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1. Locus-specific proteome decoding reveals Fpt1 as a chromatin-associated negative regulator of RNA polymerase III assembly

Author

van Breugel, Maria Elize, van Kruijsbergen, Ila, Mittal, Chitvan, Lieftink, Cor, Brouwer, Ineke, van den Brand, Teun, Kluin, Roelof J.C., Hoekman, Liesbeth, Menezes, Renée X., van Welsem, Tibor, Del Cortona, Andrea, Malik, Muddassir, Beijersbergen, Roderick L., Lenstra, Tineke L., Verstrepen, Kevin J., Pugh, B. Franklin, and van Leeuwen, Fred

Published
2023
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2. A proof-of-concept study of sequential treatment with the HDAC inhibitor vorinostat following BRAF and MEK inhibitors in BRAFV600mutated melanoma

Author

Embaby, Alaa, primary, Huijberts, Sanne C.F.A., additional, Wang, Liqin, additional, Leite de Oliveira, Rodrigo, additional, Rosing, Hilde, additional, Nuijen, Bastiaan, additional, Sanders, Joyce, additional, Hofland, Ingrid, additional, van Steenis, Charlaine, additional, Kluin, Roelof J.C., additional, Lieftink, Cor, additional, Smith, Christopher G., additional, Blank, Christian U., additional, van Thienen, Johannes V., additional, Haanen, John B.A.G., additional, Steeghs, Neeltje, additional, Opdam, Frans L., additional, Beijnen, Jos H., additional, Huitema, Alwin D.R., additional, Bernards, Rene, additional, Schellens, Jan H.M., additional, and Wilgenhof, Sofie, additional

Published
2024
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4. A chromatin-associated regulator of RNA Polymerase III assembly at tRNA genes revealed by locus-specific proteomics

Author

van Breugel, Maria Elize, primary, van Kruijsbergen, Ila, additional, Mittal, Chitvan, additional, Lieftink, Cor, additional, Brouwer, Ineke, additional, van den Brand, Teun, additional, Kluin, Roelof J.C., additional, Menezes, Renee, additional, van Welsem, Tibor, additional, Cortona, Andrea Del, additional, Malik, Muddassir, additional, Beijersbergen, Roderick, additional, Lenstra, Tineke, additional, Verstrepen, Kevin, additional, Pugh, Frank, additional, and van Leeuwen, Fred, additional

Published
2023
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5. Supplementary Figure from Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence

Author

Linder, Simon, primary, Hoogstraat, Marlous, primary, Stelloo, Suzan, primary, Eickhoff, Nils, primary, Schuurman, Karianne, primary, de Barros, Hilda, primary, Alkemade, Maartje, primary, Bekers, Elise M., primary, Severson, Tesa M., primary, Sanders, Joyce, primary, Huang, Chia-Chi Flora, primary, Morova, Tunc, primary, Altintas, Umut Berkay, primary, Hoekman, Liesbeth, primary, Kim, Yongsoo, primary, Baca, Sylvan C., primary, Sjöström, Martin, primary, Zaalberg, Anniek, primary, Hintzen, Dorine C., primary, de Jong, Jeroen, primary, Kluin, Roelof J.C., primary, de Rink, Iris, primary, Giambartolomei, Claudia, primary, Seo, Ji-Heui, primary, Pasaniuc, Bogdan, primary, Altelaar, Maarten, primary, Medema, René H., primary, Feng, Felix Y., primary, Zoubeidi, Amina, primary, Freedman, Matthew L., primary, Wessels, Lodewyk F.A., primary, Butler, Lisa M., primary, Lack, Nathan A., primary, van der Poel, Henk, primary, Bergman, Andries M., primary, and Zwart, Wilbert, primary

Published
2023
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6. Supplementary Data from Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence

