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251. Supplementary Table 3 from Reversing HOXA9 Oncogene Activation by PI3K Inhibition: Epigenetic Mechanism and Prognostic Significance in Human Glioblastoma

Author

Costa, Bruno M., primary, Smith, Justin S., primary, Chen, Ying, primary, Chen, Justin, primary, Phillips, Heidi S., primary, Aldape, Kenneth D., primary, Zardo, Giuseppe, primary, Nigro, Janice, primary, James, C. David, primary, Fridlyand, Jane, primary, Reis, Rui M., primary, and Costello, Joseph F., primary

Published
2023
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252. Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature

Author

Sievers, Philipp, primary, Sill, Martin, additional, Schrimpf, Daniel, additional, Abdullaev, Zied, additional, Donson, Andrew M., additional, Lake, Jessica A., additional, Friedel, Dennis, additional, Scheie, David, additional, Tynninen, Olli, additional, Rauramaa, Tuomas, additional, Vepsäläinen, Kaisa L., additional, Samuel, David, additional, Chapman, Rebecca, additional, Grundy, Richard G., additional, Pajtler, Kristian W., additional, Tauziède-Espariat, Arnault, additional, Métais, Alice, additional, Varlet, Pascale, additional, Snuderl, Matija, additional, Jacques, Thomas S., additional, Aldape, Kenneth, additional, Reuss, David E., additional, Korshunov, Andrey, additional, Wick, Wolfgang, additional, Pfister, Stefan M., additional, von Deimling, Andreas, additional, Sahm, Felix, additional, and Jones, David T. W., additional

Published
2023
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253. Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions

Author

Bogumil, Henri, primary, Sill, Martin, additional, Schrimpf, Daniel, additional, Ismer, Britta, additional, Blume, Christina, additional, Rahmanzade, Ramin, additional, Hinz, Felix, additional, Cherkezov, Asan, additional, Banan, Rouzbeh, additional, Friedel, Dennis, additional, Reuss, David E., additional, Selt, Florian, additional, Ecker, Jonas, additional, Milde, Till, additional, Pajtler, Kristian W., additional, Schittenhelm, Jens, additional, Hench, Jürgen, additional, Frank, Stephan, additional, Boldt, Henning B., additional, Kristensen, Bjarne Winther, additional, Scheie, David, additional, Melchior, Linea C., additional, Olesen, Viola, additional, Sehested, Astrid, additional, Boué, Daniel R., additional, Abdullaev, Zied, additional, Satgunaseelan, Laveniya, additional, Kurth, Ina, additional, Seidlitz, Annekatrin, additional, White, Christine L., additional, Ng, Ho-Keung, additional, Shi, Zhi-Feng, additional, Haberler, Christine, additional, Deckert, Martina, additional, Timmer, Marco, additional, Goldbrunner, Roland, additional, Tauziède-Espariat, Arnault, additional, Varlet, Pascale, additional, Brandner, Sebastian, additional, Alexandrescu, Sanda, additional, Snuderl, Matija, additional, Aldape, Kenneth, additional, Korshunov, Andrey, additional, Witt, Olaf, additional, Herold-Mende, Christel, additional, Unterberg, Andreas, additional, Wick, Wolfgang, additional, Pfister, Stefan M., additional, von Deimling, Andreas, additional, Jones, David T. W., additional, Sahm, Felix, additional, and Sievers, Philipp, additional

Published
2023
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254. Common molecular features of H3K27M DMGs and PFA ependymomas map to hindbrain developmental pathways

Author

Pun, Matthew, primary, Pratt, Drew, additional, Nano, Patricia R., additional, Joshi, Piyush K., additional, Jiang, Li, additional, Englinger, Bernhard, additional, Rao, Arvind, additional, Cieslik, Marcin, additional, Chinnaiyan, Arul M., additional, Aldape, Kenneth, additional, Pfister, Stefan, additional, Filbin, Mariella G., additional, Bhaduri, Aparna, additional, and Venneti, Sriram, additional

Published
2023
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256. Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas.

Author

Wang, Justin Z, Wang, Justin Z, Patil, Vikas, Liu, Jeff, Dogan, Helin, Tabatabai, Ghazaleh, Yefet, Leeor S, Behling, Felix, Hoffman, Elgin, Bunda, Severa, Yakubov, Rebecca, Kaloti, Ramneet, Brandner, Sebastian, Gao, Andrew, Cohen-Gadol, Aaron, Barnholtz-Sloan, Jill, Skardelly, Marco, Tatagiba, Marcos, Raleigh, David R, Sahm, Felix, Boutros, Paul C, Aldape, Kenneth, International Consortium on Meningiomas (ICOM), Nassiri, Farshad, Zadeh, Gelareh, Wang, Justin Z, Wang, Justin Z, Patil, Vikas, Liu, Jeff, Dogan, Helin, Tabatabai, Ghazaleh, Yefet, Leeor S, Behling, Felix, Hoffman, Elgin, Bunda, Severa, Yakubov, Rebecca, Kaloti, Ramneet, Brandner, Sebastian, Gao, Andrew, Cohen-Gadol, Aaron, Barnholtz-Sloan, Jill, Skardelly, Marco, Tatagiba, Marcos, Raleigh, David R, Sahm, Felix, Boutros, Paul C, Aldape, Kenneth, International Consortium on Meningiomas (ICOM), Nassiri, Farshad, and Zadeh, Gelareh

Abstract

Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach. Homozygous CDKN2A/B deletions were identified in only 7.1% of cases but were associated with significantly poorer outcomes compared to tumors without these deletions. Heterozygous CDKN2A/B deletions were identified in 2.6% of cases and had similarly poor outcomes as those with homozygous deletions. Among tumors with intact CDKN2A/B (without a homozygous or heterozygous deletion), we found a distinct difference in outcome based on mRNA expression of CDKN2A, with meningiomas that had elevated mRNA expression (CDKN2Ahigh) having a significantly shorter time to recurrence. The expression of CDKN2A was independently prognostic after accounting for copy number loss and consistently increased with WHO grade and more aggressive molecular and methylation groups irrespective of cohort. Despite the discordant and mutually exclusive status of the CDKN2A gene in these groups, both CDKN2Ahigh meningiomas and meningiomas with CDKN2A deletions were enriched for similar cell cycle pathways but at different checkpoints. High mRNA expression of CDKN2A was also associated with gene hypermethylation, Rb-deficiency, and lack of response to CDK inhibition. p16 immunohistochemistry could not reliably differentiate between meningiomas with and without CDKN2A deletions but appeared to correlate better with mRNA expression

Published
2023

257. Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial.

Author

Nassiri, Farshad, Nassiri, Farshad, Patil, Vikas, Yefet, Leeor, Singh, Olivia, Liu, Jeff, Dang, Rachel, Yamaguchi, Takafumi, Daras, Mariza, Cloughesy, Timothy, Colman, Howard, Kumthekar, Priya, Chen, Clark, Aiken, Robert, Groves, Morris, Ong, Shirley, Ramakrishna, Rohan, Vogelbaum, Michael, Khagi, Simon, Kaley, Thomas, Melear, Jason, Peereboom, David, Rodriguez, Analiz, Yankelevich, Maxim, Nair, Suresh, Puduvalli, Vinay, Aldape, Kenneth, Gao, Andrew, López-Janeiro, Álvaro, de Andrea, Carlos, Alonso, Marta, Boutros, Paul, Robbins, Joan, Mason, Warren, Sonabend, Adam, Stupp, Roger, Fueyo, Juan, Gomez-Manzano, Candelaria, Lang, Frederick, Zadeh, Gelareh, Nassiri, Farshad, Nassiri, Farshad, Patil, Vikas, Yefet, Leeor, Singh, Olivia, Liu, Jeff, Dang, Rachel, Yamaguchi, Takafumi, Daras, Mariza, Cloughesy, Timothy, Colman, Howard, Kumthekar, Priya, Chen, Clark, Aiken, Robert, Groves, Morris, Ong, Shirley, Ramakrishna, Rohan, Vogelbaum, Michael, Khagi, Simon, Kaley, Thomas, Melear, Jason, Peereboom, David, Rodriguez, Analiz, Yankelevich, Maxim, Nair, Suresh, Puduvalli, Vinay, Aldape, Kenneth, Gao, Andrew, López-Janeiro, Álvaro, de Andrea, Carlos, Alonso, Marta, Boutros, Paul, Robbins, Joan, Mason, Warren, Sonabend, Adam, Stupp, Roger, Fueyo, Juan, Gomez-Manzano, Candelaria, Lang, Frederick, and Zadeh, Gelareh

