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2. Comprehensive single-cell genome analysis at nucleotide resolution using the PTA Analysis Toolbox

Author

Middelkamp, Sjors, Manders, Freek, Peci, Flavia, van Roosmalen, Markus J., González, Diego Montiel, Bertrums, Eline J.M., van der Werf, Inge, Derks, Lucca L.M., Groenen, Niels M., Verheul, Mark, Trabut, Laurianne, Pleguezuelos-Manzano, Cayetano, Brandsma, Arianne M., Antoniou, Evangelia, Reinhardt, Dirk, Bierings, Marc, Belderbos, Mirjam E., and van Boxtel, Ruben

Published
2023
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12. Comprehensive single-cell genome analysis at nucleotide resolution using the PTA Analysis Toolbox

Author

Middelkamp, Sjors, primary, Manders, Freek, additional, Peci, Flavia, additional, van Roosmalen, Markus J., additional, González, Diego Montiel, additional, Bertrums, Eline J.M., additional, van der Werf, Inge, additional, Derks, Lucca L.M., additional, Groenen, Niels M., additional, Verheul, Mark, additional, Trabut, Laurianne, additional, Brandsma, Arianne M., additional, Antoniou, Evangelia, additional, Reinhardt, Dirk, additional, Bierings, Marc, additional, Belderbos, Mirjam E., additional, and van Boxtel, Ruben, additional

Published
2023
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13. Patterns of somatic mutations in normal cells

Author

Cuppen, E.P.J.G., Holstege, F.C.P., Boxtel, R. van, Manders, Freek Martijn, Cuppen, E.P.J.G., Holstege, F.C.P., Boxtel, R. van, and Manders, Freek Martijn

Published
2023

15. Comprehensive single-cell genome analysis at nucleotide resolution using the PTA Analysis Toolbox

Author

CMM Groep Snippert, CMM Groep Kloosterman, CTI Leusen, SCT patientenzorg, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, Arts-assistenten Kinderen, CMM Groep Cuppen, Middelkamp, Sjors, Manders, Freek, Peci, Flavia, van Roosmalen, Markus J., González, Diego Montiel, Bertrums, Eline J.M., van der Werf, Inge, Derks, Lucca L.M., Groenen, Niels M., Verheul, Mark, Trabut, Laurianne, Pleguezuelos-Manzano, Cayetano, Brandsma, Arianne M., Antoniou, Evangelia, Reinhardt, Dirk, Bierings, Marc, Belderbos, Mirjam E., van Boxtel, Ruben, CMM Groep Snippert, CMM Groep Kloosterman, CTI Leusen, SCT patientenzorg, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, Arts-assistenten Kinderen, CMM Groep Cuppen, Middelkamp, Sjors, Manders, Freek, Peci, Flavia, van Roosmalen, Markus J., González, Diego Montiel, Bertrums, Eline J.M., van der Werf, Inge, Derks, Lucca L.M., Groenen, Niels M., Verheul, Mark, Trabut, Laurianne, Pleguezuelos-Manzano, Cayetano, Brandsma, Arianne M., Antoniou, Evangelia, Reinhardt, Dirk, Bierings, Marc, Belderbos, Mirjam E., and van Boxtel, Ruben

Published
2023

16. Retrospective Lineage Tracing of Pediatric Acute Myeloid Leukemia Using Single-Cell Whole Genome Sequencing

Author

Bertrums, Eline J.M., primary, Middelkamp, Sjors, additional, van der Werf, Inge M., additional, Manders, Freek, additional, Brandsma, Arianne M., additional, Groenen, Niels M., additional, Verheul, Mark, additional, van Roosmalen, Markus J., additional, Zwaan, C. Michel, additional, van den Heuvel-Eibrink, Marry M., additional, Goemans, Bianca F., additional, and Van Boxtel, Ruben, additional

Published
2022
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17. Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Author

