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53. Molecular Subtypes of Pulmonary Large-cell Neuroendocrine Carcinoma Predict Chemotherapy Treatment Outcome

Author

Derks, Jules L., primary, Leblay, Noémie, additional, Thunnissen, Erik, additional, van Suylen, Robert Jan, additional, den Bakker, Michael, additional, Groen, Harry J.M., additional, Smit, Egbert F., additional, Damhuis, Ronald, additional, van den Broek, Esther C., additional, Charbrier, Amélie, additional, Foll, Matthieu, additional, McKay, James D., additional, Fernandez-Cuesta, Lynnette, additional, Speel, Ernst-Jan M., additional, and Dingemans, Anne-Marie C., additional

Published
2018
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54. Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas

Author

del Carmen Gonzalez-Vela, Maria, Curiel-Olmo, Soraya, Derdak, Sophia, Beltran, Sergi, Santibanez, Miguel, Martinez, Nerea, Castillo-Trujillo, Alfredo, Gut, Martha, Sanchez-Pacheco, Roxana, Almaraz, Carmen, Cereceda, Laura, Llombart, Beatriz, Agraz-Doblas, Antonio, Revert-Arce, Jose, Lopez Guerrero, Jose Antonio, Mollejo, Manuela, Isidro Marron, Pablo, Ortiz-Romero, Pablo, Fernandez-Cuesta, Lynnette, Varela, Ignacio, Gut, Ivo, Cerroni, Lorenzo, Angel Piris, Miguel, Pedro Vaque, Jose, del Carmen Gonzalez-Vela, Maria, Curiel-Olmo, Soraya, Derdak, Sophia, Beltran, Sergi, Santibanez, Miguel, Martinez, Nerea, Castillo-Trujillo, Alfredo, Gut, Martha, Sanchez-Pacheco, Roxana, Almaraz, Carmen, Cereceda, Laura, Llombart, Beatriz, Agraz-Doblas, Antonio, Revert-Arce, Jose, Lopez Guerrero, Jose Antonio, Mollejo, Manuela, Isidro Marron, Pablo, Ortiz-Romero, Pablo, Fernandez-Cuesta, Lynnette, Varela, Ignacio, Gut, Ivo, Cerroni, Lorenzo, Angel Piris, Miguel, and Pedro Vaque, Jose

Abstract

Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine tumor of the skin whose molecular pathogenesis is not completely understood, despite the role that Merkel cell polyomavirus can play in 55-90% of cases. To study potential mechanisms driving this disease in clinically characterized cases, we searched for somatic mutations using whole-exome sequencing, and extrapolated our findings to study functional biomarkers reporting on the activity of the mutated pathways. Confirming previous results, Merkel cell polyomavirus-negative tumors had higher mutational loads with UV signatures and more frequent mutations in TP53 and RB compared with their Merkel cell polyomavirus-positive counterparts. Despite important genetic differences, the two Merkel cell carcinoma etiologies both exhibited nuclear accumulation of oncogenic transcription factors such as NFAT or nuclear factor of activated T cells (NFAT), P-CREB, and P-STAT3, indicating commonly deregulated pathogenic mechanisms with the potential to serve as targets for therapy. A multi-variable analysis identified phosphorylated CRE-binding protein as an independent survival factor with respect to clinical variables and Merkel cell polyomavirus status in our cohort of Merkel cell carcinoma patients.

Published
2017

55. Identification of Circulating Tumor DNA for the Early Detection of Small-cell Lung Cancer

Author

Fernandez-Cuesta, Lynnette Perdomo, Sandra Avogbe, Patrice H. and Leblay, Noemie Delhomme, Tiffany M. Gaborieau, Valerie and Abedi-Ardekani, Behnoush Chanudet, Estelle Olivier, Magali and Zaridze, David Mukeria, Anush Vilensky, Marta Holcatova, Ivana Polesel, Jerry Simonato, Lorenzo Canova, Cristina and Lagiou, Pagona Brambilla, Christian Brambilla, Elisabeth and Byrnes, Graham Scelo, Ghislaine Le Calvez-Kelm, Florence and Foll, Matthieu McKay, James D. Brennan, Paul

Subjects
neoplasms
Abstract

Circulating tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays almost universal inactivation of TP53. We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. We identified mutations using a pipeline specifically designed to accurately detect variants at very low fractions. We detected TP53 mutations in the cfDNA of 49% SCLC patients and 11.4% of non-cancer controls. When stratifying the 51 initial SCLC cases by stage, TP53 mutations were detected in the cfDNA of 35.7% early-stage and 54.1% late-stage SCLC patients. The results in the controls were further replicated in 10.8% of an independent series of 102 non-cancer controls. The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests. (C) 2016 Published by Elsevier B.V.

Published
2016

56. Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas

Author

González-Vela, María del Carmen, primary, Curiel-Olmo, Soraya, additional, Derdak, Sophia, additional, Beltran, Sergi, additional, Santibañez, Miguel, additional, Martínez, Nerea, additional, Castillo-Trujillo, Alfredo, additional, Gut, Martha, additional, Sánchez-Pacheco, Roxana, additional, Almaraz, Carmen, additional, Cereceda, Laura, additional, Llombart, Beatriz, additional, Agraz-Doblas, Antonio, additional, Revert-Arce, José, additional, López Guerrero, José Antonio, additional, Mollejo, Manuela, additional, Marrón, Pablo Isidro, additional, Ortiz-Romero, Pablo, additional, Fernandez-Cuesta, Lynnette, additional, Varela, Ignacio, additional, Gut, Ivo, additional, Cerroni, Lorenzo, additional, Piris, Miguel Ángel, additional, and Vaqué, José Pedro, additional

Published
2017
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57. MA11.05 A Case-Control Study to Test the Use of ctDNA in the Early Detection of SCLC Reveals TP53 Mutations in Non-Cancer Controls

Author

Fernandez-Cuesta, Lynnette, primary, Perdomo, Sandra, additional, Avogbe, Patrice, additional, Leblay, Noémie, additional, Delhomme, Tiffany, additional, Gaborieau, Valerie, additional, Abedi-Ardekani, Behnoush, additional, Chanudet, Estelle, additional, Olivier, Magali, additional, Zaridze, David, additional, Mukeria, Anush, additional, Vilensky, Marta, additional, Holcatova, Ivana, additional, Polesel, Jerry, additional, Simonato, Lorenzo, additional, Canova, Cristina, additional, Lagiou, Pagona, additional, Brambilla, Christian, additional, Brambilla, Elisabeth, additional, Byrnes, Graham, additional, Scelo, Ghislaine, additional, Le Calvez-Kelm, Florence, additional, Foll, Matthieu, additional, Mckay, James, additional, and Brennan, Paul, additional

Published
2017
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58. P3.03-015 BAP1 is Inactivated by Copy Number Loss, Mutation, and/or Loss of Expression in More Than 70% Malignant Peritoneal Mesotheliomas

Author

Leblay, Noémie, primary, Leprêtre, Frédéric, additional, Le Stang, Nolwenn, additional, Gautier-Stein, Amandine, additional, Villeneuve, Laurent, additional, Isaac, Sylvie, additional, Maillet, Denis, additional, Galateau-Sallé, Françoise, additional, Villenet, Céline, additional, Sebda, Shéhérazade, additional, Byrnes, Graham, additional, Mckay, James, additional, Figeac, Martin, additional, Glehen, Olivier, additional, Gilly, François-Noël, additional, Foll, Matthieu, additional, Fernandez-Cuesta, Lynnette, additional, and Brevet, Marie, additional

Published
2017
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59. Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Author