Abstract

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2-20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1-69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7-13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05-0.87). A total of 56.2% (95% CI 41.1-70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Published
2023

258. Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature

Author

Sievers, Philipp, Sill, Martin, Schrimpf, Daniel, Abdullaev, Zied, Donson, Andrew M., Lake, Jessica A., Friedel, Dennis, Scheie, David, Tynninen, Olli, Rauramaa, Tuomas, Vepsäläinen, Kaisa L., Samuel, David, Chapman, Rebecca, Grundy, Richard G., Pajtler, Kristian W, Tauziède-Espariat, Arnault, Métais, Alice, Varlet, Pascale, Snuderl, Matija, Jacques, Thomas S, Aldape, Kenneth, Reuss, David E., Korshunov, Andrey, Wick, Wolfgang, Pfister, Stefan M, von Deimling, Andreas, Sahm, Felix, Jones, David T.W., Sievers, Philipp, Sill, Martin, Schrimpf, Daniel, Abdullaev, Zied, Donson, Andrew M., Lake, Jessica A., Friedel, Dennis, Scheie, David, Tynninen, Olli, Rauramaa, Tuomas, Vepsäläinen, Kaisa L., Samuel, David, Chapman, Rebecca, Grundy, Richard G., Pajtler, Kristian W, Tauziède-Espariat, Arnault, Métais, Alice, Varlet, Pascale, Snuderl, Matija, Jacques, Thomas S, Aldape, Kenneth, Reuss, David E., Korshunov, Andrey, Wick, Wolfgang, Pfister, Stefan M, von Deimling, Andreas, Sahm, Felix, and Jones, David T.W.

Abstract

Pediatric neoplasms in the central nervous system (CNS) show extensive clinical and molecular heterogeneity and are fundamentally different from those occurring in adults. Molecular genetic testing contributes to accurate diagnosis and enables an optimal clinical management of affected children. Here, we investigated a rare, molecularly distinct type of pediatric high-grade neuroepithelial tumor (n = 18), that was identified through unsupervised visualization of genome-wide DNA methylation array data, together with copy number profiling, targeted next-generation DNA sequencing, and RNA transcriptome sequencing. DNA and/or RNA sequencing revealed recurrent fusions involving the capicua transcriptional repressor (CIC) gene in 10/10 tumor samples analyzed, with the most common fusion being CIC::LEUTX (n = 9). In addition, a CIC::NUTM1 fusion was detected in one of the tumors. Apart from the detected fusion events, no additional oncogenic alteration was identified in these tumors. The histopathological review demonstrated a morphologically heterogeneous group of high-grade neuroepithelial tumors with positive immunostaining for markers of glial differentiation in combination with weak and focal expression of synaptophysin, CD56 and CD99. All tumors were located in the supratentorial compartment, occurred during childhood (median age 8.5 years) and typically showed early relapses. In summary, we expand the spectrum of pediatric-type tumors of the CNS by reporting a previously uncharacterized group of rare high-grade neuroepithelial tumors that share a common DNA methylation signature and recurrent gene fusions involving the transcriptional repressor CIC. Downstream functional consequences of the fusion protein CIC::LEUTX and potential therapeutic implications need to be further investigated.

Published
2023

259. Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA):a molecularly distinct brain tumor type with recurrent NTRK gene fusions

Author

Bogumil, Henri, Sill, Martin, Schrimpf, Daniel, Ismer, Britta, Blume, Christina, Rahmanzade, Ramin, Hinz, Felix, Cherkezov, Asan, Banan, Rouzbeh, Friedel, Dennis, Reuss, David E., Selt, Florian, Ecker, Jonas, Milde, Till, Pajtler, Kristian W., Schittenhelm, Jens, Hench, Jürgen, Frank, Stephan, Boldt, Henning B., Kristensen, Bjarne Winther, Scheie, David, Melchior, Linea C., Olesen, Viola, Sehested, Astrid, Boué, Daniel R., Abdullaev, Zied, Satgunaseelan, Laveniya, Kurth, Ina, Seidlitz, Annekatrin, White, Christine L., Ng, Ho Keung, Shi, Zhi Feng, Haberler, Christine, Deckert, Martina, Timmer, Marco, Goldbrunner, Roland, Tauziède-Espariat, Arnault, Varlet, Pascale, Brandner, Sebastian, Alexandrescu, Sanda, Snuderl, Matija, Aldape, Kenneth, Korshunov, Andrey, Witt, Olaf, Herold-Mende, Christel, Unterberg, Andreas, Wick, Wolfgang, Pfister, Stefan M., von Deimling, Andreas, Jones, David T.W., Sahm, Felix, Sievers, Philipp, Bogumil, Henri, Sill, Martin, Schrimpf, Daniel, Ismer, Britta, Blume, Christina, Rahmanzade, Ramin, Hinz, Felix, Cherkezov, Asan, Banan, Rouzbeh, Friedel, Dennis, Reuss, David E., Selt, Florian, Ecker, Jonas, Milde, Till, Pajtler, Kristian W., Schittenhelm, Jens, Hench, Jürgen, Frank, Stephan, Boldt, Henning B., Kristensen, Bjarne Winther, Scheie, David, Melchior, Linea C., Olesen, Viola, Sehested, Astrid, Boué, Daniel R., Abdullaev, Zied, Satgunaseelan, Laveniya, Kurth, Ina, Seidlitz, Annekatrin, White, Christine L., Ng, Ho Keung, Shi, Zhi Feng, Haberler, Christine, Deckert, Martina, Timmer, Marco, Goldbrunner, Roland, Tauziède-Espariat, Arnault, Varlet, Pascale, Brandner, Sebastian, Alexandrescu, Sanda, Snuderl, Matija, Aldape, Kenneth, Korshunov, Andrey, Witt, Olaf, Herold-Mende, Christel, Unterberg, Andreas, Wick, Wolfgang, Pfister, Stefan M., von Deimling, Andreas, Jones, David T.W., Sahm, Felix, and Sievers, Philipp

Abstract

Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors—distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.

Published
2023

260. Depatuxizumab-mafodotin in EGFR-amplified newly diagnosed glioblastoma: a phase III randomized clinical trial

Author

MS Medische Oncologie, Cancer, Lassman, Andrew B, Pugh, Stephanie L, Wang, Tony J C, Aldape, Kenneth, Gan, Hui K, Preusser, Matthias, Vogelbaum, Michael A, Sulman, Erik P, Won, Minhee, Zhang, Peixin, Moazami, Golnaz, Macsai, Marian S, Gilbert, Mark R, Bain, Earle E, Blot, Vincent, Ansell, Peter J, Samanta, Suvajit, Kundu, Madan G, Armstrong, Terri S, Wefel, Jeffrey S, Seidel, Clemens, de Vos, Filip Y, Hsu, Sigmund, Cardona, Andrés F, Lombardi, Giuseppe, Bentsion, Dmitry, Peterson, Richard A, Gedye, Craig, Bourg, Véronique, Wick, Antje, Curran, Walter J, Mehta, Minesh P, MS Medische Oncologie, Cancer, Lassman, Andrew B, Pugh, Stephanie L, Wang, Tony J C, Aldape, Kenneth, Gan, Hui K, Preusser, Matthias, Vogelbaum, Michael A, Sulman, Erik P, Won, Minhee, Zhang, Peixin, Moazami, Golnaz, Macsai, Marian S, Gilbert, Mark R, Bain, Earle E, Blot, Vincent, Ansell, Peter J, Samanta, Suvajit, Kundu, Madan G, Armstrong, Terri S, Wefel, Jeffrey S, Seidel, Clemens, de Vos, Filip Y, Hsu, Sigmund, Cardona, Andrés F, Lombardi, Giuseppe, Bentsion, Dmitry, Peterson, Richard A, Gedye, Craig, Bourg, Véronique, Wick, Antje, Curran, Walter J, and Mehta, Minesh P

Published
2023

262. Molecular Biomarker Testing for the Diagnosis of Diffuse Gliomas

Author

Brat, Daniel J, Aldape, Kenneth, Bridge, Julia A, Canoll, Peter, Colman, Howard, Hameed, Meera R, Harris, Brent T, Hattab, Eyas M, Huse, Jason T, Jenkins, Robert B, Lopez-Terrada, Dolores H, McDonald, William C, Rodriguez, Fausto J, Souter, Lesley H, Colasacco, Carol, Thomas, Nicole E, Yount, Michelle Hawks, van den Bent, Martin J, and Perry, Arie