Meister, Michael T., Groot Koerkamp, Marian J.A., de Souza, Terezinha, Breunis, Willemijn B., Frazer-Mendelewska, Ewa, Brok, Mariël, DeMartino, Jeff, Manders, Freek, Calandrini, Camilla, Kerstens, Hinri H.D., Janse, Alex, Dolman, M. Emmy M., Eising, Selma, Langenberg, Karin P.S., van Tuil, Marc, Knops, Rutger R.G., van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S., Flucke, Uta, Merks, Johannes H.M., van Noesel, Max M., Tops, Bastiaan B.J., Hehir-Kwa, Jayne Y., Kemmeren, Patrick, Molenaar, Jan J., van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno, Holstege, Frank C.P., Sub General Pharmaceutics, Afd Pharmaceutics, Pharmaceutics, University of Zurich, Drost, Jarno, Holstege, Frank C P, Sub General Pharmaceutics, Afd Pharmaceutics, and Pharmaceutics

Subjects
Organoids, tumoroid, 10036 Medical Clinic, 1313 Molecular Medicine, Humans, Molecular Medicine, 610 Medicine & health, drug screening, rhabdomyosarcoma, mesenchymal, Child, CRISPR/Cas9
Abstract

SummaryRhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here we describe the generation of a collection of pediatric RMS tumor organoid (tumoroid) models comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within four to eight weeks, indicating the feasibility of personalized drug screening. Molecular, genetic and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to six months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions.

Published
2022

18. Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Author

Sub General Pharmaceutics, Afd Pharmaceutics, Pharmaceutics, Meister, Michael T., Groot Koerkamp, Marian J.A., de Souza, Terezinha, Breunis, Willemijn B., Frazer-Mendelewska, Ewa, Brok, Mariël, DeMartino, Jeff, Manders, Freek, Calandrini, Camilla, Kerstens, Hinri H.D., Janse, Alex, Dolman, M. Emmy M., Eising, Selma, Langenberg, Karin P.S., van Tuil, Marc, Knops, Rutger R.G., van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S., Flucke, Uta, Merks, Johannes H.M., van Noesel, Max M., Tops, Bastiaan B.J., Hehir-Kwa, Jayne Y., Kemmeren, Patrick, Molenaar, Jan J., van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno, Holstege, Frank C.P., Sub General Pharmaceutics, Afd Pharmaceutics, Pharmaceutics, Meister, Michael T., Groot Koerkamp, Marian J.A., de Souza, Terezinha, Breunis, Willemijn B., Frazer-Mendelewska, Ewa, Brok, Mariël, DeMartino, Jeff, Manders, Freek, Calandrini, Camilla, Kerstens, Hinri H.D., Janse, Alex, Dolman, M. Emmy M., Eising, Selma, Langenberg, Karin P.S., van Tuil, Marc, Knops, Rutger R.G., van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S., Flucke, Uta, Merks, Johannes H.M., van Noesel, Max M., Tops, Bastiaan B.J., Hehir-Kwa, Jayne Y., Kemmeren, Patrick, Molenaar, Jan J., van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno, and Holstege, Frank C.P.

Published
2022

20. Somatic mutation landscape of familial Follicular Cell Thyroid Carcinoma in dogs through high depth whole-genome sequencing

Author

Yu, Y., Manders, Freek, van Roosmalen, M.J., Grinwis, Guy, Groenen, M., Crooijmans, R.P.M.A., Yu, Y., Manders, Freek, van Roosmalen, M.J., Grinwis, Guy, Groenen, M., and Crooijmans, R.P.M.A.