Ortiz-Cuaran, Sandra, primary, Scheffler, Matthias, additional, Plenker, Dennis, additional, Dahmen, llona, additional, Scheel, Andreas H., additional, Fernandez-Cuesta, Lynnette, additional, Meder, Lydia, additional, Lovly, Christine M., additional, Persigehl, Thorsten, additional, Merkelbach-Bruse, Sabine, additional, Bos, Marc, additional, Michels, Sebastian, additional, Fischer, Rieke, additional, Albus, Kerstin, additional, König, Katharina, additional, Schildhaus, Hans-Ulrich, additional, Fassunke, Jana, additional, Ihle, Michaela A., additional, Pasternack, Helen, additional, Heydt, Carina, additional, Becker, Christian, additional, Altmüller, Janine, additional, Ji, Hongbin, additional, Müller, Christian, additional, Florin, Alexandra, additional, Heuckmann, Johannes M., additional, Nuernberg, Peter, additional, Ansén, Sascha, additional, Heukamp, Lukas C., additional, Berg, Johannes, additional, Pao, William, additional, Peifer, Martin, additional, Buettner, Reinhard, additional, Wolf, Jürgen, additional, Thomas, Roman K., additional, and Sos, Martin L., additional

Published
2016
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60. Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations

Author

Lorenz, Susanne, Baroy, Tale, Sun, Jinchang, Nome, Torfinn, Vodak, Daniel, Bryne, Jan-Christian, Hakelien, Anne-Mari, Fernandez-Cuesta, Lynnette, Moehlendick, Birte, Rieder, Harald, Szuhai, Karoly, Zaikova, Olga, Ahlquist, Terje C., Thomassen, Gard O. S., Skotheim, Rolf I., Lothe, Ragnhild A., Tarpey, Patrick S., Campbell, Peter, Flanagan, Adrienne, Myklebost, Ola, Meza-Zepeda, Leonardo A., Lorenz, Susanne, Baroy, Tale, Sun, Jinchang, Nome, Torfinn, Vodak, Daniel, Bryne, Jan-Christian, Hakelien, Anne-Mari, Fernandez-Cuesta, Lynnette, Moehlendick, Birte, Rieder, Harald, Szuhai, Karoly, Zaikova, Olga, Ahlquist, Terje C., Thomassen, Gard O. S., Skotheim, Rolf I., Lothe, Ragnhild A., Tarpey, Patrick S., Campbell, Peter, Flanagan, Adrienne, Myklebost, Ola, and Meza-Zepeda, Leonardo A.

Abstract

In contrast to many other sarcoma subtypes, the chaotic karyotypes of osteosarcoma have precluded the identification of pathognomonic translocations. We here report hundreds of genomic rearrangements in osteosarcoma cell lines, showing clear characteristics of microhomology-mediated break-induced replication (MMBIR) and end-joining repair (MMEJ) mechanisms. However, at RNA level, the majority of the fused transcripts did not correspond to genomic rearrangements, suggesting the involvement of trans-splicing, which was further supported by typical trans-splicing characteristics. By combining genomic and transcriptomic analysis, certain recurrent rearrangements were identified and further validated in patient biopsies, including a PMP22-ELOVL5 gene fusion, genomic structural variations affecting RB1, MTAP/CDKN2A and MDM2, and, most frequently, rearrangements involving TP53. Most cell lines (7/11) and a large fraction of tumor samples (10/25) showed TP53 rearrangements, in addition to somatic point mutations (6 patient samples, 1 cell line) and MDM2 amplifications (2 patient samples, 2 cell lines). The resulting inactivation of p53 was demonstrated by a deficiency of the radiation-induced DNA damage response. Thus, TP53 rearrangements are the major mechanism of p53 inactivation in osteosarcoma. Together with active MMBIR and MMEJ, this inactivation probably contributes to the exceptional chromosomal instability in these tumors. Although rampant rearrangements appear to be a phenotype of osteosarcomas, we demonstrate that among the huge number of probable passenger rearrangements, specific recurrent, possibly oncogenic, events are present. For the first time the genomic chaos of osteosarcoma is characterized so thoroughly and delivered new insights in mechanisms involved in osteosarcoma development and may contribute to new diagnostic and therapeutic strategies.

Published
2016

61. Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Author

Ortiz-Cuaran, Sandra, Scheffler, Matthias, Plenker, Dennis, Dahmen, Ilona, Scheel, Andreas H., Fernandez-Cuesta, Lynnette, Meder, Lydia, Lovly, Christine M., Persigehl, Thorsten, Merkelbach-Bruse, Sabine, Bos, Marc, Michels, Sebastian, Fischer, Rieke, Albus, Kerstin, Koenig, Katharina, Schildhaus, Hans-Ulrich, Fassunke, Jana, Ihle, Michaela A., PasternackO, Helen, Heydt, Carina, Becker, Christian, Altmueller, Janine, Ji, Hongbin, Mueller, Christian, Florin, Alexandra, Heuckmann, Johannes M., Nuernberg, Peter, Ansen, Sascha, Heukamp, Lukas C., Berg, Johannes, Pao, William, Peifer, Martin, Buettner, Reinhard, Wolfe, Juergen, Thomas, Roman K., Sos, Martin L., Ortiz-Cuaran, Sandra, Scheffler, Matthias, Plenker, Dennis, Dahmen, Ilona, Scheel, Andreas H., Fernandez-Cuesta, Lynnette, Meder, Lydia, Lovly, Christine M., Persigehl, Thorsten, Merkelbach-Bruse, Sabine, Bos, Marc, Michels, Sebastian, Fischer, Rieke, Albus, Kerstin, Koenig, Katharina, Schildhaus, Hans-Ulrich, Fassunke, Jana, Ihle, Michaela A., PasternackO, Helen, Heydt, Carina, Becker, Christian, Altmueller, Janine, Ji, Hongbin, Mueller, Christian, Florin, Alexandra, Heuckmann, Johannes M., Nuernberg, Peter, Ansen, Sascha, Heukamp, Lukas C., Berg, Johannes, Pao, William, Peifer, Martin, Buettner, Reinhard, Wolfe, Juergen, Thomas, Roman K., and Sos, Martin L.

Abstract

Purpose: To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686). Experimental Design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models. Results: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRAS(G12S) mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS. Conclusions: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. (C) 2016 AACR.

Published
2016

62. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids

Author

Fernandez-Cuesta, Lynnette, Peifer, Martin, Lu, Xin, et al, Soltermann, Alex, and University of Zurich

Subjects
1300 General Biochemistry, Genetics and Molecular Biology, 10049 Institute of Pathology and Molecular Pathology, 610 Medicine & health, 1600 General Chemistry, 3100 General Physics and Astronomy
Published
2014

63. Identification of Circulating Tumor DNA for the Early Detection of Small-cell Lung Cancer

Author

Fernandez-Cuesta, Lynnette, primary, Perdomo, Sandra, additional, Avogbe, Patrice H., additional, Leblay, Noemie, additional, Delhomme, Tiffany M., additional, Gaborieau, Valerie, additional, Abedi-Ardekani, Behnoush, additional, Chanudet, Estelle, additional, Olivier, Magali, additional, Zaridze, David, additional, Mukeria, Anush, additional, Vilensky, Marta, additional, Holcatova, Ivana, additional, Polesel, Jerry, additional, Simonato, Lorenzo, additional, Canova, Cristina, additional, Lagiou, Pagona, additional, Brambilla, Christian, additional, Brambilla, Elisabeth, additional, Byrnes, Graham, additional, Scelo, Ghislaine, additional, Le Calvez-Kelm, Florence, additional, Foll, Matthieu, additional, McKay, James D., additional, and Brennan, Paul, additional

Published
2016
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65. Abstract 3156: NGS-based screening for TP53 mutations in circulating cell-free DNA: A first step towards early detection of lung cancers

Author

Avogbe, Patrice H., primary, Delhomme, Tiffany, additional, Leblay, Noémie, additional, Le Calvez-Kelm, Florence, additional, Chopard, Priscilia, additional, Gaborieau, Valérie, additional, Scelo, Ghislaine, additional, Abedi-Ardekani, Behnoush, additional, Zaridze, David, additional, Mukeria, Anush, additional, Byrnes, Graham, additional, Brennan, Paul, additional, Fernandez-Cuesta, Lynnette, additional, Foll, Matthieu, additional, and McKay, James D., additional