Author

Linder, Simon, primary, Hoogstraat, Marlous, primary, Stelloo, Suzan, primary, Eickhoff, Nils, primary, Schuurman, Karianne, primary, de Barros, Hilda, primary, Alkemade, Maartje, primary, Bekers, Elise M., primary, Severson, Tesa M., primary, Sanders, Joyce, primary, Huang, Chia-Chi Flora, primary, Morova, Tunc, primary, Altintas, Umut Berkay, primary, Hoekman, Liesbeth, primary, Kim, Yongsoo, primary, Baca, Sylvan C., primary, Sjöström, Martin, primary, Zaalberg, Anniek, primary, Hintzen, Dorine C., primary, de Jong, Jeroen, primary, Kluin, Roelof J.C., primary, de Rink, Iris, primary, Giambartolomei, Claudia, primary, Seo, Ji-Heui, primary, Pasaniuc, Bogdan, primary, Altelaar, Maarten, primary, Medema, René H., primary, Feng, Felix Y., primary, Zoubeidi, Amina, primary, Freedman, Matthew L., primary, Wessels, Lodewyk F.A., primary, Butler, Lisa M., primary, Lack, Nathan A., primary, van der Poel, Henk, primary, Bergman, Andries M., primary, and Zwart, Wilbert, primary

Published
2023
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7. Data from Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence

Author

Linder, Simon, primary, Hoogstraat, Marlous, primary, Stelloo, Suzan, primary, Eickhoff, Nils, primary, Schuurman, Karianne, primary, de Barros, Hilda, primary, Alkemade, Maartje, primary, Bekers, Elise M., primary, Severson, Tesa M., primary, Sanders, Joyce, primary, Huang, Chia-Chi Flora, primary, Morova, Tunc, primary, Altintas, Umut Berkay, primary, Hoekman, Liesbeth, primary, Kim, Yongsoo, primary, Baca, Sylvan C., primary, Sjöström, Martin, primary, Zaalberg, Anniek, primary, Hintzen, Dorine C., primary, de Jong, Jeroen, primary, Kluin, Roelof J.C., primary, de Rink, Iris, primary, Giambartolomei, Claudia, primary, Seo, Ji-Heui, primary, Pasaniuc, Bogdan, primary, Altelaar, Maarten, primary, Medema, René H., primary, Feng, Felix Y., primary, Zoubeidi, Amina, primary, Freedman, Matthew L., primary, Wessels, Lodewyk F.A., primary, Butler, Lisa M., primary, Lack, Nathan A., primary, van der Poel, Henk, primary, Bergman, Andries M., primary, and Zwart, Wilbert, primary

Published
2023
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8. Figure S1 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Author

Caumanns, Joseph J., primary, Berns, Katrien, primary, Wisman, G. Bea A., primary, Fehrmann, Rudolf S.N., primary, Tomar, Tushar, primary, Klip, Harry, primary, Meersma, Gert J., primary, Hijmans, E. Marielle, primary, Gennissen, Annemiek M.C., primary, Duiker, Evelien W., primary, Weening, Desiree, primary, Itamochi, Hiroaki, primary, Kluin, Roelof J.C., primary, Reyners, Anna K.L., primary, Birrer, Michael J., primary, Salvesen, Helga B., primary, Vergote, Ignace, primary, van Nieuwenhuysen, Els, primary, Brenton, James, primary, Braicu, E. Ioana, primary, Kupryjanczyk, Jolanta, primary, Spiewankiewicz, Beata, primary, Mittempergher, Lorenza, primary, Bernards, René, primary, van der Zee, Ate G.J., primary, and de Jong, Steven, primary

Published
2023
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9. Table S2 from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Author

Caumanns, Joseph J., primary, Berns, Katrien, primary, Wisman, G. Bea A., primary, Fehrmann, Rudolf S.N., primary, Tomar, Tushar, primary, Klip, Harry, primary, Meersma, Gert J., primary, Hijmans, E. Marielle, primary, Gennissen, Annemiek M.C., primary, Duiker, Evelien W., primary, Weening, Desiree, primary, Itamochi, Hiroaki, primary, Kluin, Roelof J.C., primary, Reyners, Anna K.L., primary, Birrer, Michael J., primary, Salvesen, Helga B., primary, Vergote, Ignace, primary, van Nieuwenhuysen, Els, primary, Brenton, James, primary, Braicu, E. Ioana, primary, Kupryjanczyk, Jolanta, primary, Spiewankiewicz, Beata, primary, Mittempergher, Lorenza, primary, Bernards, René, primary, van der Zee, Ate G.J., primary, and de Jong, Steven, primary

Published
2023
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11. Supplementary figures and tables legends from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Author