Abstract

Somatic mutation profile of thyroid cancer in dogs has not been investigated. We previously reported a familial thyroid follicular cell carcinoma (FCC) in a large number of Dutch German longhaired pointers and identified two deleterious mutations in the TPO gene associated with the disease predisposition. In this study, we comprehensively investigated the somatic mutations in the tumors that potentially contribute to the inherited tumor formation and development using high depth whole-genome sequencing. A GNAS A204D missense mutation was identified in 4 of 7 tumors by whole-genome sequencing and xx of 36 FCC tumors by PCR-RFLP. In humans, somatic mutations in the GNAS gene were also identified but in low prevalence. Meanwhile, the homologous mutation has not been reported. It suggested the potential interaction between germline risk factor and driver mutation by comparing to prevalence of GNAS mutations in human samples. Moreover, tumors with GNAS A204D mutation had significantly less somatic SNVs and Indels, suggesting that this mutation could be a marker for less malignant form of thyroid tumor in dogs., Background We previously reported a familial thyroid follicular cell carcinoma (FCC) in a large number of Dutch German longhaired pointers and identified two deleterious germline mutations in the TPO gene associated with disease predisposition. However, the somatic mutation profile of the FCC in dogs has not been investigated at a genome-wide scale. Results Herein, we comprehensively investigated the somatic mutations that potentially contribute to the inherited tumor formation and progression using high depth whole-genome sequencing. A GNAS p.A204D missense mutation was identified in 4 out of 7 FCC tumors by whole-genome sequencing and in 20 out of 32 dogs’ tumors by targeted sequencing. In contrast to this, in the human TC, mutations in GNAS gene have lower prevalence. Meanwhile, the homologous somatic mutation in humans has not been reported. These findings suggest a difference in the somatic mutation landscape between TC in these dogs and human TC. Moreover, tumors with the GNAS p.A204D mutation had a significantly lower somatic mutation burden in these dogs. Somatic structural variant and copy number alterations were also investigated, but no potential driver event was identified. Conclusion This study provides novel insight in the molecular mechanism of thyroid carcinoma development in dogs. German longhaired pointers carrying GNAS mutations in the tumor may be used as a disease model for the development and testing of novel therapies to kill the tumor with somatic mutations in the GNAS gene.

Published
2022

21. Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Author

Groep Holstege, CMM Groep Klumperman, PMC Medisch specialisten, Cancer, CMM, CMM Groep Burgering, Meister, Michael T, Groot Koerkamp, Marian J A, de Souza, Terezinha, Breunis, Willemijn B, Frazer-Mendelewska, Ewa, Brok, Mariël, DeMartino, Jeff, Manders, Freek, Calandrini, Camilla, Kerstens, Hinri H D, Janse, Alex, Dolman, M Emmy M, Eising, Selma, Langenberg, Karin P S, van Tuil, Marc, Knops, Rutger R G, van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S, Flucke, Uta, Merks, Johannes H M, van Noesel, Max M, Tops, Bastiaan B J, Hehir-Kwa, Jayne Y, Kemmeren, Patrick, Molenaar, Jan J, van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno, Holstege, Frank C P, Groep Holstege, CMM Groep Klumperman, PMC Medisch specialisten, Cancer, CMM, CMM Groep Burgering, Meister, Michael T, Groot Koerkamp, Marian J A, de Souza, Terezinha, Breunis, Willemijn B, Frazer-Mendelewska, Ewa, Brok, Mariël, DeMartino, Jeff, Manders, Freek, Calandrini, Camilla, Kerstens, Hinri H D, Janse, Alex, Dolman, M Emmy M, Eising, Selma, Langenberg, Karin P S, van Tuil, Marc, Knops, Rutger R G, van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S, Flucke, Uta, Merks, Johannes H M, van Noesel, Max M, Tops, Bastiaan B J, Hehir-Kwa, Jayne Y, Kemmeren, Patrick, Molenaar, Jan J, van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno, and Holstege, Frank C P

Published
2022

22. Article Human induced pluripotent stem cells display a similar mutation burden as embryonic pluripotent cells in vivo

Author

CMM Groep Cuppen, CMM Groep Kloosterman, Cancer, Hasaart, Karlijn A L, Manders, Freek, Ubels, Joske, Verheul, Mark, van Roosmalen, Markus J, Groenen, Niels M, Oka, Rurika, Kuijk, Ewart, Lopes, Susana M Chuva de Sousa, Boxtel, Ruben van, CMM Groep Cuppen, CMM Groep Kloosterman, Cancer, Hasaart, Karlijn A L, Manders, Freek, Ubels, Joske, Verheul, Mark, van Roosmalen, Markus J, Groenen, Niels M, Oka, Rurika, Kuijk, Ewart, Lopes, Susana M Chuva de Sousa, and Boxtel, Ruben van