Subjects
Adult, screening and diagnosis, Tumor, Clinical Sciences, Glioma, General Medicine, 4.1 Discovery and preclinical testing of markers and technologies, Pathology and Forensic Medicine, Pathologists, Detection, Medical Laboratory Technology, ErbB-2, Good Health and Well Being, Molecular Diagnostic Techniques, Pathology, Humans, Patient Safety, Child, Biomarkers, Receptor, Systematic Reviews as Topic, Cancer, 4.2 Evaluation of markers and technologies
Abstract

Context.— The diagnosis and clinical management of patients with diffuse gliomas (DGs) have evolved rapidly over the past decade with the emergence of molecular biomarkers that are used to classify, stratify risk, and predict treatment response for optimal clinical care. Objective.— To develop evidence-based recommendations for informing molecular biomarker testing for pediatric and adult patients with DGs and provide guidance for appropriate laboratory test and biomarker selection for optimal diagnosis, risk stratification, and prediction. Design.— The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. A systematic review of literature was conducted to address the overarching question, “What ancillary tests are needed to classify DGs and sufficiently inform the clinical management of patients?” Recommendations were derived from quality of evidence, open comment feedback, and expert panel consensus. Results.— Thirteen recommendations and 3 good practice statements were established to guide pathologists and treating physicians on the most appropriate methods and molecular biomarkers to include in laboratory testing to inform clinical management of patients with DGs. Conclusions.— Evidence-based incorporation of laboratory results from molecular biomarker testing into integrated diagnoses of DGs provides reproducible and clinically meaningful information for patient management.

Published
2022

263. Utility of Immunohistochemistry With Antibodies to SS18-SSX Chimeric Proteins and C-Terminus of SSX Protein for Synovial Sarcoma Differential Diagnosis

Author

Lasota, Jerzy, Chłopek, Małgorzata, Kaczorowski, Maciej, Natálie, Klubíčková, Ryś, Janusz, Kopczyński, Janusz, Sulaieva, Oksana, Michal, Michael, Kruczak, Anna, Harazin-Lechowska, Agnieszka, Szczepaniak, Magdalena, Koshyk, Olena, Hałoń, Agnieszka, Czapiewski, Piotr, Abdullaev, Zied, Kowalik, Artur, Aldape, Kenneth D., Michal, Michal, and Miettinen, Markku

Abstract

Synovial sarcoma is a relatively common soft tissue tumor characterized by highly specific t(X;18)(p11;q11) translocation resulting in the fusion of SS18with members of SSXgene family. Typically, detection of SS18locus rearrangement by fluorescence in situ hybridization or SS18::SSXfusion transcripts confirms the diagnosis. More recently, immunohistochemistry (IHC) for SS18-SSX chimeric protein (E9X9V) and C-terminus of SSX (E5A2C) showed high specificity and sensitivity for synovial sarcoma. This study screened a cohort of >1000 soft tissue and melanocytic tumors using IHC and E9X9V and E5A2C antibodies. Three percent (6/212) of synovial sarcomas were either negative for SS18-SSX or had scattered positive tumor cells (n=1). In these cases, targeted RNA next-generation sequencing detected variants of SS18::SSXchimeric transcripts. DNA methylation profiles of 2 such tumors matched with synovial sarcoma. A few nonsynovial sarcoma tumors (n=6) revealed either focal SS18-SSX positivity (n=1) or scattered positive tumor cells. However, targeted RNA next-generation sequencing failed to detect SS18::SSXtranscripts in these cases. The nature of this immunopositivity remains elusive and may require single cell sequencing studies. All synovial sarcomas showed positive SSX IHC. However, a mosaic staining pattern or focal loss of expression was noticed in a few cases. Strong and diffuse SSX immunoreactivity was also seen in epithelioid sclerosing osteosarcoma harboring EWSR1::SSX1fusion, while several sarcomas and melanocytic tumors including cellular blue nevus (5/7, 71%) revealed focal to diffuse, mostly weak to intermediate SSX staining. The SS18-SSX and SSX IHC is a useful tool for synovial sarcoma differential diagnosis, but unusual immunophenotype should trigger molecular genetic testing.

Published
2024
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264. Assessment of The Utility of The Sarcoma DNA Methylation Classifier In Surgical Pathology

Author

Miettinen, Markku, Abdullaev, Zied, Turakulov, Rust, Quezado, Martha, Luiña Contreras, Alejandro, Curcio, Christian A., Rys, Janusz, Chlopek, Malgorzata, Lasota, Jerzy, and Aldape, Kenneth D.

Abstract

Diagnostic classification of soft tissue tumors is based on histology, immunohistochemistry, genetic findings, and radiologic and clinical correlations. Recently, a sarcoma DNA methylation classifier was developed, covering 62 soft tissue and bone tumor entities. The classifier is based on large-scale analysis of methylation sites across the genome. It includes DNA copy number analysis and determines O6methylguanine DNA methyl-transferase methylation status. In this study, we evaluated 619 well-studied soft tissue and bone tumors with the sarcoma classifier. Problem cases and typical examples of different entities were included. The classifier had high sensitivity and specificity for fusion sarcomas: Ewing, synovial, CIC-rearranged, and BCOR-rearranged. It also performed well for leiomyosarcoma, malignant peripheral nerve sheath tumors (MPNST), and malignant vascular tumors. There was low sensitivity for diagnoses of desmoid fibromatosis, neurofibroma, and schwannoma. Low specificity of matches was observed for angiomatoid fibrous histiocytoma, inflammatory myofibroblastic tumor, Langerhans histiocytosis, schwannoma, undifferentiated sarcoma, and well-differentiated/dedifferentiated liposarcoma. Diagnosis of lipomatous tumors was greatly assisted by the detection of MDM2amplification and RB1loss in the copy plot. The classifier helped to establish diagnoses for KIT-negative gastrointestinal stromal tumors, MPNSTs with unusual immunophenotypes, and undifferentiated melanomas. O6methylguanine DNA methyl-transferase methylation was infrequent and most common in melanomas (35%), MPNSTs (11%), and undifferentiated sarcomas (11%). The Sarcoma Methylation Classifier will likely evolve with the addition of new entities and refinement of the present methylation classes. The classifier may also help to define new entities and give new insight into the interrelationships of sarcomas.

Published
2024
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265. Prediction of DNA methylation-based tumor types from histopathology in central nervous system tumors with deep learning

Author

Hoang, Danh-Tai, Shulman, Eldad D., Turakulov, Rust, Abdullaev, Zied, Singh, Omkar, Campagnolo, Emma M., Lalchungnunga, H., Stone, Eric A., Nasrallah, MacLean P., Ruppin, Eytan, and Aldape, Kenneth

Abstract

Precision in the diagnosis of diverse central nervous system (CNS) tumor types is crucial for optimal treatment. DNA methylation profiles, which capture the methylation status of thousands of individual CpG sites, are state-of-the-art data-driven means to enhance diagnostic accuracy but are also time consuming and not widely available. Here, to address these limitations, we developed Deep lEarning from histoPathoLOgy and methYlation (DEPLOY), a deep learning model that classifies CNS tumors to ten major categories from histopathology. DEPLOY integrates three distinct components: the first classifies CNS tumors directly from slide images (‘direct model’), the second initially generates predictions for DNA methylation beta values, which are subsequently used for tumor classification (‘indirect model’), and the third classifies tumor types directly from routinely available patient demographics. First, we find that DEPLOY accurately predicts beta values from histopathology images. Second, using a ten-class model trained on an internal dataset of 1,796 patients, we predict the tumor categories in three independent external test datasets including 2,156 patients, achieving an overall accuracy of 95% and balanced accuracy of 91% on samples that are predicted with high confidence. These results showcase the potential future use of DEPLOY to assist pathologists in diagnosing CNS tumors within a clinically relevant short time frame.

Published
2024
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266. Haploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype

Author

Nuechterlein, Nicholas, Shelbourn, Allison, Szulzewsky, Frank, Arora, Sonali, Casad, Michelle, Pattwell, Siobhan, Merino-Galan, Leyre, Sulman, Erik, Arowa, Sumaita, Alvinez, Neriah, Jung, Miyeon, Brown, Desmond, Tang, Kayen, Jackson, Sadhana, Stoica, Stefan, Chittaboina, Prashant, Banasavadi-Siddegowda, Yeshavanth K., Wirsching, Hans-Georg, Stella, Nephi, Shapiro, Linda, Paddison, Patrick, Patel, Anoop P., Gilbert, Mark R., Abdullaev, Zied, Aldape, Kenneth, Pratt, Drew, Holland, Eric C., and Cimino, Patrick J.

Abstract

In this study, Nuechterlein et al. show that the deficiency of phosphodiesterase PDE10A activates PI3K/AKT/mTOR signaling independent of PTEN and promotes proneural-to-mesenchymal transition and gliomagenesis. Their work highlights that PDE10A may function as a potential tumor suppressor and that PDE10A-deficient glioblastomas may be therapeutically vulnerable to PI3K inhibition.