Published
2016
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67. Comprehensive genomic profiles of small cell lung cancer

Author

George, Julie, Lim, Jing Shan, Jang, Se Jin, Cun, Yupeng, Ozretic, Luka, Kong, Gu, Leenders, Frauke, Lu, Xin, Fernandez-Cuesta, Lynnette, Bosco, Graziella, Mueller, Christian, Dahmen, Ilona, Jahchan, Nadine S., Park, Kwon-Sik, Yang, Dian, Karnezis, Anthony N., Vaka, Dedeepya, Torres, Angela, Wang, Maia Segura, Korbel, Jan O., Menon, Roopika, Chun, Sung-Min, Kim, Deokhoon, Wilkerson, Matt, Hayes, Neil, Engelmann, David, Puetzer, Brigitte, Bos, Marc, Michels, Sebastian, Vlasic, Ignacija, Seidel, Danila, Pinther, Berit, Schaub, Philipp, Becker, Christian, Altmueller, Janine, Yokota, Jun, Kohno, Takashi, Iwakawa, Reika, Tsuta, Koji, Noguchi, Masayuki, Muley, Thomas, Hoffmann, Hans, Schnabel, Philipp A., Petersen, Iver, Chen, Yuan, Soltermann, Alex, Tischler, Verena, Choi, Chang-min, Kim, Yong-Hee, Massion, Pierre P., Zou, Yong, Jovanovic, Dragana, Kontic, Milica, Wright, Gavin M., Russell, Prudence A., Solomon, Benjamin, Koch, Ina, Lindner, Michael, Muscarella, Lucia A., la Torre, Annamaria, Field, John K., Jakopovic, Marko, Knezevic, Jelena, Castanos-Velez, Esmeralda, Roz, Luca, Pastorino, Ugo, Brustugun, Odd-Terje, Lund-Iversen, Marius, Thunnissen, Erik, Koehler, Jens, Schuler, Martin, Botling, Johan, Sandelin, Martin, Sanchez-Cespedes, Montserrat, Salvesen, Helga B., Achter, Viktor, Lang, Ulrich, Bogus, Magdalena, Schneider, Peter M., Zander, Thomas, Ansen, Sascha, Hallek, Michael, Wolf, Juergen, Vingron, Martin, Yatabe, Yasushi, Travis, William D., Nuernberg, Peter, Reinhardt, Christian, Perner, Sven, Heukamp, Lukas, Buettner, Reinhard, Haas, Stefan A., Brambilla, Elisabeth, Peifer, Martin, Sage, Julien, Thomas, Roman K., George, Julie, Lim, Jing Shan, Jang, Se Jin, Cun, Yupeng, Ozretic, Luka, Kong, Gu, Leenders, Frauke, Lu, Xin, Fernandez-Cuesta, Lynnette, Bosco, Graziella, Mueller, Christian, Dahmen, Ilona, Jahchan, Nadine S., Park, Kwon-Sik, Yang, Dian, Karnezis, Anthony N., Vaka, Dedeepya, Torres, Angela, Wang, Maia Segura, Korbel, Jan O., Menon, Roopika, Chun, Sung-Min, Kim, Deokhoon, Wilkerson, Matt, Hayes, Neil, Engelmann, David, Puetzer, Brigitte, Bos, Marc, Michels, Sebastian, Vlasic, Ignacija, Seidel, Danila, Pinther, Berit, Schaub, Philipp, Becker, Christian, Altmueller, Janine, Yokota, Jun, Kohno, Takashi, Iwakawa, Reika, Tsuta, Koji, Noguchi, Masayuki, Muley, Thomas, Hoffmann, Hans, Schnabel, Philipp A., Petersen, Iver, Chen, Yuan, Soltermann, Alex, Tischler, Verena, Choi, Chang-min, Kim, Yong-Hee, Massion, Pierre P., Zou, Yong, Jovanovic, Dragana, Kontic, Milica, Wright, Gavin M., Russell, Prudence A., Solomon, Benjamin, Koch, Ina, Lindner, Michael, Muscarella, Lucia A., la Torre, Annamaria, Field, John K., Jakopovic, Marko, Knezevic, Jelena, Castanos-Velez, Esmeralda, Roz, Luca, Pastorino, Ugo, Brustugun, Odd-Terje, Lund-Iversen, Marius, Thunnissen, Erik, Koehler, Jens, Schuler, Martin, Botling, Johan, Sandelin, Martin, Sanchez-Cespedes, Montserrat, Salvesen, Helga B., Achter, Viktor, Lang, Ulrich, Bogus, Magdalena, Schneider, Peter M., Zander, Thomas, Ansen, Sascha, Hallek, Michael, Wolf, Juergen, Vingron, Martin, Yatabe, Yasushi, Travis, William D., Nuernberg, Peter, Reinhardt, Christian, Perner, Sven, Heukamp, Lukas, Buettner, Reinhard, Haas, Stefan A., Brambilla, Elisabeth, Peifer, Martin, Sage, Julien, and Thomas, Roman K.

Abstract

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Dex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.

Published
2015
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68. Identification of novel fusion genes in lung cancer using breakpoint assembly of transcriptome sequencing data

Author

Fernandez-Cuesta, Lynnette, Sun, Ruping, Menon, Roopika, George, Julie, Lorenz, Susanne, Meza-Zepeda, Leonardo A., Peifer, Martin, Plenker, Dennis, Heuckmann, Johannes M., Leenders, Frauke, Zander, Thomas, Dahmen, Ilona, Koker, Mirjam, Schoettle, Jakob, Ullrich, Roland T., Altmueller, Janine, Becker, Christian, Nuernberg, Peter, Seidel, Henrik, Boehm, Diana, Goeke, Friederike, Ansen, Sascha, Russell, Prudence A., Wright, Gavin M., Wainer, Zoe, Solomon, Benjamin, Petersen, Iver, Clement, Joachim H., Saenger, Joerg, Brustugun, Odd-Terje, Helland, Aslaug, Solberg, Steinar, Lund-Iversen, Marius, Buettner, Reinhard, Wolf, Juergen, Brambilla, Elisabeth, Vingron, Martin, Perner, Sven, Haas, Stefan A., Thomas, Roman K., Fernandez-Cuesta, Lynnette, Sun, Ruping, Menon, Roopika, George, Julie, Lorenz, Susanne, Meza-Zepeda, Leonardo A., Peifer, Martin, Plenker, Dennis, Heuckmann, Johannes M., Leenders, Frauke, Zander, Thomas, Dahmen, Ilona, Koker, Mirjam, Schoettle, Jakob, Ullrich, Roland T., Altmueller, Janine, Becker, Christian, Nuernberg, Peter, Seidel, Henrik, Boehm, Diana, Goeke, Friederike, Ansen, Sascha, Russell, Prudence A., Wright, Gavin M., Wainer, Zoe, Solomon, Benjamin, Petersen, Iver, Clement, Joachim H., Saenger, Joerg, Brustugun, Odd-Terje, Helland, Aslaug, Solberg, Steinar, Lund-Iversen, Marius, Buettner, Reinhard, Wolf, Juergen, Brambilla, Elisabeth, Vingron, Martin, Perner, Sven, Haas, Stefan A., and Thomas, Roman K.

Abstract

Genomic translocation events frequently underlie cancer development through generation of gene fusions with oncogenic properties. Identification of such fusion transcripts by transcriptome sequencing might help to discover new potential therapeutic targets. We developed TRUP (Tumor-specimen suited RNA-seq Unified Pipeline) (https://github.com/ruping/TRUP), a computational approach that combines split-read and read-pair analysis with de novo assembly for the identification of chimeric transcripts in cancer specimens. We apply TRUP to RNA-seq data of different tumor types, and find it to be more sensitive than alternative tools in detecting chimeric transcripts, such as secondary rearrangements in EML4-ALK-positive lung tumors, or recurrent inactivating rearrangements affecting RASSF8.