Caumanns, Joseph J., primary, Berns, Katrien, primary, Wisman, G. Bea A., primary, Fehrmann, Rudolf S.N., primary, Tomar, Tushar, primary, Klip, Harry, primary, Meersma, Gert J., primary, Hijmans, E. Marielle, primary, Gennissen, Annemiek M.C., primary, Duiker, Evelien W., primary, Weening, Desiree, primary, Itamochi, Hiroaki, primary, Kluin, Roelof J.C., primary, Reyners, Anna K.L., primary, Birrer, Michael J., primary, Salvesen, Helga B., primary, Vergote, Ignace, primary, van Nieuwenhuysen, Els, primary, Brenton, James, primary, Braicu, E. Ioana, primary, Kupryjanczyk, Jolanta, primary, Spiewankiewicz, Beata, primary, Mittempergher, Lorenza, primary, Bernards, René, primary, van der Zee, Ate G.J., primary, and de Jong, Steven, primary

Published
2023
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12. Supplementary Methods from Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Author

Caumanns, Joseph J., primary, Berns, Katrien, primary, Wisman, G. Bea A., primary, Fehrmann, Rudolf S.N., primary, Tomar, Tushar, primary, Klip, Harry, primary, Meersma, Gert J., primary, Hijmans, E. Marielle, primary, Gennissen, Annemiek M.C., primary, Duiker, Evelien W., primary, Weening, Desiree, primary, Itamochi, Hiroaki, primary, Kluin, Roelof J.C., primary, Reyners, Anna K.L., primary, Birrer, Michael J., primary, Salvesen, Helga B., primary, Vergote, Ignace, primary, van Nieuwenhuysen, Els, primary, Brenton, James, primary, Braicu, E. Ioana, primary, Kupryjanczyk, Jolanta, primary, Spiewankiewicz, Beata, primary, Mittempergher, Lorenza, primary, Bernards, René, primary, van der Zee, Ate G.J., primary, and de Jong, Steven, primary

Published
2023
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16. Supplementary Figures from Predictive Immune-Checkpoint Blockade Classifiers Identify Tumors Responding to Inhibition of PD-1 and/or CTLA-4

Author

Krijgsman, Oscar, primary, Kemper, Kristel, primary, Boshuizen, Julia, primary, Vredevoogd, David W., primary, Rozeman, Elisa A., primary, Ibanez Molero, Sofia, primary, de Bruijn, Beaunelle, primary, Cornelissen-Steijger, Paulien, primary, Shahrabi, Aida, primary, Del Castillo Velasco-Herrera, Martin, primary, Song, Ji-Ying, primary, Ligtenberg, Maarten A., primary, Kluin, Roelof J.C., primary, Kuilman, Thomas, primary, Ross-Macdonald, Petra, primary, Haanen, John B.A.G., primary, Adams, David J., primary, Blank, Christian U., primary, and Peeper, Daniel S., primary

Published
2023
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17. Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence

Author

Linder, Simon, primary, Hoogstraat, Marlous, additional, Stelloo, Suzan, additional, Eickhoff, Nils, additional, Schuurman, Karianne, additional, de Barros, Hilda, additional, Alkemade, Maartje, additional, Bekers, Elise M., additional, Severson, Tesa M., additional, Sanders, Joyce, additional, Huang, Chia-Chi Flora, additional, Morova, Tunc, additional, Altintas, Umut Berkay, additional, Hoekman, Liesbeth, additional, Kim, Yongsoo, additional, Baca, Sylvan C., additional, Sjöström, Martin, additional, Zaalberg, Anniek, additional, Hintzen, Dorine C., additional, de Jong, Jeroen, additional, Kluin, Roelof J.C., additional, de Rink, Iris, additional, Giambartolomei, Claudia, additional, Seo, Ji-Heui, additional, Pasaniuc, Bogdan, additional, Altelaar, Maarten, additional, Medema, René H., additional, Feng, Felix Y., additional, Zoubeidi, Amina, additional, Freedman, Matthew L., additional, Wessels, Lodewyk F.A., additional, Butler, Lisa M., additional, Lack, Nathan A., additional, van der Poel, Henk, additional, Bergman, Andries M., additional, and Zwart, Wilbert, additional

Published
2022
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18. Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence

Author

Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Linder, Simon, Hoogstraat, Marlous, Stelloo, Suzan, Eickhoff, Nils, Schuurman, Karianne, de Barros, Hilda, Alkemade, Maartje, Bekers, Elise M., Severson, Tesa M., Sanders, Joyce, Huang, Chia Chi Flora, Morova, Tunc, Altintas, Umut Berkay, Hoekman, Liesbeth, Kim, Yongsoo, Baca, Sylvan C., Sjöström, Martin, Zaalberg, Anniek, Hintzen, Dorine C., de Jong, Jeroen, Kluin, Roelof J.C., de Rink, Iris, Giambartolomei, Claudia, Seo, Ji Heui, Pasaniuc, Bogdan, Altelaar, Maarten, Medema, René H., Feng, Felix Y., Zoubeidi, Amina, Freedman, Matthew L., Wessels, Lodewyk F.A., Butler, Lisa M., Lack, Nathan A., van der Poel, Henk, Bergman, Andries M., Zwart, Wilbert, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Linder, Simon, Hoogstraat, Marlous, Stelloo, Suzan, Eickhoff, Nils, Schuurman, Karianne, de Barros, Hilda, Alkemade, Maartje, Bekers, Elise M., Severson, Tesa M., Sanders, Joyce, Huang, Chia Chi Flora, Morova, Tunc, Altintas, Umut Berkay, Hoekman, Liesbeth, Kim, Yongsoo, Baca, Sylvan C., Sjöström, Martin, Zaalberg, Anniek, Hintzen, Dorine C., de Jong, Jeroen, Kluin, Roelof J.C., de Rink, Iris, Giambartolomei, Claudia, Seo, Ji Heui, Pasaniuc, Bogdan, Altelaar, Maarten, Medema, René H., Feng, Felix Y., Zoubeidi, Amina, Freedman, Matthew L., Wessels, Lodewyk F.A., Butler, Lisa M., Lack, Nathan A., van der Poel, Henk, Bergman, Andries M., and Zwart, Wilbert

Published
2022

19. Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence

Author

Linder, Simon, Hoogstraat, Marlous, Stelloo, Suzan, Eickhoff, Nils, Schuurman, Karianne, de Barros, Hilda, Alkemade, Maartje, Bekers, Elise M., Severson, Tesa M., Sanders, Joyce, Huang, Chia Chi Flora, Morova, Tunc, Altintas, Umut Berkay, Hoekman, Liesbeth, Kim, Yongsoo, Baca, Sylvan C., Sjöström, Martin, Zaalberg, Anniek, Hintzen, Dorine C., de Jong, Jeroen, Kluin, Roelof J.C., de Rink, Iris, Giambartolomei, Claudia, Seo, Ji Heui, Pasaniuc, Bogdan, Altelaar, Maarten, Medema, René H., Feng, Felix Y., Zoubeidi, Amina, Freedman, Matthew L., Wessels, Lodewyk F.A., Butler, Lisa M., Lack, Nathan A., van der Poel, Henk, Bergman, Andries M., Zwart, Wilbert, Linder, Simon, Hoogstraat, Marlous, Stelloo, Suzan, Eickhoff, Nils, Schuurman, Karianne, de Barros, Hilda, Alkemade, Maartje, Bekers, Elise M., Severson, Tesa M., Sanders, Joyce, Huang, Chia Chi Flora, Morova, Tunc, Altintas, Umut Berkay, Hoekman, Liesbeth, Kim, Yongsoo, Baca, Sylvan C., Sjöström, Martin, Zaalberg, Anniek, Hintzen, Dorine C., de Jong, Jeroen, Kluin, Roelof J.C., de Rink, Iris, Giambartolomei, Claudia, Seo, Ji Heui, Pasaniuc, Bogdan, Altelaar, Maarten, Medema, René H., Feng, Felix Y., Zoubeidi, Amina, Freedman, Matthew L., Wessels, Lodewyk F.A., Butler, Lisa M., Lack, Nathan A., van der Poel, Henk, Bergman, Andries M., and Zwart, Wilbert

Abstract

In prostate cancer, androgen receptor (AR)–targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosur-vival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients’ clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target. SIGNIFICANCE: Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development.