Published
2024
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267. Molecular classification to refine surgical and radiotherapeutic decision-making in meningioma

Author

Wang, Justin Z., Patil, Vikas, Landry, Alexander P., Gui, Chloe, Ajisebutu, Andrew, Liu, Jeff, Saarela, Olli, Pugh, Stephanie L., Won, Minhee, Patel, Zeel, Yakubov, Rebeca, Kaloti, Ramneet, Wilson, Christopher, Cohen-Gadol, Aaron, Zaazoue, Mohamed A., Tabatabai, Ghazaleh, Tatagiba, Marcos, Behling, Felix, Almiron Bonnin, Damian A., Holland, Eric C., Kruser, Tim J., Barnholtz-Sloan, Jill S., Sloan, Andrew E., Horbinski, Craig, Chotai, Silky, Chambless, Lola B., Gao, Andrew, Rebchuk, Alexander D., Makarenko, Serge, Yip, Stephen, Sahm, Felix, Maas, Sybren L. N., Tsang, Derek S., Rogers, C. Leland, Aldape, Kenneth, Nassiri, Farshad, and Zadeh, Gelareh

Abstract

Treatment of the tumor and dural margin with surgery and sometimes radiation are cornerstones of therapy for meningioma. Molecular classifications have provided insights into the biology of disease; however, response to treatment remains heterogeneous. In this study, we used retrospective data on 2,824 meningiomas, including molecular data on 1,686 tumors and 100 prospective meningiomas, from the RTOG-0539 phase 2 trial to define molecular biomarkers of treatment response. Using propensity score matching, we found that gross tumor resection was associated with longer progression-free survival (PFS) across all molecular groups and longer overall survival in proliferative meningiomas. Dural margin treatment (Simpson grade 1/2) prolonged PFS compared to no treatment (Simpson grade 3). Molecular group classification predicted response to radiotherapy, including in the RTOG-0539 cohort. We subsequently developed a molecular model to predict response to radiotherapy that discriminates outcome better than standard-of-care classification. This study highlights the potential for molecular profiling to refine surgical and radiotherapy decision-making.

Published
2024
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268. CIC protein instability contributes to tumorigenesis in glioblastoma

Author

Bunda, Severa, Heir, Pardeep, Metcalf, Julie, Li, Annie Si Cong, Agnihotri, Sameer, Pusch, Stefan, Yasin, Mamatjan, Li, Mira, Burrell, Kelly, Mansouri, Sheila, Singh, Olivia, Wilson, Mark, Alamsahebpour, Amir, Nejad, Romina, Choi, Bethany, Kim, David, von Deimling, Andreas, Zadeh, Gelareh, and Aldape, Kenneth

Published
2019
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269. NCI intramural program approach to rare tumors: Natural history study of rare solid tumors in children and adults: A longitudinal, comprehensive data and biospecimen collection protocol.

Author

Wedekind, Mary Frances, Reilly, Karlyne M., Rivero, Jaydira Del, Lockridge, Robin, Allen, Taryn, Raygada, Margarita, Bernstein, Donna, Thomas, Barbara J., Vivelo, Christina, Levine, Jason, Shonkoev, Nurlan, Aldape, Kenneth, Glod, John, Sandler, Abby B., and Widemann, Brigitte C.

Published
2023
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270. Author Correction: Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes

Author

Lehman, Norman L., primary, Spassky, Nathalie, additional, Sak, Müge, additional, Webb, Amy, additional, Zumbar, Cory T., additional, Usubalieva, Aisulu, additional, Alkhateeb, Khaled J., additional, McElroy, Joseph P., additional, Maclean, Kirsteen H., additional, Fadda, Paolo, additional, Liu, Tom, additional, Gangalapudi, Vineela, additional, Carver, Jamie, additional, Abdullaev, Zied, additional, Timmers, Cynthia, additional, Parker, John R., additional, Pierson, Christopher R., additional, Mobley, Bret C., additional, Gokden, Murat, additional, Hattab, Eyas M., additional, Parrett, Timothy, additional, Cooke, Ralph X., additional, Lehman, Trang D., additional, Costinean, Stefan, additional, Parwani, Anil, additional, Williams, Brian J., additional, Jensen, Randy L., additional, Aldape, Kenneth, additional, and Mistry, Akshitkumar M., additional

Published
2023
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272. Heterogeneous clinicopathological findings and patient-reported outcomes in adults with MN1-altered CNS tumors: A case report and systematic literature review

Author

Frederico, Stephen C., primary, Vera, Elizabeth, additional, Abdullaev, Zied, additional, Acquaye, Alvina, additional, Aldape, Kenneth, additional, Boris, Lisa, additional, Briceno, Nicole, additional, Choi, Anna, additional, Christ, Alexa, additional, Cooper, Diane, additional, Grajkowska, Ewa, additional, Kunst, Tricia, additional, Leeper, Heather E., additional, Levine, Jason, additional, Lollo, Nicole, additional, Pratt, Drew, additional, Quezado, Martha, additional, Shah, Ritu, additional, Wall, Kathleen, additional, Gilbert, Mark R., additional, Armstrong, Terri S., additional, and Penas-Prado, Marta, additional

Published
2023
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273. Clinically oriented prediction of patient response to targeted and immunotherapies from the tumor transcriptome

Author

Dinstag, Gal, primary, Shulman, Eldad D., additional, Elis, Efrat, additional, Ben-Zvi, Doreen S., additional, Tirosh, Omer, additional, Maimon, Eden, additional, Meilijson, Isaac, additional, Elalouf, Emmanuel, additional, Temkin, Boris, additional, Vitkovsky, Philipp, additional, Schiff, Eyal, additional, Hoang, Danh-Tai, additional, Sinha, Sanju, additional, Nair, Nishanth Ulhas, additional, Lee, Joo Sang, additional, Schäffer, Alejandro A., additional, Ronai, Ze’ev, additional, Juric, Dejan, additional, Apolo, Andrea B., additional, Dahut, William L., additional, Lipkowitz, Stanley, additional, Berger, Raanan, additional, Kurzrock, Razelle, additional, Papanicolau-Sengos, Antonios, additional, Karzai, Fatima, additional, Gilbert, Mark R., additional, Aldape, Kenneth, additional, Rajagopal, Padma S., additional, Beker, Tuvik, additional, Ruppin, Eytan, additional, and Aharonov, Ranit, additional

Published
2023
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277. Intratumoral morphologic and molecular heterogeneity of rhabdoid renal cell carcinoma: challenges for personalized therapy

Author

Singh, Rajesh R, Murugan, Paari, Patel, Lalit R, Voicu, Horatiu, Yoo, Suk-Young, Majewski, Tadeusz, Mehrotra, Meenakshi, Wani, Khalida, Tannir, Nizar, Karam, Jose A, Jonasch, Eric, Wood, Christopher G, Creighton, Chad J, Medeiros, L Jeffrey, Broaddus, Russell R, Tamboli, Pheroze, Baggerly, Keith A, Aldape, Kenneth D, Czerniak, Bogdan, Luthra, Rajyalakshmi, and Sircar, Kanishka

Published
2015
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278. Correction to: Epigenomic, genomic, and transcriptomic landscape of schwannomatosis

Author

Mansouri, Sheila, Suppiah, Suganth, Mamatjan, Yasin, Paganini, Irene, Liu, Jeffrey C., Karimi, Shirin, Patil, Vikas, Nassiri, Farshad, Singh, Olivia, Sundaravadanam, Yogi, Rath, Prisni, Sestini, Roberta, Gensini, Francesca, Agnihotri, Sameer, Blakeley, Jaishri, Ostrow, Kimberly, Largaespada, David, Plotkin, Scott R., Stemmer-Rachamimov, Anat, Ferrer, Marcela Maria, Pugh, Trevor J., Aldape, Kenneth D., Papi, Laura, and Zadeh, Gelareh

Published
2021
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280. Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas

Author

Wang, Justin Z., primary, Patil, Vikas, additional, Liu, Jeff, additional, Dogin, Helin, additional, Behling, Felix, additional, Skardelly, Marco, additional, Tatagiba, Marcos, additional, Hoffman, Elgin, additional, Bunda, Severa, additional, Yakubov, Rebecca, additional, Kaloti, Ramneet, additional, Brandner, Sebastian, additional, Gao, Andrew, additional, Gadol, Aaron-Cohen, additional, Barnholtz-Sloan, Jennifer, additional, Raleigh, David, additional, Sahm, Felix, additional, Boutros, Paul C., additional, Tabatabai, Ghazaleh, additional, Aldape, Kenneth, additional, Nassiri, Farshad, additional, and Zadeh, Gelareh, additional