Published
2022

23. MutationalPatterns: the one stop shop for the analysis of mutational processes

Author

CTI Leusen, CMM Groep Kloosterman, Epi Infectieziekten Team 2, Infection & Immunity, CMM Groep Cuppen, Cancer, Manders, Freek, Brandsma, Arianne M, de Kanter, Jurrian, Verheul, Mark, Oka, Rurika, van Roosmalen, Markus J, van der Roest, Bastiaan, van Hoeck, Arne, Cuppen, Edwin, van Boxtel, Ruben, CTI Leusen, CMM Groep Kloosterman, Epi Infectieziekten Team 2, Infection & Immunity, CMM Groep Cuppen, Cancer, Manders, Freek, Brandsma, Arianne M, de Kanter, Jurrian, Verheul, Mark, Oka, Rurika, van Roosmalen, Markus J, van der Roest, Bastiaan, van Hoeck, Arne, Cuppen, Edwin, and van Boxtel, Ruben

Published
2022

24. Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Author

Meister, Michael T; https://orcid.org/0000-0001-8311-721X, Groot Koerkamp, Marian J A; https://orcid.org/0000-0002-0867-0821, de Souza, Terezinha, Breunis, Willemijn B, Frazer-Mendelewska, Ewa; https://orcid.org/0000-0003-0903-869X, Brok, Mariël; https://orcid.org/0000-0001-6018-900X, DeMartino, Jeff; https://orcid.org/0000-0001-7366-4789, Manders, Freek; https://orcid.org/0000-0001-6197-347X, Calandrini, Camilla, Kerstens, Hinri H D, Janse, Alex, Dolman, M Emmy M, Eising, Selma, Langenberg, Karin P S; https://orcid.org/0000-0002-6780-0585, van Tuil, Marc, Knops, Rutger R G, van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S, Flucke, Uta, Merks, Johannes H M; https://orcid.org/0000-0001-7659-1028, van Noesel, Max M; https://orcid.org/0000-0003-0503-5838, Tops, Bastiaan B J, Hehir-Kwa, Jayne Y, Kemmeren, Patrick; https://orcid.org/0000-0003-2237-7354, Molenaar, Jan J, van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno; https://orcid.org/0000-0002-2941-6179, Holstege, Frank C P; https://orcid.org/0000-0002-8090-5146, Meister, Michael T; https://orcid.org/0000-0001-8311-721X, Groot Koerkamp, Marian J A; https://orcid.org/0000-0002-0867-0821, de Souza, Terezinha, Breunis, Willemijn B, Frazer-Mendelewska, Ewa; https://orcid.org/0000-0003-0903-869X, Brok, Mariël; https://orcid.org/0000-0001-6018-900X, DeMartino, Jeff; https://orcid.org/0000-0001-7366-4789, Manders, Freek; https://orcid.org/0000-0001-6197-347X, Calandrini, Camilla, Kerstens, Hinri H D, Janse, Alex, Dolman, M Emmy M, Eising, Selma, Langenberg, Karin P S; https://orcid.org/0000-0002-6780-0585, van Tuil, Marc, Knops, Rutger R G, van Scheltinga, Sheila Terwisscha, Hiemcke-Jiwa, Laura S, Flucke, Uta, Merks, Johannes H M; https://orcid.org/0000-0001-7659-1028, van Noesel, Max M; https://orcid.org/0000-0003-0503-5838, Tops, Bastiaan B J, Hehir-Kwa, Jayne Y, Kemmeren, Patrick; https://orcid.org/0000-0003-2237-7354, Molenaar, Jan J, van de Wetering, Marc, van Boxtel, Ruben, Drost, Jarno; https://orcid.org/0000-0002-2941-6179, and Holstege, Frank C P; https://orcid.org/0000-0002-8090-5146

Abstract

Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here, we describe the generation of a collection of 19 pediatric RMS tumor organoid (tumoroid) models (success rate of 41%) comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within 4-8 weeks, indicating the feasibility of personalized drug screening. Molecular, genetic, and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to 6 months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions.