Published
2015

69. Genomic Characterization of Large-Cell Neuroendocrine Lung Tumors

Author

Fernandez-Cuesta, Lynnette, Peifer, Martin, George, Julie, De Reynies, Aurelien, Sun, Ruping, Altmueller, Janine, Nuernberg, Peter, Olivier, Magali, Ardin, Maude, Blum, Yuna, Laffaire, Julien, Elarouci, Nabila, Petel, Fabien, Mckay, James, Byrnes, Graham, Nagy-Mignotte, Helene, Moro-Sibilot, Denis, Brambilla, Christian, Lantuejoul, Sylvie, Mcleer, Anne, Soltermann, Alex, Brustugun, Odd T., Helland, Aslaug, Solberg, Steinar, Lund-Iversen, Marius, Ansen, Sascha, Wright, Gavin, Russell, Prudence A., Solomon, Benjamin J., Roz, Luca, Pastorino, Ugo, Petersen, Iver, Clement, Joachim H., Saenger, Joerg, Zander, Thomas, Buettner, Reinhard, Haas, Stefan, Brambilla, Elisabeth, Thomas, Roman K., Fernandez-Cuesta, Lynnette, Peifer, Martin, George, Julie, De Reynies, Aurelien, Sun, Ruping, Altmueller, Janine, Nuernberg, Peter, Olivier, Magali, Ardin, Maude, Blum, Yuna, Laffaire, Julien, Elarouci, Nabila, Petel, Fabien, Mckay, James, Byrnes, Graham, Nagy-Mignotte, Helene, Moro-Sibilot, Denis, Brambilla, Christian, Lantuejoul, Sylvie, Mcleer, Anne, Soltermann, Alex, Brustugun, Odd T., Helland, Aslaug, Solberg, Steinar, Lund-Iversen, Marius, Ansen, Sascha, Wright, Gavin, Russell, Prudence A., Solomon, Benjamin J., Roz, Luca, Pastorino, Ugo, Petersen, Iver, Clement, Joachim H., Saenger, Joerg, Zander, Thomas, Buettner, Reinhard, Haas, Stefan, Brambilla, Elisabeth, and Thomas, Roman K.

Published
2015

70. Elucidating the mechanisms of acquired resistance in lung adenocarcinomas

Author

Ortiz-Cuaran, Sandra, Fernandez-Cuesta, Lynnette, Lovly, Christine M., Bos, Marc, Scheffler, Matthias, Michels, Sebastian, Albus, Kerstin, Meyer, Lydia, Koenig, Katharina, Dahmen, Ilona, Mueller, Christian, Ozretic, Luca, Tharun, Lars, Schaub, Philipp, Florin, Alexandra, Pinther, Berit, Bahlmann, Nike, Ansen, Sascha, Peifer, Martin, Heukamp, Lukas C., Buettner, Reinhard, Sos, Martin L., Wolf, Juergen, Pao, William, Thomas, Roman K., Ortiz-Cuaran, Sandra, Fernandez-Cuesta, Lynnette, Lovly, Christine M., Bos, Marc, Scheffler, Matthias, Michels, Sebastian, Albus, Kerstin, Meyer, Lydia, Koenig, Katharina, Dahmen, Ilona, Mueller, Christian, Ozretic, Luca, Tharun, Lars, Schaub, Philipp, Florin, Alexandra, Pinther, Berit, Bahlmann, Nike, Ansen, Sascha, Peifer, Martin, Heukamp, Lukas C., Buettner, Reinhard, Sos, Martin L., Wolf, Juergen, Pao, William, and Thomas, Roman K.

Published
2015

71. Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations

Author

Lorenz, Susanne, primary, Barøy, Tale, additional, Sun, Jinchang, additional, Nome, Torfinn, additional, Vodák, Daniel, additional, Bryne, Jan-Christian, additional, Håkelien, Anne-Mari, additional, Fernandez-Cuesta, Lynnette, additional, Möhlendick, Birte, additional, Rieder, Harald, additional, Szuhai, Karoly, additional, Zaikova, Olga, additional, Ahlquist, Terje C., additional, Thomassen, Gard O. S., additional, Skotheim, Rolf I., additional, Lothe, Ragnhild A., additional, Tarpey, Patrick S., additional, Campbell, Peter, additional, Flanagan, Adrienne, additional, Myklebost, Ola, additional, and Meza-Zepeda, Leonardo A., additional

Published
2015
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72. Abstract 752: Elucidating the mechanisms of acquired resistance in lung adenocarcinomas

Author

Ortiz-Cuarán, Sandra, primary, Fernandez-Cuesta, Lynnette, additional, Lovly, Christine M., additional, Bos, Marc, additional, Scheffler, Matthias, additional, Michels, Sebastian, additional, Albus, Kerstin, additional, Meyer, Lydia, additional, König, Katharina, additional, Dahmen, Ilona, additional, Mueller, Christian, additional, Ozretić, Luca, additional, Tharun, Lars, additional, Schaub, Philipp, additional, Florin, Alexandra, additional, Pinther, Berit, additional, Bahlmann, Nike, additional, Ansén, Sascha, additional, Peifer, Martin, additional, Heukamp, Lukas C., additional, Buettner, Reinhard, additional, Sos, Martin L., additional, Wolf, Jürgen, additional, Pao, William, additional, and Thomas, Roman K., additional

Published
2015
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74. Identification of novel fusion genes in lung cancer using breakpoint assembly of transcriptome sequencing data

Author

Fernandez-Cuesta, Lynnette, primary, Sun, Ruping, additional, Menon, Roopika, additional, George, Julie, additional, Lorenz, Susanne, additional, Meza-Zepeda, Leonardo A, additional, Peifer, Martin, additional, Plenker, Dennis, additional, Heuckmann, Johannes M, additional, Leenders, Frauke, additional, Zander, Thomas, additional, Dahmen, Ilona, additional, Koker, Mirjam, additional, Schöttle, Jakob, additional, Ullrich, Roland T, additional, Altmüller, Janine, additional, Becker, Christian, additional, Nürnberg, Peter, additional, Seidel, Henrik, additional, Böhm, Diana, additional, Göke, Friederike, additional, Ansén, Sascha, additional, Russell, Prudence A, additional, Wright, Gavin M, additional, Wainer, Zoe, additional, Solomon, Benjamin, additional, Petersen, Iver, additional, Clement, Joachim H, additional, Sänger, Jörg, additional, Brustugun, Odd-Terje, additional, Helland, Åslaug, additional, Solberg, Steinar, additional, Lund-Iversen, Marius, additional, Buettner, Reinhard, additional, Wolf, Jürgen, additional, Brambilla, Elisabeth, additional, Vingron, Martin, additional, Perner, Sven, additional, Haas, Stefan A, additional, and Thomas, Roman K, additional

Published
2015
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75. Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

Author

Malchers, Florian, Dietlein, Felix, Schottle, Jakob, Lu, Xin, Nogova, Lucia, Albus, Kerstin, Fernandez-Cuesta, Lynnette, Heuckmann, Johannes M., Gautschi, Oliver, Diebold, Joachim, Plenker, Dennis, Gardizi, Masyar, Er, Matthias Scheffl, Bos, Marc, Seidel, Danila, Leenders, Frauke, Richters, Andre, Peifer, Martin, Florin, Alexandra, Mainkar, Prathama S., Karre, Nagaraju, Chandrasekhar, Srivari, George, Julie, Silling, Steffi, Rauh, Daniel, Zander, Thomas, Ullrich, Roland T., Reinhardt, H. Christian, Ringeisen, Francois, Buettner, Reinhard, Heukamp, Lukas C., Wolf, Juergen, Thomas, Roman K., Malchers, Florian, Dietlein, Felix, Schottle, Jakob, Lu, Xin, Nogova, Lucia, Albus, Kerstin, Fernandez-Cuesta, Lynnette, Heuckmann, Johannes M., Gautschi, Oliver, Diebold, Joachim, Plenker, Dennis, Gardizi, Masyar, Er, Matthias Scheffl, Bos, Marc, Seidel, Danila, Leenders, Frauke, Richters, Andre, Peifer, Martin, Florin, Alexandra, Mainkar, Prathama S., Karre, Nagaraju, Chandrasekhar, Srivari, George, Julie, Silling, Steffi, Rauh, Daniel, Zander, Thomas, Ullrich, Roland T., Reinhardt, H. Christian, Ringeisen, Francois, Buettner, Reinhard, Heukamp, Lukas C., Wolf, Juergen, and Thomas, Roman K.