Published
2022
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283. Sex Biases in Cancer and Autoimmune Disease Incidence Are Strongly Positively Correlated with Mitochondrial Gene Expression across Human Tissues

Author

Crawford, David R., primary, Sinha, Sanju, additional, Nair, Nishanth Ulhas, additional, Ryan, Bríd M., additional, Barnholtz-Sloan, Jill S., additional, Mount, Stephen M., additional, Erez, Ayelet, additional, Aldape, Kenneth, additional, Castle, Philip E., additional, Rajagopal, Padma S., additional, Day, Chi-Ping, additional, Schäffer, Alejandro A., additional, and Ruppin, Eytan, additional

Published
2022
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284. Common molecular features of H3K27M DMGs and PFA ependymomas map to hindbrain developmental pathways

Author

Pun, Matthew, primary, Pratt, Drew, additional, Nano, Patricia R., additional, Joshi, Piyush K., additional, Jiang, Li, additional, Englinger, Bernhard, additional, Rao, Arvind, additional, Cieslik, Marcin, additional, Chinnaiyan, Arul M., additional, Aldape, Kenneth, additional, Pfister, Stefan, additional, Filbin, Mariella G., additional, Bhaduri, Aparna, additional, and Venneti, Sriram, additional

Published
2022
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287. BIOM-46. EXPLORING CLINICAL AND PATHOLOGIC CHARACTERISTICS IN GLIOBLASTOMA LONG -TERM SURVIVORS (LTS) VERSUS SHORT-TERM SURVIVORS (STS)

Author

Briceno, Nicole, primary, Abdullaev, Zied, additional, Vera, Elizabeth, additional, Komlodi-Pasztor, Edina, additional, Choi, Anna, additional, Christ, Alexa, additional, Grajkowska, Ewa, additional, Leeper, Heather, additional, Levine, Jason, additional, Lindsley, Matthew, additional, Reyes, Jennifer, additional, Boris, Lisa, additional, Burton, Eric, additional, Lollo, Nicole, additional, Panzer, Marissa, additional, Penas-Prado, Marta, additional, Pillai, Valentina, additional, Theeler, Brett, additional, Kunst, Tricia, additional, Evans, Karen, additional, Mentges, Kelly, additional, Wu, Jing, additional, Polskin, Lily, additional, Papanicolau-Sengos, Antonios, additional, Quezado, Martha, additional, Aldape, Kenneth, additional, Gilbert, Mark, additional, and Armstrong, Terri, additional

Published
2022
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288. TMIC-73. HIGH-DIMENSIONAL HISTOPATHOLOGIC EVALUATION OF THE HYPOXIC MICROENVIRONMENT IN GLIOBLASTOMA

Author

Mansouri, Sheila, primary, Zaidi, Mark, additional, Singh, Olivia, additional, Ali, Hafsah, additional, Karimi, Shirin, additional, Lombard, Phoebe, additional, Dvorkin-Gheva, Anna, additional, Velasquez, Carlos, additional, Devaraja, Kaviya, additional, Sosa, Julio, additional, Patil, Vikas, additional, Wei, Qingxia, additional, Wu, Ronald, additional, Li, Mira, additional, Cheung, May, additional, Voisin, Mathew, additional, Gao, Andrew, additional, Hedley, David, additional, Aldape, Kenneth, additional, Wouters, Bradly, additional, and Zadeh, Gelareh, additional

Published
2022
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291. EXTH-88. DOCETAXEL TARGETS AGGRESSIVE METHYLATION PROFILES AND SERVES AS A RADIOSENSITIZER IN HIGH-RISK MENINGIOMAS

Author

Youngblood, Mark, primary, Tran, Anh, additional, Wang, Wenxia, additional, An, Shejuan, additional, Scholtens, Denise, additional, Zhang, Lyndsee, additional, O’Shea, Kaitlyn, additional, Pokorny, Jenny, additional, Magill, Stephen, additional, Sachdev, Sean, additional, Lukas, Rimas, additional, Ahmed, Atique, additional, Unruh, Dusten, additional, Walshon, Jordain, additional, McCortney, Kathleen, additional, Wang, Yufen, additional, Baran, Aneta, additional, Sahm, Felix, additional, Aldape, Kenneth, additional, Chandler, James, additional, Heimberger, Amy, additional, James, David, additional, and Horbinski, Craig, additional

Published
2022
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294. A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns

Author

Jiao, Wei, Atwal, Gurnit, Polak, Paz, Karlic, Rosa, Cuppen, Edwin, Al-Shahrour, Fatima, Bailey, Peter J, Biankin, Andrew V, Boutros, Paul C, Campbell, Peter J, Chang, David K, Cooke, Susanna L, Deshpande, Vikram, Faltas, Bishoy M, Faquin, William C, Garraway, Levi, Getz, Gad, Grimmond, Sean M, Haider, Syed, Hoadley, Katherine A, Kaiser, Vera B, Kato, Mamoru, Kübler, Kirsten, Lazar, Alexander J, Li, Constance H, Louis, David N, Margolin, Adam, Martin, Sancha, Nahal-Bose, Hardeep K, Nielsen, G Petur, Nik-Zainal, Serena, Omberg, Larsson, P’ng, Christine, Perry, Marc D, Rheinbay, Esther, Rubin, Mark A, Semple, Colin A, Sgroi, Dennis C, Shibata, Tatsuhiro, Siebert, Reiner, Smith, Jaclyn, Stein, Lincoln D, Stobbe, Miranda D, Sun, Ren X, Thai, Kevin, Wright, Derek W, Wu, Chin-Lee, Yuan, Ke, Zhang, Junjun, Danyi, Alexandra, de Ridder, Jeroen, van Herpen, Carla, Lolkema, Martijn P, Steeghs, Neeltje, Morris, Quaid D, Aaltonen, Lauri A, Abascal, Federico, Abeshouse, Adam, Aburatani, Hiroyuki, Adams, David J, Agrawal, Nishant, Ahn, Keun Soo, Ahn, Sung-Min, Aikata, Hiroshi, Akbani, Rehan, Akdemir, Kadir C, Al-Ahmadie, Hikmat, Al-Sedairy, Sultan T, Alawi, Malik, Albert, Monique, Aldape, Kenneth, Alexandrov, Ludmil B, Ally, Adrian, Alsop, Kathryn, Alvarez, Eva G, Amary, Fernanda, Amin, Samirkumar B, Aminou, Brice, Ammerpohl, Ole, Anderson, Matthew J, Ang, Yeng, Antonello, Davide, Anur, Pavana, Aparicio, Samuel, Appelbaum, Elizabeth L, Arai, Yasuhito, Aretz, Axel, Arihiro, Koji, Ariizumi, Shun-ichi, Armenia, Joshua, Arnould, Laurent, Asa, Sylvia, Assenov, Yassen, Aukema, Sietse, Auman, J Todd, Aure, Miriam RR, Awadalla, Philip, Aymerich, Marta, Bader, Gary D, Baez-Ortega, Adrian, Bailey, Matthew H, Balasundaram, Miruna, Balu, Saianand, Bandopadhayay, Pratiti, Banks, Rosamonde E, Barbi, Stefano, Barbour, Andrew P, Barenboim, Jonathan, Barnholtz-Sloan, Jill, Barr, Hugh, Barrera, Elisabet, Bartlett, John, Bartolome, Javier, Bassi, Claudio, Bathe, Oliver F, Baumhoer, Daniel, Bavi, Prashant, Baylin, Stephen B, Bazant, Wojciech, Beardsmore, Duncan, Beck, Timothy A, Behjati, Sam, Behren, Andreas, Niu, Beifang, Bell, Cindy, Beltran, Sergi, Benz, Christopher, Berchuck, Andrew, Bergmann, Anke K, Bergstrom, Erik N, Berman, Benjamin P, Berney, Daniel M, Bernhart, Stephan H, Beroukhim, Rameen, Berrios, Mario, Bersani, Samantha, Bertl, Johanna, Betancourt, Miguel, Bhandari, Vinayak, Bhosle, Shriram G, Bieg, Matthias, Bigner, Darell, Binder, Hans, Birney, Ewan, Birrer, Michael, Biswas, Nidhan K, Bjerkehagen, Bodil, Bodenheimer, Tom, Boice, Lori, Bonizzato, Giada, De Bono, Johann S, Boot, Arnoud, Bootwalla, Moiz S, Borg, Ake, Borkhardt, Arndt, Boroevich, Keith A, Borozan, Ivan, Borst, Christoph, Bosenberg, Marcus, Bosio, Mattia, Boultwood, Jacqueline, Bourque, Guillaume, Bova, G Steven, Bowen, David T, Bowlby, Reanne, Bowtell, David DL, Boyault, Sandrine, Boyce, Rich, Boyd, Jeffrey, Brazma, Alvis, Brennan, Paul, Brewer, Daniel S, Brinkman, Arie B, Bristow, Robert G, Broaddus, Russell R, Brock, Jane E, Brock, Malcolm, Broeks, Annegien, Brooks, Angela N, Brooks, Denise, Brors, Benedikt, Brunak, Søren, Bruxner, Timothy JC, Bruzos, Alicia L, Buchanan, Alex, Buchhalter, Ivo, Buchholz, Christiane, Bullman, Susan, Burke, Hazel, Burkhardt, Birgit, Burns, Kathleen H, Busanovich, John, Bustamante, Carlos D, Butler, Adam P, Butte, Atul J, Byrne, Niall J, Børresen-Dale, Anne-Lise, Caesar-Johnson, Samantha J, Cafferkey, Andy, Cahill, Declan, Calabrese, Claudia, Caldas, Carlos, Calvo, Fabien, Camacho, Niedzica, Campo, Elias, Cantù, Cinzia, Cao, Shaolong, Carey, Thomas E, Carlevaro-Fita, Joana, Carlsen, Rebecca, Cataldo, Ivana, Cazzola, Mario, Cebon, Jonathan, Cerfolio, Robert, Chadwick, Dianne E, Chakravarty, Dimple, Chalmers, Don, Chan, Calvin Wing Yiu, Chan, Kin, Chan-Seng-Yue, Michelle, Chandan, Vishal S, Chanock, Stephen J, Chantrill, Lorraine A, Chateigner, Aurélien, Chatterjee, Nilanjan, Chayama, Kazuaki, Chen, Hsiao-Wei, Chen, Jieming, Chen, Ken, Chen, Yiwen, Chen, Zhaohong, Cherniack, Andrew D, Chien, Jeremy, Chiew, Yoke-Eng, Chin, Suet-Feung, Cho, Juok, Cho, Sunghoon, Choi, Jung Kyoon, Choi, Wan, Chomienne, Christine, Chong, Zechen, Choo, Su Pin, Chou, Angela, Christ, Angelika N, Christie, Elizabeth L, Chuah, Eric, Cibulskis, Carrie, Cibulskis, Kristian, Cingarlini, Sara, Clapham, Peter, Claviez, Alexander, Cleary, Sean, Cloonan, Nicole, Cmero, Marek, Collins, Colin C, Connor, Ashton A, Cooper, Colin S, Cope, Leslie, Corbo, Vincenzo, Cordes, Matthew G, Cordner, Stephen M, Cortés-Ciriano, Isidro, Covington, Kyle, Cowin, Prue A, Craft, Brian, Craft, David, Creighton, Chad J, Cun, Yupeng, Curley, Erin, Cutcutache, Ioana, Czajka, Karolina, Czerniak, Bogdan, Dagg, Rebecca A, Danilova, Ludmila, Davi, Maria Vittoria, Davidson, Natalie R, Davies, Helen, Davis, Ian J, Davis-Dusenbery, Brandi N, Dawson, Kevin J, De La Vega, Francisco M, De Paoli-Iseppi, Ricardo, Defreitas, Timothy, Dei Tos, Angelo P, Delaneau, Olivier, Demchok, John A, Demeulemeester, Jonas, Demidov, German M, Demircioğlu, Deniz, Dennis, Nening M, Denroche, Robert E, Dentro, Stefan C, Desai, Nikita, Deshwar, Amit G, Desmedt, Christine, Deu-Pons, Jordi, Dhalla, Noreen, Dhani, Neesha C, Dhingra, Priyanka, Dhir, Rajiv, DiBiase, Anthony, Diamanti, Klev, Ding, Li, Ding, Shuai, Dinh, Huy Q, Dirix, Luc, Doddapaneni, HarshaVardhan, Donmez, Nilgun, Dow, Michelle T, Drapkin, Ronny, Drechsel, Oliver, Drews, Ruben M, Serge, Serge, Dudderidge, Tim, Dueso-Barroso, Ana, Dunford, Andrew J, Dunn, Michael, Dursi, Lewis Jonathan, Duthie, Fraser R, Dutton-Regester, Ken, Eagles, Jenna, Easton, Douglas F, Edmonds, Stuart, Edwards, Paul A, Edwards, Sandra E, Eeles, Rosalind A, Ehinger, Anna, Eils, Juergen, Eils, Roland, El-Naggar, Adel, Eldridge, Matthew, Ellrott, Kyle, Erkek, Serap, Escaramis, Georgia, Espiritu, Shadrielle MG, Estivill, Xavier, Etemadmoghadam, Dariush, Eyfjord, Jorunn E, Fan, Daiming, Fan, Yu, Farcas, Claudiu, Fassan, Matteo, Fatima, Aquila, Favero, Francesco, Fayzullaev, Nodirjon, Felau, Ina, Fereday, Sian, Ferguson, Martin L, Ferretti, Vincent, Feuerbach, Lars, Field, Matthew A, Fink, J Lynn, Finocchiaro, Gaetano, Fisher, Cyril, Fittall, Matthew W, Fitzgerald, Anna, Fitzgerald, Rebecca C, Flanagan, Adrienne M, Fleshner, Neil E, Flicek, Paul, Foekens, John A, Fong, Kwun M, Fonseca, Nuno A, Foster, Christopher S, Fox, Natalie S, Fraser, Michael, Frazer, Scott, Frenkel-Morgenstern, Milana, Friedman, William, Frigola, Joan, Fronick, Catrina C, Fujimoto, Akihiro, Fujita, Masashi, Fukayama, Masashi, Fulton, Lucinda A, Fulton, Robert S, Furuta, Mayuko, Futreal, P Andrew, Füllgrabe, Anja, Gabriel, Stacey B, Gallinger, Steven, Gambacorti-Passerini, Carlo, Gao, Jianjiong, Gao, Shengjie, Garred, Øystein, Garrison, Erik, Garsed, Dale W, Gehlenborg, Nils, Gelpi, Josep LL, George, Joshy, Gerhard, Daniela S, Gerhauser, Clarissa, Gershenwald, Jeffrey E, Gerstein, Mark, Gerstung, Moritz, Ghori, Mohammed, Ghossein, Ronald, Giama, Nasra H, Gibbs, Richard A, Gibson, Bob, Gill, Anthony J, Gill, Pelvender, Giri, Dilip D, Glodzik, Dominik, Gnanapragasam, Vincent J, Goebler, Maria Elisabeth, Goldman, Mary J, Gomez, Carmen, Gonzalez, Santiago, Gonzalez-Perez, Abel, Gordenin, Dmitry A, Gossage, James, Gotoh, Kunihito, Govindan, Ramaswamy, Grabau, Dorthe, Graham, Janet S, Grant, Robert C, Green, Anthony R, Green, Eric, Greger, Liliana, Grehan, Nicola, Grimaldi, Sonia, Grossman, Robert L, Grundhoff, Adam, Gundem, Gunes, Guo, Qianyun, Gupta, Manaswi, Gupta, Shailja, Gut, Ivo G, Gut, Marta, Göke, Jonathan, Ha, Gavin, Haake, Andrea, Haan, David, Haas, Siegfried, Haase, Kerstin, Haber, James E, Habermann, Nina, Hach, Faraz, Hama, Natsuko, Hamdy, Freddie C, Hamilton, Anne, Hamilton, Mark P, Han, Leng, Hanna, George B, Hansmann, Martin, Haradhvala, Nicholas J, Harismendy, Olivier, Harliwong, Ivon, Harmanci, Arif O, Harrington, Eoghan, Hasegawa, Takanori, Haussler, David, Hawkins, Steve, Hayami, Shinya, Hayashi, Shuto, Hayes, D Neil, Hayes, Stephen J, Hayward, Nicholas K, Hazell, Steven, He, Yao, Heath, Allison P, Heath, Simon C, Hedley, David, Hegde, Apurva M, Heiman, David I, Heinold, Michael C, Heins, Zachary, Heisler, Lawrence E, Hellstrom-Lindberg, Eva, Helmy, Mohamed, Heo, Seong Gu, Hepperla, Austin J, Heredia-Genestar, José María, Herrmann, Carl, Hersey, Peter, Hess, Julian M, Hilmarsdottir, Holmfridur, Hinton, Jonathan, Hirano, Satoshi, Hiraoka, Nobuyoshi, Hobolth, Asger, Hodzic, Ermin, Hoell, Jessica I, Hoffmann, Steve, Hofmann, Oliver, Holbrook, Andrea, Holik, Aliaksei Z, Hollingsworth, Michael A, Holmes, Oliver, Holt, Robert A, Hong, Chen, Hong, Eun Pyo, Hong, Jongwhi H, Hooijer, Gerrit K, Hornshøj, Henrik, Hosoda, Fumie, Hou, Yong, Hovestadt, Volker, Howat, William, Hoyle, Alan P, Hruban, Ralph H, Hu, Jianhong, Hu, Taobo, Hua, Xing, Huang, Kuan-lin, Huang, Mei, Huang, Mi Ni, Huang, Vincent, Huang, Yi, Huber, Wolfgang, Hudson, Thomas J, Hummel, Michael, Hung, Jillian A, Huntsman, David, Hupp, Ted R, Huse, Jason, Huska, Matthew R, Hutter, Barbara, Hutter, Carolyn M, Hübschmann, Daniel, Iacobuzio-Donahue, Christine A, Imbusch, Charles David, Imielinski, Marcin, Imoto, Seiya, Isaacs, William B, Isaev, Keren, Ishikawa, Shumpei, Iskar, Murat, Islam, SM Ashiqul, Ittmann, Michael, Ivkovic, Sinisa, Izarzugaza, Jose MG, Jacquemier, Jocelyne, Jakrot, Valerie, Jamieson, Nigel B, Jang, Gun Ho, Jang, Se Jin, Jayaseelan, Joy C, Jayasinghe, Reyka, Jefferys, Stuart R, Jegalian, Karine, Jennings, Jennifer L, Jeon, Seung-Hyup, Jerman, Lara, Ji, Yuan, Johansson, Peter A, Johns, Amber L, Johns, Jeremy, Johnson, Rory, Johnson, Todd A, Jolly, Clemency, Joly, Yann, Jonasson, Jon G, Jones, Corbin D, Jones, David R, Jones, David TW, Jones, Nic, Jones, Steven JM, Jonkers, Jos, Ju, Young Seok, Juhl, Hartmut, Jung, Jongsun, Juul, Malene, Juul, Randi Istrup, Juul, Sissel, Jäger, Natalie, Kabbe, Rolf, Kahles, Andre, Kahraman, Abdullah, Kakavand, Hojabr, Kalimuthu, Sangeetha, von Kalle, Christof, Kang, Koo Jeong, Karaszi, Katalin, Karlan, Beth, Karlić, Rosa, Karsch, Dennis, Kasaian, Katayoon, Kassahn, Karin S, Katai, Hitoshi, Katoh, Hiroto, Kawakami, Yoshiiku, Kay, Jonathan D, Kazakoff, Stephen H, Kazanov, Marat D, Keays, Maria, Kebebew, Electron, Kefford, Richard F, Kellis, Manolis, Kench, James G, Kennedy, Catherine J, Kerssemakers, Jules NA, Khoo, David, Khoo, Vincent, Khuntikeo, Narong, Khurana, Ekta, Kilpinen, Helena, Kim, Hark Kyun, Kim, Hyung-Lae, Kim, Hyung-Yong, Kim, Hyunghwan, Kim, Jaegil, Kim, Jihoon, Kim, Jong K, Kim, Youngwook, King, Tari A, Klapper, Wolfram, Kleinheinz, Kortine, Klimczak, Leszek J, Knappskog, Stian, Kneba, Michael, Knoppers, Bartha M, Koh, Youngil, Komorowski, Jan, Komura, Daisuke, Komura, Mitsuhiro, Kong, Gu, Kool, Marcel, Korbel, Jan O, Korchina, Viktoriya, Korshunov, Andrey, Koscher, Michael, Koster, Roelof, Kote-Jarai, Zsofia, Koures, Antonios, Kovacevic, Milena, Kremeyer, Barbara, Kretzmer, Helene, Kreuz, Markus, Krishnamurthy, Savitri, Kube, Dieter, Kumar, 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Deurzen, Carolien HM, van de Vijver, Marc J, Veer, L van’t, and von Mering, Christian

Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

In cancer, the primary tumour’s organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.

Published
2023
Full Text
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295. Combined burden and functional impact tests for cancer driver discovery using DriverPower

Author

Shuai, Shimin, Abascal, Federico, Amin, Samirkumar B, Bader, Gary D, Bandopadhayay, Pratiti, Barenboim, Jonathan, Beroukhim, Rameen, Bertl, Johanna, Boroevich, Keith A, Brunak, Søren, Campbell, Peter J, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Chen, Ken, Choi, Jung Kyoon, Deu-Pons, Jordi, Dhingra, Priyanka, Diamanti, Klev, Feuerbach, Lars, Fink, J Lynn, Fonseca, Nuno A, Frigola, Joan, Gambacorti-Passerini, Carlo, Garsed, Dale W, Gerstein, Mark, Getz, Gad, Guo, Qianyun, Gut, Ivo G, Haan, David, Hamilton, Mark P, Haradhvala, Nicholas J, Harmanci, Arif O, Helmy, Mohamed, Herrmann, Carl, Hess, Julian M, Hobolth, Asger, Hodzic, Ermin, Hong, Chen, Hornshøj, Henrik, Isaev, Keren, Izarzugaza, Jose MG, Johnson, Rory, Johnson, Todd A, Juul, Malene, Juul, Randi Istrup, Kahles, Andre, Kahraman, Abdullah, Kellis, Manolis, Khurana, Ekta, Kim, Jaegil, Kim, Jong K, Kim, Youngwook, Komorowski, Jan, Korbel, Jan O, Kumar, Sushant, Lanzós, Andrés, Larsson, Erik, Lawrence, Michael S, Lee, Donghoon, Lehmann, Kjong-Van, Li, Shantao, Li, Xiaotong, Lin, Ziao, Liu, Eric Minwei, Lochovsky, Lucas, Lou, Shaoke, Madsen, Tobias, Marchal, Kathleen, Martincorena, Iñigo, Martinez-Fundichely, Alexander, Maruvka, Yosef E, McGillivray, Patrick D, Meyerson, William, Muiños, Ferran, Mularoni, Loris, Nakagawa, Hidewaki, Nielsen, Morten Muhlig, Paczkowska, Marta, Park, Keunchil, Park, Kiejung, Pedersen, Jakob Skou, Pons, Tirso, Pulido-Tamayo, Sergio, Raphael, Benjamin J, Reimand, Jüri, Reyes-Salazar, Iker, Reyna, Matthew A, Rheinbay, Esther, Rubin, Mark A, Rubio-Perez, Carlota, Sahinalp, S Cenk, Saksena, Gordon, Salichos, Leonidas, Sander, Chris, Schumacher, Steven E, Shackleton, Mark, Shapira, Ofer, Shen, Ciyue, Shrestha, Raunak, Sidiropoulos, Nikos, Sieverling, Lina, Sinnott-Armstrong, Nasa, Stein, Lincoln D, Stuart, Joshua M, Tamborero, David, Tiao, Grace, Tsunoda, Tatsuhiko, Umer, Husen M, Uusküla-Reimand, Liis, Valencia, Alfonso, Vazquez, Miguel, Verbeke, Lieven PC, Wadelius, 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Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

The discovery of driver mutations is one of the key motivations for cancer genome sequencing. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we describe DriverPower, a software package that uses mutational burden and functional impact evidence to identify driver mutations in coding and non-coding sites within cancer whole genomes. Using a total of 1373 genomic features derived from public sources, DriverPower’s background mutation model explains up to 93% of the regional variance in the mutation rate across multiple tumour types. By incorporating functional impact scores, we are able to further increase the accuracy of driver discovery. Testing across a collection of 2583 cancer genomes from the PCAWG project, DriverPower identifies 217 coding and 95 non-coding driver candidates. Comparing to six published methods used by the PCAWG Drivers and Functional Interpretation Working Group, DriverPower has the highest F1 score for both coding and non-coding driver discovery. This demonstrates that DriverPower is an effective framework for computational driver discovery.