Published
2022

20. Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency in early-stage triple-negative breast cancer patients

Author

Medisch Oncologische Disciplines, Pathologie, Cancer, de Boo, Leonora W., Jóźwiak, Katarzyna, Joensuu, Heikki, Lindman, Henrik, Lauttia, Susanna, Opdam, Mark, van Steenis, Charlaine, Brugman, Wim, Kluin, Roelof J.C., Schouten, Philip C., Kok, Marleen, Nederlof, Petra M., Hauptmann, Michael, Linn, Sabine C., Medisch Oncologische Disciplines, Pathologie, Cancer, de Boo, Leonora W., Jóźwiak, Katarzyna, Joensuu, Heikki, Lindman, Henrik, Lauttia, Susanna, Opdam, Mark, van Steenis, Charlaine, Brugman, Wim, Kluin, Roelof J.C., Schouten, Philip C., Kok, Marleen, Nederlof, Petra M., Hauptmann, Michael, and Linn, Sabine C.

Published
2022

21. Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence

Author

Linder, Simon, primary, Hoogstraat, Marlous, additional, Stelloo, Suzan, additional, Schuurman, Karianne, additional, de Barros, Hilda, additional, Alkemade, Maartje, additional, Sanders, Joyce, additional, Kim, Yongsoo, additional, Bekers, Elise, additional, de Jong, Jeroen, additional, Kluin, Roelof J.C., additional, Giambartolomei, Claudia, additional, Seo, Ji-Heui, additional, Pasaniuc, Bogdan, additional, Zoubeidi, Amina, additional, Freedman, Matthew L., additional, Wessels, Lodewyk F.A., additional, Butler, Lisa M., additional, Lack, Nathan A., additional, van der Poel, Henk, additional, Bergman, Andries M., additional, and Zwart, Wilbert, additional

Published
2021
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22. High-throughput identification of antigen-specific TCRs by TCR gene capture

Author

Linnemann, Carsten, Heemskerk, Bianca, Kvistborg, Pia, Kluin, Roelof J.C., Bolotin, Dmitriy A., Chen, Xiaojing, Bresser, Kaspar, Nieuwland, Marja, Schotte, Remko, Michels, Samira, Gomez-Eerland, Raquel, Jahn, Lorenz, Hombrink, Pleun, Legrand, Nicolas, Shu, Chengyi Jenny, Mamedov, Ilgar Z., Blank, Christian U., Haanen, John B.A.G., Turchaninova, Maria A., Kerkhoven, Ron M., Spits, Hergen, Hadrup, Sine Reker, Heemskerk, Mirjam H.M., Blankenstein, Thomas, Chudakov, Dmitriy M., Bendle, Gavin M., and Schumacher, Ton N.M.

Subjects
Nucleotide sequencing -- Research, T cells -- Receptors, Antigen receptors, T cell -- Identification and classification, Gene therapy -- Methods, Viral antibodies -- Identification and classification, DNA sequencing -- Research, Cancer -- Care and treatment, Antibodies -- Identification and classification, Biological sciences, Health
Abstract

The transfer of T cell receptor (TCR) genes into patient T cells is a promising approach for the treatment of both viral infections and cancer. Although efficient methods exist to [...]

Published
2013
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23. Ovarian Cancer–Specific BRCA-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial

Author

Schouten, Philip C., primary, Richters, Lisa, additional, Vis, Daniel J., additional, Kommoss, Stefan, additional, van Dijk, Ewald, additional, Ernst, Corinna, additional, Kluin, Roelof J.C., additional, Marmé, Frederik, additional, Lips, Esther H., additional, Schmidt, Sandra, additional, Scheerman, Esther, additional, Prieske, Katharina, additional, van Deurzen, Carolien H.M., additional, Burges, Alexander, additional, Ewing-Graham, Patricia C., additional, Dietrich, Dimo, additional, Jager, Agnes, additional, de Gregorio, Nikolaus, additional, Hauke, Jan, additional, du Bois, Andreas, additional, Nederlof, Petra M., additional, Wessels, Lodewyk F., additional, Hahnen, Eric, additional, Harter, Philipp, additional, Linn, Sabine C., additional, and Schmutzler, Rita K., additional

Published
2021
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24. BRCA1-like signature in triple negative breast cancer: Molecular and clinical characterization reveals subgroups with therapeutic potential