Abstract

The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplified tumors are also sensitive to fibroblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifications, the 8p12 region included multiple centers of amplification, suggesting marked genomic heterogeneity. FGFR1-amplified tumor cells were dependent on FGFR ligands in vitro and in vivo. Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1 amplified tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplified and MYC-overexpressing tumors may benefit from FGFR inhibitor therapy. Thus, both cell-autonomous and non-cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1-amplified lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors. SIGNIFICANCE: Amplification of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1, thus providing clinical hypotheses for refinement of patient selection.

Published
2014

76. CD74-NRG1 Fusions in Lung Adenocarcinoma

Author

Fernandez-Cuesta, Lynnette, Plenker, Dennis, Osada, Hirotaka, Sun, Ruping, Menon, Roopika, Leenders, Frauke, Ortiz-Cuaran, Sandra, Peifer, Martin, Bos, Marc, Dassler, Juliane, Malchers, Florian, Schottle, Jakob, Vogel, Wenzel, Dahmen, Ilona, Koker, Mirjam, Ullrich, Roland T., Wright, Gavin M., Russell, Prudence A., Wainer, Zoe, Solomon, Benjamin, Brambilla, Elisabeth, Nagy-Mignotte, Helene, Moro-Sibilot, Denis, Brambilla, Christian G., Lantuejoul, Sylvie, Altmuller, Janine, Becker, Christian, Nurnberg, Peter, Heuckmann, Johannes M., Stoelben, Erich, Petersen, Iver, Clement, Joachim H., Saenger, Joerg, Muscarella, Lucia A., la Torre, Annamaria, Fazio, Vito M., Lahortiga, Idoya, Perera, Timothy, Ogata, Souichi, Parade, Marc, Brehmer, Dirk, Vingron, Martin, Heukamp, Lukas C., Buettner, Reinhard, Zander, Thomas, Wolf, Jurgen, Perner, Sven, Ansen, Sascha, Haas, Stefan A., Yatabe, Yasushi, Thomas, Roman K., Fernandez-Cuesta, Lynnette, Plenker, Dennis, Osada, Hirotaka, Sun, Ruping, Menon, Roopika, Leenders, Frauke, Ortiz-Cuaran, Sandra, Peifer, Martin, Bos, Marc, Dassler, Juliane, Malchers, Florian, Schottle, Jakob, Vogel, Wenzel, Dahmen, Ilona, Koker, Mirjam, Ullrich, Roland T., Wright, Gavin M., Russell, Prudence A., Wainer, Zoe, Solomon, Benjamin, Brambilla, Elisabeth, Nagy-Mignotte, Helene, Moro-Sibilot, Denis, Brambilla, Christian G., Lantuejoul, Sylvie, Altmuller, Janine, Becker, Christian, Nurnberg, Peter, Heuckmann, Johannes M., Stoelben, Erich, Petersen, Iver, Clement, Joachim H., Saenger, Joerg, Muscarella, Lucia A., la Torre, Annamaria, Fazio, Vito M., Lahortiga, Idoya, Perera, Timothy, Ogata, Souichi, Parade, Marc, Brehmer, Dirk, Vingron, Martin, Heukamp, Lukas C., Buettner, Reinhard, Zander, Thomas, Wolf, Jurgen, Perner, Sven, Ansen, Sascha, Haas, Stefan A., Yatabe, Yasushi, and Thomas, Roman K.

Abstract

We discovered a novel somatic gene fusion, CD74-NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74-NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III- ss 3, thereby providing the ligand for ERBB2-ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion ( P < 0.0001). Ectopic expression of CD74-NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K-AKT pathway, and led to increased colony formation in soft agar. Thus, CD74-NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment. SIGNIFICANCE: CD74-NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov; 4(4); 415- 22. (c) 2014 AACR.

Published
2014

77. Elucidating the mechanisms of acquired resistance in lung adenocarcinomas

Author

Ortiz-Cuaran, Sandra, Fernandez-Cuesta, Lynnette, Bos, Marc, Heukamp, Lukas, Lovly, Christine M., Peifer, Martin, Gardizi, Masyar, Scheffler, Matthias, Dahmen, Ilona, Mueller, Christian, Koenig, Katharina, Albus, Kerstin, Florin, Alexandra, Ansen, Sascha, Buettner, Reinhard, Wolf, Juergen, Pao, William, Thomas, Roman K., Ortiz-Cuaran, Sandra, Fernandez-Cuesta, Lynnette, Bos, Marc, Heukamp, Lukas, Lovly, Christine M., Peifer, Martin, Gardizi, Masyar, Scheffler, Matthias, Dahmen, Ilona, Mueller, Christian, Koenig, Katharina, Albus, Kerstin, Florin, Alexandra, Ansen, Sascha, Buettner, Reinhard, Wolf, Juergen, Pao, William, and Thomas, Roman K.

Published
2014

78. Functional characterization of recurrent CD74-NRG1 fusions in lung adenocarcinoma

Author

Plenker, Dennis, Fernandez-Cuesta, Lynnette, Osada, Hirotaka, Sun, Ruping, Bos, Marc, Dassler, Juliane, Wright, Gavin, Brambilla, Elisabeth, Buettner, Reinhard, Ansen, Sascha, Haas, Stefan, Yatabe, Yasushi, Thomas, Roman K., Plenker, Dennis, Fernandez-Cuesta, Lynnette, Osada, Hirotaka, Sun, Ruping, Bos, Marc, Dassler, Juliane, Wright, Gavin, Brambilla, Elisabeth, Buettner, Reinhard, Ansen, Sascha, Haas, Stefan, Yatabe, Yasushi, and Thomas, Roman K.

Published
2014

79. Cross-entity mutation analysis of lung neuroendocrine tumors sheds light into their molecular origin and identifies new therapeutic targets

Author

Fernandez-Cuesta, Lynnette, Peifer, Martin, Lu, Xin, Seidel, Danila, Zander, Thomas, Leenders, Frauke, Ozretic, Luka, Brustugun, Odd-Terje, Field, John K., Wright, Gavin, Solomon, Benjamin, Buettner, Reinhard, Brambilla, Christian, Brambilla, Elisabeth, Thomas, Roman K., Fernandez-Cuesta, Lynnette, Peifer, Martin, Lu, Xin, Seidel, Danila, Zander, Thomas, Leenders, Frauke, Ozretic, Luka, Brustugun, Odd-Terje, Field, John K., Wright, Gavin, Solomon, Benjamin, Buettner, Reinhard, Brambilla, Christian, Brambilla, Elisabeth, and Thomas, Roman K.