Published
2023
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296. Integrative pathway enrichment analysis of multivariate omics data

Author

Paczkowska, Marta, Barenboim, Jonathan, Sintupisut, Nardnisa, Fox, Natalie S, Zhu, Helen, Abd-Rabbo, Diala, Mee, Miles W, Boutros, Paul C, Abascal, Federico, Amin, Samirkumar B, Bader, Gary D, Beroukhim, Rameen, Bertl, Johanna, Boroevich, Keith A, Brunak, Søren, Campbell, Peter J, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Chen, Ken, Choi, Jung Kyoon, Deu-Pons, Jordi, Dhingra, Priyanka, Diamanti, Klev, Feuerbach, Lars, Fink, J Lynn, Fonseca, Nuno A, Frigola, Joan, Gambacorti-Passerini, Carlo, Garsed, Dale W, Gerstein, Mark, Getz, Gad, Gonzalez-Perez, Abel, Guo, Qianyun, Gut, Ivo G, Haan, David, Hamilton, Mark P, Haradhvala, Nicholas J, Harmanci, Arif O, Helmy, Mohamed, Herrmann, Carl, Hess, Julian M, Hobolth, Asger, Hodzic, Ermin, Hong, Chen, Hornshøj, Henrik, Isaev, Keren, Izarzugaza, Jose MG, Johnson, Rory, Johnson, Todd A, Juul, Malene, Juul, Randi Istrup, Kahles, Andre, Kahraman, Abdullah, Kellis, Manolis, Khurana, Ekta, Kim, Jaegil, Kim, Jong K, Kim, 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Vijver, Marc J, and Veer, L van’t

Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

Multi-omics datasets represent distinct aspects of the central dogma of molecular biology. Such high-dimensional molecular profiles pose challenges to data interpretation and hypothesis generation. ActivePathways is an integrative method that discovers significantly enriched pathways across multiple datasets using statistical data fusion, rationalizes contributing evidence and highlights associated genes. As part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumor types, we integrated genes with coding and non-coding mutations and revealed frequently mutated pathways and additional cancer genes with infrequent mutations. We also analyzed prognostic molecular pathways by integrating genomic and transcriptomic features of 1780 breast cancers and highlighted associations with immune response and anti-apoptotic signaling. Integration of ChIP-seq and RNA-seq data for master regulators of the Hippo pathway across normal human tissues identified processes of tissue regeneration and stem cell regulation. ActivePathways is a versatile method that improves systems-level understanding of cellular organization in health and disease through integration of multiple molecular datasets and pathway annotations.

Published
2023
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297. Pathway and network analysis of more than 2500 whole cancer genomes

Author

Reyna, Matthew A, Haan, David, Paczkowska, Marta, Verbeke, Lieven PC, Vazquez, Miguel, Kahraman, Abdullah, Pulido-Tamayo, Sergio, Barenboim, Jonathan, Wadi, Lina, Dhingra, Priyanka, Shrestha, Raunak, Getz, Gad, Lawrence, Michael S, Pedersen, Jakob Skou, Rubin, Mark A, Wheeler, David A, Brunak, Søren, Izarzugaza, Jose MG, Khurana, Ekta, Marchal, Kathleen, von Mering, Christian, Sahinalp, S Cenk, Valencia, Alfonso, Abascal, Federico, Amin, Samirkumar B, Bader, Gary D, Bandopadhayay, Pratiti, Beroukhim, Rameen, Bertl, Johanna, Boroevich, Keith A, Busanovich, John, Campbell, Peter J, Carlevaro-Fita, Joana, Chakravarty, Dimple, Chan, Calvin Wing Yiu, Chen, Ken, Choi, Jung Kyoon, Deu-Pons, Jordi, Diamanti, Klev, Feuerbach, Lars, Fink, J Lynn, Fonseca, Nuno A, Frigola, Joan, Gambacorti-Passerini, Carlo, Garsed, Dale W, Gerstein, Mark, Guo, Qianyun, Gut, Ivo G, Hamilton, Mark P, Haradhvala, Nicholas J, Harmanci, Arif O, Helmy, Mohamed, Herrmann, Carl, Hess, Julian M, Hobolth, Asger, Hodzic, Ermin, Hong, Chen, Hornshøj, Henrik, Isaev, Keren, Johnson, Rory, Johnson, Todd A, Juul, Malene, Juul, Randi Istrup, Kahles, Andre, Kellis, Manolis, Kim, Jaegil, Kim, Jong K, Kim, Youngwook, Komorowski, Jan, Korbel, Jan O, Kumar, Sushant, Lanzós, Andrés, Larsson, Erik, Lee, Donghoon, Lehmann, Kjong-Van, Li, Shantao, Li, Xiaotong, Lin, Ziao, Liu, Eric Minwei, Lochovsky, Lucas, Lou, Shaoke, Madsen, Tobias, Martincorena, Iñigo, Martinez-Fundichely, Alexander, Maruvka, Yosef E, McGillivray, Patrick D, Meyerson, William, Muiños, Ferran, Mularoni, Loris, Nakagawa, Hidewaki, Nielsen, Morten Muhlig, Park, Keunchil, Park, Kiejung, Pons, Tirso, Reyes-Salazar, Iker, Rheinbay, Esther, Rubio-Perez, Carlota, Saksena, Gordon, Salichos, Leonidas, Sander, Chris, Schumacher, Steven E, Shackleton, Mark, Shapira, Ofer, Shen, Ciyue, Shuai, Shimin, Sidiropoulos, Nikos, Sieverling, Lina, Sinnott-Armstrong, Nasa, Stein, Lincoln D, Tamborero, David, Tiao, Grace, Tsunoda, Tatsuhiko, Umer, Husen M, 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Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.

Published
2023
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298. Divergent mutational processes distinguish hypoxic and normoxic tumours

Author

Bhandari, Vinayak, Li, Constance H, Bristow, Robert G, Boutros, Paul C, Aaltonen, Lauri A, Abascal, Federico, Abeshouse, Adam, Aburatani, Hiroyuki, Adams, David J, Agrawal, Nishant, Ahn, Keun Soo, Ahn, Sung-Min, Aikata, Hiroshi, Akbani, Rehan, Akdemir, Kadir C, Al-Ahmadie, Hikmat, Al-Sedairy, Sultan T, Al-Shahrour, Fatima, Alawi, Malik, Albert, Monique, Aldape, Kenneth, Alexandrov, Ludmil B, Ally, Adrian, Alsop, Kathryn, Alvarez, Eva G, Amary, Fernanda, Amin, Samirkumar B, Aminou, Brice, Ammerpohl, Ole, Anderson, Matthew J, Ang, Yeng, Antonello, Davide, Anur, Pavana, Aparicio, Samuel, Appelbaum, Elizabeth L, Arai, Yasuhito, Aretz, Axel, Arihiro, Koji, Ariizumi, Shun-ichi, Armenia, Joshua, Arnould, Laurent, Asa, Sylvia, Assenov, Yassen, Atwal, Gurnit, Aukema, Sietse, Auman, J Todd, Aure, Miriam RR, Awadalla, Philip, Aymerich, Marta, Bader, Gary D, Baez-Ortega, Adrian, Bailey, Matthew H, Bailey, Peter J, Balasundaram, Miruna, Balu, Saianand, Bandopadhayay, Pratiti, Banks, Rosamonde E, 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Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.

Published
2023
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299. Genomic footprints of activated telomere maintenance mechanisms in cancer

Author

Sieverling, Lina, Hong, Chen, Koser, Sandra D, Ginsbach, Philip, Kleinheinz, Kortine, Hutter, Barbara, Braun, Delia M, Cortés-Ciriano, Isidro, Xi, Ruibin, Kabbe, Rolf, Park, Peter J, Eils, Roland, Schlesner, Matthias, Akdemir, Kadir C, Alvarez, Eva G, Baez-Ortega, Adrian, Beroukhim, Rameen, Boutros, Paul C, Bowtell, David DL, Brors, Benedikt, Burns, Kathleen H, Campbell, Peter J, Chan, Kin, Chen, Ken, Dueso-Barroso, Ana, Dunford, Andrew J, Edwards, Paul A, Estivill, Xavier, Etemadmoghadam, Dariush, Feuerbach, Lars, Fink, J Lynn, Frenkel-Morgenstern, Milana, Garsed, Dale W, Gerstein, Mark, Gordenin, Dmitry A, Haan, David, Haber, James E, Hess, Julian M, Imielinski, Marcin, Jones, David TW, Ju, Young Seok, Kazanov, Marat D, Klimczak, Leszek J, Koh, Youngil, Korbel, Jan O, Kumar, Kiran, Lee, Eunjung Alice, Lee, Jake June-Koo, Li, Yilong, Lynch, Andy G, Macintyre, Geoff, Markowetz, Florian, Martincorena, Iñigo, Martinez-Fundichely, Alexander, Meyerson, Matthew, Miyano, Satoru, Nakagawa, 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Christian

Subjects
Human Biology & Physiology, Ecology,Evolution & Ethology, Tumour Biology, Genetics & Genomics, Structural Biology & Biophysics, Computational & Systems Biology
Abstract

Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.

Published
2023
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