Author

Severson, Tesa M., Peeters, Justine, Majewski, Ian, Michaut, Magali, Bosma, Astrid, Schouten, Philip C., Chin, Suet-Feung, Pereira, Bernard, Goldgraben, Mae A., Bismeijer, Tycho, Kluin, Roelof J.C., Muris, Jettie J.F., Jirström, Karin, Kerkhoven, Ron M., Wessels, Lodewyk, Caldas, Carlos, Bernards, René, Simon, Iris M., and Linn, Sabine

Published
2015
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25. Predictive Immune-Checkpoint Blockade Classifiers Identify Tumors Responding to Inhibition of PD-1 and/or CTLA-4

Author

Krijgsman, Oscar, primary, Kemper, Kristel, additional, Boshuizen, Julia, additional, Vredevoogd, David W., additional, Rozeman, Elisa A., additional, Ibanez Molero, Sofia, additional, de Bruijn, Beaunelle, additional, Cornelissen-Steijger, Paulien, additional, Shahrabi, Aida, additional, Del Castillo Velasco-Herrera, Martin, additional, Song, Ji-Ying, additional, Ligtenberg, Maarten A., additional, Kluin, Roelof J.C., additional, Kuilman, Thomas, additional, Ross-Macdonald, Petra, additional, Haanen, John B.A.G., additional, Adams, David J., additional, Blank, Christian U., additional, and Peeper, Daniel S., additional

Published
2021
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26. Ovarian Cancer-Specific BRCA-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial

Author

Schouten, Philip C. (author), Richters, Lisa (author), Vis, Daniel J. (author), Kommoss, Stefan (author), Kluin, Roelof J.C. (author), Lips, Esther H. (author), Schmidt, Sandra (author), Nederlof, Petra M. (author), Wessels, L.F.A. (author), Schouten, Philip C. (author), Richters, Lisa (author), Vis, Daniel J. (author), Kommoss, Stefan (author), Kluin, Roelof J.C. (author), Lips, Esther H. (author), Schmidt, Sandra (author), Nederlof, Petra M. (author), and Wessels, L.F.A. (author)

Abstract

Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). Results: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/ 2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non-BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. Conclusions: The newly trained classifiers detected most BRCAmutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like. _2021 The Authors; Published by the American Association for Cancer Research., Pattern Recognition and Bioinformatics

Published
2021
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27. Ovarian Cancer-Specific BRCA-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial

Author

Schouten, Philip C., Richters, Lisa, Vis, Daniel J., Kommoss, Stefan, Dijk, Ewald Van, Ernst, Corinna, Kluin, Roelof J.C., Marm, Frederik M., Lips, Esther H., Schmidt, Sandra, Scheerman, Esther, Prieske, Katharina, Deurzen, Carolien H.M.Van, Burges, Alexander, Ewing-Graham, Patricia C., Dietrich, Dimo, Jager, Agnes, Gregorio, Nikolaus De, Hauke, Jan, Bois, Andreas Du, Nederlof, Petra M., Wessels, Lodewyk F., Hahnen, Eric, Harter, Philipp, Linn, Sabine C., Schmutzle, Rita K., Schouten, Philip C., Richters, Lisa, Vis, Daniel J., Kommoss, Stefan, Dijk, Ewald Van, Ernst, Corinna, Kluin, Roelof J.C., Marm, Frederik M., Lips, Esther H., Schmidt, Sandra, Scheerman, Esther, Prieske, Katharina, Deurzen, Carolien H.M.Van, Burges, Alexander, Ewing-Graham, Patricia C., Dietrich, Dimo, Jager, Agnes, Gregorio, Nikolaus De, Hauke, Jan, Bois, Andreas Du, Nederlof, Petra M., Wessels, Lodewyk F., Hahnen, Eric, Harter, Philipp, Linn, Sabine C., and Schmutzle, Rita K.

Abstract

Purpose: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer. Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883). Results: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/ 2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non-BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype. Conclusions: The newly trained classifiers detected most BRCAmutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like. _2021 The Authors; Published by the American Association for Cancer Research.