Published
2022

25. Author Reply to Peer Reviews of Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Author

Holstege, Frank C. P., primary, Drost, Jarno, additional, van Boxtel, Ruben, additional, van de Wetering, Marc, additional, Molenaar, Jan J., additional, Kemmeren, Patrick, additional, Hehir-Kwa, Jayne Y., additional, Tops, Bastiaan B. J., additional, van Noesel, Max M., additional, Merks, Johannes H. M., additional, Flucke, Uta, additional, Hiemcke-Jiwa, Laura S., additional, van Scheltinga, Sheila Terwisscha, additional, Knops, Rutger R. G., additional, van Tuil, Marc, additional, Langenberg, Karin P. S., additional, Eising, Selma, additional, Dolman, M. Emmy M., additional, Janse, Alex, additional, Kerstens, Hinri H. D., additional, Calandrini, Camilla, additional, Manders, Freek, additional, DeMartino, Jeff, additional, Brok, Mariël, additional, Frazer-Mendelewska, Ewa, additional, Breunis, Willemijn B., additional, de Souza, Terezinha, additional, Groot Koerkamp, Marian J. A., additional, and Meister, Michael T., additional

Published
2022
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27. Additional file 2 of MutationalPatterns: the one stop shop for the analysis of mutational processes

Author

Manders, Freek, Brandsma, Arianne M., de Kanter, Jurrian, Verheul, Mark, Oka, Rurika, van Roosmalen, Markus J., van der Roest, Bastiaan, van Hoeck, Arne, Cuppen, Edwin, and van Boxtel, Ruben

Abstract

Additional file 2. Description of the wet-lab generation and sequencing analysis of the knockout lines. These lines were used to illustrate the functions of the MutationalPatterns package on novel real-world data and provide new biological conclusions.

Published
2022
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28. Additional file 1 of MutationalPatterns: the one stop shop for the analysis of mutational processes

Author

Manders, Freek, Brandsma, Arianne M., de Kanter, Jurrian, Verheul, Mark, Oka, Rurika, van Roosmalen, Markus J., van der Roest, Bastiaan, van Hoeck, Arne, Cuppen, Edwin, and van Boxtel, Ruben

Abstract

Additional file 1: Additional figures, which help to illustrate the data present in this work and provide the reader with a more comprehensive understanding of the manuscript. Figure S1. Removing the DBSs and MBSs results in an improved SBS profile. Figure S2. Mutation contexts can be visualized with a river plot. Figure S3. Lesion segregation can be visualized. Figure S4. Variational Bayes NMF can be used to predict the optimal number of signatures to extract. Figure S5. Strict refitting iteratively removes signatures. Figure S6. Bootstrapped signature refitting can be visualized with a jitter plot. Figure S7. TT[C > T]CT is the most common substitution type in metastatic melanomas. Figure S8. The matrix generating functions have O(n) or better scaling. Figure S9. Benchmark of the ���mut_matrix��� function. Figure S10. Recall-precision plot of different refitting methods in MutationalPatterns. Figure S11. Western blot analysis of AHH-1 CRISPR-Cas9 edited clonal lines. Figure S12. Uncropped original version of the western blots in Fig. S11. Figure S13. SBS profiles of knockout samples.

Published
2022
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29. Additional file 1 of A recurrent somatic missense mutation in GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs

Author

Yu, Yun, Manders, Freek, Grinwis, Guy C. M., Groenen, Martien A. M., and Crooijmans, Richard P. M. A.

Abstract

Additional file 1: Figure S1. Landscape of somatic SVs identified in thetumors of 4 dogs. The circles represent deletion, insertion, inversion,duplication from the outside inwards respectively. The links inside representthe translocations. Different colors represent specific tumor sample, namelyred - DogWUR108, blue - DogWUR112, yellow - DogWUR113, green - DogWUR114. Figure S2. Recurrent copy number alteration identified byGISTIC2 in 4 dogs used in the analysis. A. Recurrent amplifications acrosscanine chromosome 1 - 38. A solid green line indicates the significancethreshold. B. Recurrent deletions across canine chromosome 1 - 38. A solidgreen line indicates significance threshold. Figure S3. Summary of somatic SNVs and Indels identified in the 7 canine tumors. A.Summary of somatic SNVs and Indels derived from maftools package, includingvariant classification, variant type, SNV class, number of variants in codingregion, and top 10 mutated genes. B. Somatic SNVs substitution type andtransition and transversion. Figure S4. Correlation between age at diagnosis and tumormutation burden (mutation per Mb). Figure S5. A. PCA plot of the 7 tumors based on geneexpression. B. Expression level of the GNAS gene in tumors with andwithout somatic GNAS mutation. Figure S6. Coverage of RNA-seq reads mapped to CNTN4(A), JAK3 (B), CATSPERE (C) gene for the 7 tumor samples. Table S1. Genotypes of the somatic GNAS mutation and germline TPO mutation in dogs.