Published
2014

82. Abstract 1531: Cross-entity mutation analysis of lung neuroendocrine tumors sheds light into their molecular origin and identifies new therapeutic targets

Author

Fernandez-Cuesta, Lynnette, primary, Peifer, Martin, additional, Lu, Xin, additional, Seidel, Danila, additional, Zander, Thomas, additional, Leenders, Frauke, additional, Ozretić, Luka, additional, Brustugun, Odd-Terje, additional, Field, John K., additional, Wright, Gavin, additional, Solomon, Benjamin, additional, Buettner, Reinhard, additional, Brambilla, Christian, additional, Brambilla, Elisabeth, additional, and Thomas, Roman K., additional

Published
2014
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83. Abstract 441: Functional characterization of recurrent CD74-NRG1 fusions in lung adenocarcinoma

Author

Plenker, Dennis, primary, Fernandez-Cuesta, Lynnette, additional, Osada, Hirotaka, additional, Sun, Ruping, additional, Bos, Marc, additional, Daßler, Juliane, additional, Wright, Gavin, additional, Brambilla, Elisabeth, additional, Büttner, Reinhard, additional, Ansen, Sascha, additional, Haas, Stefan, additional, Yatabe, Yasushi, additional, and Thomas, Roman K., additional

Published
2014
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84. Abstract 956: Elucidating the mechanisms of acquired resistance in lung adenocarcinomas

Author

Ortiz-Cuarán, Sandra, primary, Fernandez-Cuesta, Lynnette, additional, Bos, Marc, additional, Heukamp, Lukas, additional, Lovly, Christine M., additional, Peifer, Martin, additional, Gardizi, Masyar, additional, Scheffler, Matthias, additional, Dahmen, Ilona, additional, Müller, Christian, additional, König, Katharina, additional, Albus, Kerstin, additional, Florin, Alexandra, additional, Ansén, Sascha, additional, Buettner, Reinhard, additional, Wolf, Jürgen, additional, Pao, William, additional, and Thomas, Roman K., additional

Published
2014
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85. CD74–NRG1 Fusions in Lung Adenocarcinoma

Author

Fernandez-Cuesta, Lynnette, primary, Plenker, Dennis, additional, Osada, Hirotaka, additional, Sun, Ruping, additional, Menon, Roopika, additional, Leenders, Frauke, additional, Ortiz-Cuaran, Sandra, additional, Peifer, Martin, additional, Bos, Marc, additional, Daßler, Juliane, additional, Malchers, Florian, additional, Schöttle, Jakob, additional, Vogel, Wenzel, additional, Dahmen, Ilona, additional, Koker, Mirjam, additional, Ullrich, Roland T., additional, Wright, Gavin M., additional, Russell, Prudence A., additional, Wainer, Zoe, additional, Solomon, Benjamin, additional, Brambilla, Elisabeth, additional, Nagy-Mignotte, Hélène, additional, Moro-Sibilot, Denis, additional, Brambilla, Christian G., additional, Lantuejoul, Sylvie, additional, Altmüller, Janine, additional, Becker, Christian, additional, Nürnberg, Peter, additional, Heuckmann, Johannes M., additional, Stoelben, Erich, additional, Petersen, Iver, additional, Clement, Joachim H., additional, Sänger, Jörg, additional, Muscarella, Lucia A., additional, la Torre, Annamaria, additional, Fazio, Vito M., additional, Lahortiga, Idoya, additional, Perera, Timothy, additional, Ogata, Souichi, additional, Parade, Marc, additional, Brehmer, Dirk, additional, Vingron, Martin, additional, Heukamp, Lukas C., additional, Buettner, Reinhard, additional, Zander, Thomas, additional, Wolf, Jürgen, additional, Perner, Sven, additional, Ansén, Sascha, additional, Haas, Stefan A., additional, Yatabe, Yasushi, additional, and Thomas, Roman K., additional

Published
2014
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86. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids

Author

Fernandez-Cuesta, Lynnette, primary, Peifer, Martin, additional, Lu, Xin, additional, Sun, Ruping, additional, Ozretić, Luka, additional, Seidel, Danila, additional, Zander, Thomas, additional, Leenders, Frauke, additional, George, Julie, additional, Müller, Christian, additional, Dahmen, Ilona, additional, Pinther, Berit, additional, Bosco, Graziella, additional, Konrad, Kathryn, additional, Altmüller, Janine, additional, Nürnberg, Peter, additional, Achter, Viktor, additional, Lang, Ulrich, additional, Schneider, Peter M., additional, Bogus, Magdalena, additional, Soltermann, Alex, additional, Brustugun, Odd Terje, additional, Helland, Åslaug, additional, Solberg, Steinar, additional, Lund-Iversen, Marius, additional, Ansén, Sascha, additional, Stoelben, Erich, additional, Wright, Gavin M., additional, Russell, Prudence, additional, Wainer, Zoe, additional, Solomon, Benjamin, additional, Field, John K., additional, Hyde, Russell, additional, Davies, Michael P. A., additional, Heukamp, Lukas C., additional, Petersen, Iver, additional, Perner, Sven, additional, Lovly, Christine M., additional, Cappuzzo, Federico, additional, Travis, William D., additional, Wolf, Jürgen, additional, Vingron, Martin, additional, Brambilla, Elisabeth, additional, Haas, Stefan A., additional, Buettner, Reinhard, additional, and Thomas, Roman K., additional

Published
2014
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87. Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

Author

Malchers, Florian, primary, Dietlein, Felix, additional, Schöttle, Jakob, additional, Lu, Xin, additional, Nogova, Lucia, additional, Albus, Kerstin, additional, Fernandez-Cuesta, Lynnette, additional, Heuckmann, Johannes M., additional, Gautschi, Oliver, additional, Diebold, Joachim, additional, Plenker, Dennis, additional, Gardizi, Masyar, additional, Scheffler, Matthias, additional, Bos, Marc, additional, Seidel, Danila, additional, Leenders, Frauke, additional, Richters, André, additional, Peifer, Martin, additional, Florin, Alexandra, additional, Mainkar, Prathama S., additional, Karre, Nagaraju, additional, Chandrasekhar, Srivari, additional, George, Julie, additional, Silling, Steffi, additional, Rauh, Daniel, additional, Zander, Thomas, additional, Ullrich, Roland T., additional, Reinhardt, H. Christian, additional, Ringeisen, Francois, additional, Büttner, Reinhard, additional, Heukamp, Lukas C., additional, Wolf, Jürgen, additional, and Thomas, Roman K., additional

Published
2014
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88. A Genomics-Based Classification of Human Lung Tumors