Published
2021

28. Adjuvant Capecitabine-Containing Chemotherapy Benefit and Homologous Recombination Deficiency Status Among Early-Stage TNBC Patients in the FinXX trial

Author

de Boo, Leonora W., primary, Jóźwiak, Katarzyna, additional, Joensuu, Heikki, additional, Lindman, Henrik, additional, Lauttia, Susanna, additional, Opdam, Mark, additional, Steenis, Charlaine van, additional, Brugman, Wim, additional, Kluin, Roelof J.C., additional, Schouten, Philip C., additional, Kok, Marleen, additional, Nederlof, Petra M., additional, Hauptmann, Michael, additional, and Linn, Sabine, additional

Published
2020
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30. PREDICTIVE IMMUNE CHECKPOINT BLOCKADE CLASSIFIERS DISTINGUISHING MONO- VERSUS COMBINATION THERAPY REQUIREMENT

Author

Krijgsman, Oscar, primary, Kemper, Kristel, additional, Boshuizen, Julia, additional, Vredevoogd, David W., additional, Rozeman, Elisa A., additional, Ibanez Molero, Sofia, additional, de Bruijn, Beaunelle, additional, Cornelissen-Steijger, Paulien, additional, Shahrabi, Aida, additional, Velasco-Herrera, Martin Del Castillo, additional, Song, Ji-Ying, additional, Ligtenberg, Maarten A., additional, Kluin, Roelof J.C., additional, Kuilman, Thomas, additional, Ross-MacDonald, Petra, additional, Haanen, John, additional, Adams, David J., additional, Blank, Christian, additional, and Peeper, Daniel S., additional

Published
2020
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31. Endonuclease FEN1 Coregulates ERα Activity and Provides a Novel Drug Interface in Tamoxifen-Resistant Breast Cancer

Author

Flach, Koen D., primary, Periyasamy, Manikandan, additional, Jadhav, Ajit, additional, Dorjsuren, Dorjbal, additional, Siefert, Joseph C., additional, Hickey, Theresa E., additional, Opdam, Mark, additional, Patel, Hetal, additional, Canisius, Sander, additional, Wilson, David M., additional, Donaldson Collier, Maria, additional, Prekovic, Stefan, additional, Nieuwland, Marja, additional, Kluin, Roelof J.C., additional, Zakharov, Alexey V., additional, Wesseling, Jelle, additional, Wessels, Lodewyk F.A., additional, Linn, Sabine C., additional, Tilley, Wayne D., additional, Simeonov, Anton, additional, Ali, Simak, additional, and Zwart, Wilbert, additional

Published
2020
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32. Role of variant allele fraction and rare SNP filtering to improve cellular DNA repair endpoint association

Author

Vossen, David M. (author), Verhagen, Caroline V.M. (author), Grénman, Reidar (author), Kluin, Roelof J.C. (author), Verheij, Marcel (author), Van Den Brekel, Michiel W.M. (author), Wessels, L.F.A. (author), Vens, Conchita (author), Vossen, David M. (author), Verhagen, Caroline V.M. (author), Grénman, Reidar (author), Kluin, Roelof J.C. (author), Verheij, Marcel (author), Van Den Brekel, Michiel W.M. (author), Wessels, L.F.A. (author), and Vens, Conchita (author)

Abstract

Background Large cancer genome studies continue to reveal new players in treatment response and tumorigenesis. The discrimination of functional alterations from the abundance of passenger genetic alterations still poses challenges and determines DNA sequence variant selection procedures. Here we evaluate variant selection strategies that select homozygous variants and rare SNPs and assess its value in detecting tumor cells with DNA repair defects. Methods To this end we employed a panel of 29 patient-derived head and neck squamous cell carcinoma (HNSCC) cell lines, of which a subset harbors DNA repair defects. Mitomycin C (MMC) sensitivity was used as functional endpoint of DNA crosslink repair deficiency. 556 genes including the Fanconi anemia (FA) and homologous recombination (HR) genes, whose products strongly determine MMC response, were capture-sequenced. Results We show a strong association between MMC sensitivity, thus loss of DNA repair function, and the presence of homozygous and rare SNPs in the relevant FA/HR genes. Excluding such selection criteria impedes the discrimination of crosslink repair status by mutation analysis. Applied to all KEGG pathways, we find that the association with MMC sensitivity is strongest in the KEGG FA pathway, therefore also demonstrating the value of such selection strategies for exploratory analyses. Variant analyses in 56 clinical samples demonstrate that homozygous variants occur more frequently in tumor suppressor genes than oncogenes further supporting the role of a homozygosity criterion to improve gene function association or tumor suppressor gene identification studies. Conclusion Together our data show that the detection of relevant genes or of repair pathway defected tumor cells can be improved by the consideration of allele zygosity and SNP allele frequencies., Pattern Recognition and Bioinformatics

