ,Oncology ,Neoplasms ,Humans ,Female ,Genetic Predisposition to Disease ,Child ,Germ-Line Mutation - Abstract
Background Genetic predisposition is has been identified as a cause of cancer, yet little is known about the role of adult cancer predisposition syndromes in childhood cancer. We examined the extent to which heterozygous pathogenic germline variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, MSH2, MSH6, MLH1, and PMS2 contribute to cancer risk in children and adolescents. Methods We conducted a meta-analysis of 11 studies that incorporated comprehensive germline testing for children and adolescents with cancer. ClinVar pathogenic or likely pathogenic variants (PVs) in genes of interest were compared with 2 control groups. Results were validated in a cohort of mainly European patients and controls. We employed the Proxy External Controls Association Test to account for different pipelines. Results Among 3975 children and adolescents with cancer, statistically significant associations with cancer risk were observed for PVs in BRCA1 and 2 (26 PVs vs 63 PVs among 27 501 controls, odds ratio = 2.78, 95% confidence interval = 1.69 to 4.45; P < .001) and mismatch repair genes (19 PVs vs 14 PVs among 27 501 controls, odds ratio = 7.33, 95% confidence interval = 3.64 to 14.82; P Conclusion These data suggest that heterozygous PVs in BRCA1 and 2 and mismatch repair genes contribute with reduced penetrance to cancer risk in children and adolescents. No changes to predictive genetic testing and surveillance recommendations are required.
- Published
- 2022
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