Author

Seidel, Danila, Zander, Thomas, Heukamp, Lukas C., Peifer, Martin, Bos, Marc, Fernandez-Cuesta, Lynnette, Leenders, Frauke, Lu, Xin, Ansen, Sascha, Gardizi, Masyar, Nguyen, Chau, Berg, Johannes, Russell, Prudence, Wainer, Zoe, Schildhaus, Hans-Ulrich, Rogers, Toni-Maree, Solomon, Benjamin, Pao, William, Carter, Scott L., Getz, Gad, Hayes, D. Neil, Wilkerson, Matthew D., Thunnissen, Erik, Travis, William D., Perner, Sven, Wright, Gavin, Brambilla, Elisabeth, Buettner, Reinhard, Wolf, Juergen, Thomas, Roman, Gabler, Franziska, Wilkening, Ines, Mueller, Christian, Dahmen, Ilona, Menon, Roopika, Koenig, Katharina, Albus, Kerstin, Merkelbach-Bruse, Sabine, Fassunke, Jana, Schmitz, Katja, Kuenstlinger, Helen, Kleine, Michaela, Binot, Elke, Querings, Silvia, Altmueller, Janine, Boessmann, Ingelore, Nuemberg, Peter, Schneider, Peter, Bogus, Magdalena, Soltermann, Alex, Moch, Holger, Brustugun, Odd Terje, Solberg, Steinar, Lund-Iversen, Marius, Helland, Aslaug, Muley, Thomas, Hoffmann, Hans, Schnabel, Philipp A., Chen, Yuan, Groen, Harry, Timens, Wim, Sietsma, Hannie, Clement, Joachim H., Weder, Walter, Saenger, Joerg, Stoelben, Erich, Ludwig, Corinna, Engel-Riedel, Walburga, Smit, Egbert, Heideman, Danille A. M., Snijders, Peter J. F., Nogova, Lucia, Sos, Martin L., Mattonet, Christian, Toepelt, Karin, Scheffler, Matthias, Goekkurt, Eray, Kappes, Rainer, Krueger, Stefan, Kambartel, Kato, Behringer, Dirk, Schulte, Wolfgang, Galetke, Wolfgang, Randerath, Winfried, Heldwein, Matthias, Schlesinger, Andreas, Serke, Monika, Hekmat, Khosro, Frank, Konrad F., Schnell, Roland, Reiser, Marcel, Huenerlituerkoglu, Ali-Nuri, Schmitz, Stephan, Meffert, Lisa, Ko, Yon-Dschun, Litt-Lampe, Markus, Gerigk, Ulrich, Fricke, Rainer, Besse, Benjamin, Brambilla, Christian, Lantuejoul, Sylvie, Lorimier, Philippe, Moro-Sibilot, Denis, Cappuzzo, Federico, Ligorio, Claudia, Damiani, Stefania, Field, John K., Hyde, Russell, Validire, Pierre, Girard, Philippe, Muscarella, Lucia A., Fazio, Vito M., Hallek, Michael, Soria, Jean-Charles, Achter, Viktor, Lang, Ulrich, Thomas, Roman K., Seidel, Danila, Zander, Thomas, Heukamp, Lukas C., Peifer, Martin, Bos, Marc, Fernandez-Cuesta, Lynnette, Leenders, Frauke, Lu, Xin, Ansen, Sascha, Gardizi, Masyar, Nguyen, Chau, Berg, Johannes, Russell, Prudence, Wainer, Zoe, Schildhaus, Hans-Ulrich, Rogers, Toni-Maree, Solomon, Benjamin, Pao, William, Carter, Scott L., Getz, Gad, Hayes, D. Neil, Wilkerson, Matthew D., Thunnissen, Erik, Travis, William D., Perner, Sven, Wright, Gavin, Brambilla, Elisabeth, Buettner, Reinhard, Wolf, Juergen, Thomas, Roman, Gabler, Franziska, Wilkening, Ines, Mueller, Christian, Dahmen, Ilona, Menon, Roopika, Koenig, Katharina, Albus, Kerstin, Merkelbach-Bruse, Sabine, Fassunke, Jana, Schmitz, Katja, Kuenstlinger, Helen, Kleine, Michaela, Binot, Elke, Querings, Silvia, Altmueller, Janine, Boessmann, Ingelore, Nuemberg, Peter, Schneider, Peter, Bogus, Magdalena, Soltermann, Alex, Moch, Holger, Brustugun, Odd Terje, Solberg, Steinar, Lund-Iversen, Marius, Helland, Aslaug, Muley, Thomas, Hoffmann, Hans, Schnabel, Philipp A., Chen, Yuan, Groen, Harry, Timens, Wim, Sietsma, Hannie, Clement, Joachim H., Weder, Walter, Saenger, Joerg, Stoelben, Erich, Ludwig, Corinna, Engel-Riedel, Walburga, Smit, Egbert, Heideman, Danille A. M., Snijders, Peter J. F., Nogova, Lucia, Sos, Martin L., Mattonet, Christian, Toepelt, Karin, Scheffler, Matthias, Goekkurt, Eray, Kappes, Rainer, Krueger, Stefan, Kambartel, Kato, Behringer, Dirk, Schulte, Wolfgang, Galetke, Wolfgang, Randerath, Winfried, Heldwein, Matthias, Schlesinger, Andreas, Serke, Monika, Hekmat, Khosro, Frank, Konrad F., Schnell, Roland, Reiser, Marcel, Huenerlituerkoglu, Ali-Nuri, Schmitz, Stephan, Meffert, Lisa, Ko, Yon-Dschun, Litt-Lampe, Markus, Gerigk, Ulrich, Fricke, Rainer, Besse, Benjamin, Brambilla, Christian, Lantuejoul, Sylvie, Lorimier, Philippe, Moro-Sibilot, Denis, Cappuzzo, Federico, Ligorio, Claudia, Damiani, Stefania, Field, John K., Hyde, Russell, Validire, Pierre, Girard, Philippe, Muscarella, Lucia A., Fazio, Vito M., Hallek, Michael, Soria, Jean-Charles, Achter, Viktor, Lang, Ulrich, and Thomas, Roman K.

Published
2013

89. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

Author

Peifer, Martin, Fernandez-Cuesta, Lynnette, Sos, Martin L., George, Julie, Seidel, Danila, Kasper, Lawryn H., Plenker, Dennis, Leenders, Frauke, Sun, Ruping, Zander, Thomas, Menon, Roopika, Koker, Mirjam, Dahmen, Ilona, Mueller, Christian, Di Cerbo, Vincenzo, Schildhaus, Hans-Ulrich, Altmueller, Janine, Baessmann, Ingelore, Becker, Christian, de Wilde, Bram, Vandesompele, Jo, Boehm, Diana, Ansen, Sascha, Gabler, Franziska, Wilkening, Ines, Heynck, Stefanie, Heuckmann, Johannes M., Lu, Xin, Carter, Scott L., Cibulskis, Kristian, Banerji, Shantanu, Getz, Gad, Park, Kwon-Sik, Rauh, Daniel, Gruetter, Christian, Fischer, Matthias, Pasqualucci, Laura, Wright, Gavin, Wainer, Zoe, Russell, Prudence, Petersen, Iver, Chen, Yuan, Stoelben, Erich, Ludwig, Corinna, Schnabel, Philipp, Hoffmann, Hans, Muley, Thomas, Brockmann, Michael, Engel-Riedel, Walburga, Muscarella, Lucia A., Fazio, Vito M., Groen, Harry, Timens, Wim, Sietsma, Hannie, Thunnissen, Erik, Smit, Egbert, Heideman, Danielle A. M., Snijders, Peter J. F., Cappuzzo, Federico, Ligorio, Claudia, Damiani, Stefania, Field, John, Solberg, Steinar, Brustugun, Odd Terje, Lund-Iversen, Marius, Saenger, Joerg, Clement, Joachim H., Soltermann, Alex, Moch, Holger, Weder, Walter, Solomon, Benjamin, Soria, Jean-Charles, Validire, Pierre, Besse, Benjamin, Brambilla, Elisabeth, Brambilla, Christian, Lantuejoul, Sylvie, Lorimier, Philippe, Schneider, Peter M., Hallek, Michael, Pao, William, Meyerson, Matthew, Sage, Julien, Shendure, Jay, Schneider, Robert, Buettner, Reinhard, Wolf, Juergen, Nuernberg, Peter, Perner, Sven, Heukamp, Lukas C., Brindle, Paul K., Haas, Stefan, Thomas, Roman K., Peifer, Martin, Fernandez-Cuesta, Lynnette, Sos, Martin L., George, Julie, Seidel, Danila, Kasper, Lawryn H., Plenker, Dennis, Leenders, Frauke, Sun, Ruping, Zander, Thomas, Menon, Roopika, Koker, Mirjam, Dahmen, Ilona, Mueller, Christian, Di Cerbo, Vincenzo, Schildhaus, Hans-Ulrich, Altmueller, Janine, Baessmann, Ingelore, Becker, Christian, de Wilde, Bram, Vandesompele, Jo, Boehm, Diana, Ansen, Sascha, Gabler, Franziska, Wilkening, Ines, Heynck, Stefanie, Heuckmann, Johannes M., Lu, Xin, Carter, Scott L., Cibulskis, Kristian, Banerji, Shantanu, Getz, Gad, Park, Kwon-Sik, Rauh, Daniel, Gruetter, Christian, Fischer, Matthias, Pasqualucci, Laura, Wright, Gavin, Wainer, Zoe, Russell, Prudence, Petersen, Iver, Chen, Yuan, Stoelben, Erich, Ludwig, Corinna, Schnabel, Philipp, Hoffmann, Hans, Muley, Thomas, Brockmann, Michael, Engel-Riedel, Walburga, Muscarella, Lucia A., Fazio, Vito M., Groen, Harry, Timens, Wim, Sietsma, Hannie, Thunnissen, Erik, Smit, Egbert, Heideman, Danielle A. M., Snijders, Peter J. F., Cappuzzo, Federico, Ligorio, Claudia, Damiani, Stefania, Field, John, Solberg, Steinar, Brustugun, Odd Terje, Lund-Iversen, Marius, Saenger, Joerg, Clement, Joachim H., Soltermann, Alex, Moch, Holger, Weder, Walter, Solomon, Benjamin, Soria, Jean-Charles, Validire, Pierre, Besse, Benjamin, Brambilla, Elisabeth, Brambilla, Christian, Lantuejoul, Sylvie, Lorimier, Philippe, Schneider, Peter M., Hallek, Michael, Pao, William, Meyerson, Matthew, Sage, Julien, Shendure, Jay, Schneider, Robert, Buettner, Reinhard, Wolf, Juergen, Nuernberg, Peter, Perner, Sven, Heukamp, Lukas C., Brindle, Paul K., Haas, Stefan, and Thomas, Roman K.