Published
2018
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33. Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma

Author

Caumanns, Joseph J., primary, Berns, Katrien, additional, Wisman, G. Bea A., additional, Fehrmann, Rudolf S.N., additional, Tomar, Tushar, additional, Klip, Harry, additional, Meersma, Gert J., additional, Hijmans, E. Marielle, additional, Gennissen, Annemiek M.C., additional, Duiker, Evelien W., additional, Weening, Desiree, additional, Itamochi, Hiroaki, additional, Kluin, Roelof J.C., additional, Reyners, Anna K.L., additional, Birrer, Michael J., additional, Salvesen, Helga B., additional, Vergote, Ignace, additional, van Nieuwenhuysen, Els, additional, Brenton, James, additional, Braicu, E. Ioana, additional, Kupryjanczyk, Jolanta, additional, Spiewankiewicz, Beata, additional, Mittempergher, Lorenza, additional, Bernards, René, additional, van der Zee, Ate G.J., additional, and de Jong, Steven, additional

Published
2018
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35. Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer

Author

Michaut, Magali, primary, Chin, Suet-Feung, additional, Majewski, Ian, additional, Severson, Tesa M., additional, Bismeijer, Tycho, additional, de Koning, Leanne, additional, Peeters, Justine K., additional, Schouten, Philip C., additional, Rueda, Oscar M., additional, Bosma, Astrid J., additional, Tarrant, Finbarr, additional, Fan, Yue, additional, He, Beilei, additional, Xue, Zheng, additional, Mittempergher, Lorenza, additional, Kluin, Roelof J.C., additional, Heijmans, Jeroen, additional, Snel, Mireille, additional, Pereira, Bernard, additional, Schlicker, Andreas, additional, Provenzano, Elena, additional, Ali, Hamid Raza, additional, Gaber, Alexander, additional, O’Hurley, Gillian, additional, Lehn, Sophie, additional, Muris, Jettie J.F., additional, Wesseling, Jelle, additional, Kay, Elaine, additional, Sammut, Stephen John, additional, Bardwell, Helen A., additional, Barbet, Aurélie S., additional, Bard, Floriane, additional, Lecerf, Caroline, additional, O’Connor, Darran P., additional, Vis, Daniël J., additional, Benes, Cyril H., additional, McDermott, Ultan, additional, Garnett, Mathew J., additional, Simon, Iris M., additional, Jirström, Karin, additional, Dubois, Thierry, additional, Linn, Sabine C., additional, Gallagher, William M., additional, Wessels, Lodewyk F.A., additional, Caldas, Carlos, additional, and Bernards, Rene, additional

Published
2016
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36. Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer

Author

Michaut, Magali, Chin, Suet-Feung, Majewski, Ian, Severson, Tesa M., Bismeijer, Tycho, de Koning, Leanne, Peeters, Justine K., Schouten, Philip C., Rueda, Oscar M., Bosma, Astrid J., Tarrant, Finbarr, Fan, Yue, He, Beilei, Xue, Zheng, Mittempergher, Lorenza, Kluin, Roelof J.C., Heijmans, Jeroen, Snel, Mireille, Pereira, Bernard, Schlicker, Andreas, Provenzano, Elena, Ali, Hamid Raza, Gaber, Alexander, O’Hurley, Gillian, Lehn, Sophie, Muris, Jettie J.F., Wesseling, Jelle, Kay, Elaine, Sammut, Stephen John, Bardwell, Helen A., Barbet, Aurélie S., Bard, Floriane, Lecerf, Caroline, O’Connor, Darran P., Vis, Daniël J., Benes, Cyril H., McDermott, Ultan, Garnett, Mathew J., Simon, Iris M., Jirström, Karin, Dubois, Thierry, Linn, Sabine C., Gallagher, William M., Wessels, Lodewyk F.A., Caldas, Carlos, and Bernards, Rene

Abstract

Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.

Published
2015
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