Abstract

Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis(1-3). We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 +/- 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice(4). Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.

Published
2012

90. BAP1Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas

Author

Leblay, Noémie, Leprêtre, Frédéric, Le Stang, Nolwenn, Gautier-Stein, Amandine, Villeneuve, Laurent, Isaac, Sylvie, Maillet, Denis, Galateau-Sallé, Françoise, Villenet, Céline, Sebda, Shéhérazade, Goracci, Alexandra, Byrnes, Graham, McKay, James D, Figeac, Martin, Glehen, Olivier, Gilly, François-Noël, Foll, Matthieu, Fernandez-Cuesta, Lynnette, and Brevet, Marie

Abstract

Malignant mesothelioma is a deadly disease that is strongly associated with asbestos exposure. Peritoneal mesotheliomas account for 10% of all the cases. BRCA1 associated protein 1 (BAP1) is a deubiquitinating hydrolase that plays a key role in various cellular processes. Germline and somatic inactivation of BRCA1 associated protein 1 gene (BAP1) is frequent in pleural mesothelioma; however, little is known about its status in peritoneal mesothelioma.

Published
2017
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92. Identification of novel fusion genes in lung cancer using breakpoint assembly of transcriptome sequencing data

Author

Fernandez-Cuesta, Lynnette, Sun, Ruping, Menon, Roopika, George, Julie, Lorenz, Susanne, Meza-Zepeda, Leonardo, Peifer, Martin, Plenker, Dennis, Heuckmann, Johannes, Leenders, Frauke, Zander, Thomas, Dahmen, Ilona, Koker, Mirjam, Schöttle, Jakob, Ullrich, Roland, Altmüller, Janine, Becker, Christian, Nürnberg, Peter, Seidel, Henrik, Böhm, Diana, Göke, Friederike, Ansén, Sascha, Russell, Prudence, Wright, Gavin, Wainer, Zoe, Solomon, Benjamin, Petersen, Iver, Clement, Joachim, Sänger, Jörg, Brustugun, Odd-Terje, Helland, Åslaug, Solberg, Steinar, Lund-Iversen, Marius, Buettner, Reinhard, Wolf, Jürgen, Brambilla, Elisabeth, Vingron, Martin, Perner, Sven, Haas, Stefan, and Thomas, Roman

Subjects
Oncology, FOS: Biological sciences, Genetics, 3. Good health
Abstract

Genomic translocation events frequently underlie cancer development through generation of gene fusions with oncogenic properties. Identification of such fusion transcripts by transcriptome sequencing might help to discover new potential therapeutic targets. We developed TRUP (Tumor-specimen suited RNA-seq Unified Pipeline) (https://github.com/ruping/TRUP), a computational approach that combines split-read and read-pair analysis with de novo assembly for the identification of chimeric transcripts in cancer specimens. We apply TRUP to RNA-seq data of different tumor types, and find it to be more sensitive than alternative tools in detecting chimeric transcripts, such as secondary rearrangements in EML4-ALK-positive lung tumors, or recurrent inactivating rearrangements affecting RASSF8.

93. Multi-omic dataset of patient-derived tumor organoids of neuroendocrine neoplasms.

Author

Alcala N, Voegele C, Mangiante L, Sexton-Oates A, Clevers H, Fernandez-Cuesta L, Dayton TL, and Foll M

Subjects
Humans, Eosine Yellowish-(YS), Genomics, Multiomics, Neuroendocrine Tumors genetics
Abstract

Background: Organoids are 3-dimensional experimental models that summarize the anatomical and functional structure of an organ. Although a promising experimental model for precision medicine, patient-derived tumor organoids (PDTOs) have currently been developed only for a fraction of tumor types., Results: We have generated the first multi-omic dataset (whole-genome sequencing [WGS] and RNA-sequencing [RNA-seq]) of PDTOs from the rare and understudied pulmonary neuroendocrine tumors (n = 12; 6 grade 1, 6 grade 2) and provide data from other rare neuroendocrine neoplasms: small intestine (ileal) neuroendocrine tumors (n = 6; 2 grade 1 and 4 grade 2) and large-cell neuroendocrine carcinoma (n = 5; 1 pancreatic and 4 pulmonary). This dataset includes a matched sample from the parental sample (primary tumor or metastasis) for a majority of samples (21/23) and longitudinal sampling of the PDTOs (1 to 2 time points), for a total of n = 47 RNA-seq and n = 33 WGS. We here provide quality control for each technique and the raw and processed data as well as all scripts for genomic analyses to ensure an optimal reuse of the data. In addition, we report gene expression data and somatic small variant calls and describe how they were generated, in particular how we used WGS somatic calls to train a random forest classifier to detect variants in tumor-only RNA-seq. We also report all histopathological images used for medical diagnosis: hematoxylin and eosin-stained slides, brightfield images, and immunohistochemistry images of protein markers of clinical relevance., Conclusions: This dataset will be critical to future studies relying on this PDTO biobank, such as drug screens for novel therapies and experiments investigating the mechanisms of carcinogenesis in these understudied diseases., (© The Author(s) 2024. Published by Oxford University Press GigaScience.)

Published
2024
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94. Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations.

Author

Lorenz S, Barøy T, Sun J, Nome T, Vodák D, Bryne JC, Håkelien AM, Fernandez-Cuesta L, Möhlendick B, Rieder H, Szuhai K, Zaikova O, Ahlquist TC, Thomassen GO, Skotheim RI, Lothe RA, Tarpey PS, Campbell P, Flanagan A, Myklebost O, and Meza-Zepeda LA

Subjects
Genes, Tumor Suppressor, Genomics, Humans, Osteosarcoma pathology, Translocation, Genetic, DNA Repair genetics, Genes, p53 genetics, Osteosarcoma genetics
Abstract

In contrast to many other sarcoma subtypes, the chaotic karyotypes of osteosarcoma have precluded the identification of pathognomonic translocations. We here report hundreds of genomic rearrangements in osteosarcoma cell lines, showing clear characteristics of microhomology-mediated break-induced replication (MMBIR) and end-joining repair (MMEJ) mechanisms. However, at RNA level, the majority of the fused transcripts did not correspond to genomic rearrangements, suggesting the involvement of trans-splicing, which was further supported by typical trans-splicing characteristics. By combining genomic and transcriptomic analysis, certain recurrent rearrangements were identified and further validated in patient biopsies, including a PMP22-ELOVL5 gene fusion, genomic structural variations affecting RB1, MTAP/CDKN2A and MDM2, and, most frequently, rearrangements involving TP53. Most cell lines (7/11) and a large fraction of tumor samples (10/25) showed TP53 rearrangements, in addition to somatic point mutations (6 patient samples, 1 cell line) and MDM2 amplifications (2 patient samples, 2 cell lines). The resulting inactivation of p53 was demonstrated by a deficiency of the radiation-induced DNA damage response. Thus, TP53 rearrangements are the major mechanism of p53 inactivation in osteosarcoma. Together with active MMBIR and MMEJ, this inactivation probably contributes to the exceptional chromosomal instability in these tumors. Although rampant rearrangements appear to be a phenotype of osteosarcomas, we demonstrate that among the huge number of probable passenger rearrangements, specific recurrent, possibly oncogenic, events are present. For the first time the genomic chaos of osteosarcoma is characterized so thoroughly and delivered new insights in mechanisms involved in osteosarcoma development and may contribute to new diagnostic and therapeutic strategies.

Published
2016
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