Published
2022
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30. Additional file 3 of MutationalPatterns: the one stop shop for the analysis of mutational processes

Author

Manders, Freek, Brandsma, Arianne M., de Kanter, Jurrian, Verheul, Mark, Oka, Rurika, van Roosmalen, Markus J., van der Roest, Bastiaan, van Hoeck, Arne, Cuppen, Edwin, and van Boxtel, Ruben

Abstract

Additional file 3: Additional tables containing extra data that can help the reader better understand the manuscript. Table S1. List of new features and bugfixes. Table S2. The potential damage of mutational signatures. Table S3. The genes used for the signature potential damage analysis. Table S4. Overview of the source of the replication timing data.

Published
2022
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31. Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

Author

Meister, Michael T., primary, Groot Koerkamp, Marian J. A., additional, de Souza, Terezinha, additional, Breunis, Willemijn B., additional, Frazer-Mendelewska, Ewa, additional, Brok, Mariël, additional, DeMartino, Jeff, additional, Manders, Freek, additional, Calandrini, Camilla, additional, Kerstens, Hinri H. D., additional, Janse, Alex, additional, Dolman, M. Emmy M., additional, Eising, Selma, additional, Langenberg, Karin P. S., additional, van Tuil, Marc, additional, Knops, Rutger R. G., additional, van Scheltinga, Sheila Terwisscha, additional, Hiemcke-Jiwa, Laura S., additional, Flucke, Uta, additional, Merks, Johannes H. M., additional, van Noesel, Max M., additional, Tops, Bastiaan B. J., additional, Hehir-Kwa, Jayne Y., additional, Kemmeren, Patrick, additional, Molenaar, Jan J., additional, van de Wetering, Marc, additional, van Boxtel, Ruben, additional, Drost, Jarno, additional, and Holstege, Frank C. P., additional

Published
2022
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34. Antiviral treatment causes a unique mutational signature in cancers of transplantation recipients

Author

de Kanter, Jurrian K., primary, Peci, Flavia, additional, Bertrums, Eline, additional, Rosendahl Huber, Axel, additional, van Leeuwen, Anaïs, additional, van Roosmalen, Markus J., additional, Manders, Freek, additional, Verheul, Mark, additional, Oka, Rurika, additional, Brandsma, Arianne M., additional, Bierings, Marc, additional, Belderbos, Mirjam, additional, and van Boxtel, Ruben, additional

Published
2021
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36. Antiviral treatment causes a unique mutational signature in cancers of transplantation recipients

Author

de Kanter, Jurrian K., Peci, Flavia, Bertrums, Eline, Rosendahl Huber, Axel, van Leeuwen, Anaïs, van Roosmalen, Markus J., Manders, Freek, Verheul, Mark, Oka, Rurika, Brandsma, Arianne M., Bierings, Marc, Belderbos, Mirjam, van Boxtel, Ruben, de Kanter, Jurrian K., Peci, Flavia, Bertrums, Eline, Rosendahl Huber, Axel, van Leeuwen, Anaïs, van Roosmalen, Markus J., Manders, Freek, Verheul, Mark, Oka, Rurika, Brandsma, Arianne M., Bierings, Marc, Belderbos, Mirjam, and van Boxtel, Ruben

Abstract

Genetic instability is a major concern for successful application of stem cells in regenerative medicine. However, the mutational consequences of the most applied stem cell therapy in humans, hematopoietic stem cell transplantation (HSCT), remain unknown. Here we characterized the mutation burden of hematopoietic stem and progenitor cells (HSPCs) of human HSCT recipients and their donors using whole-genome sequencing. We demonstrate that the majority of transplanted HSPCs did not display altered mutation accumulation. However, in some HSCT recipients, we identified multiple HSPCs with an increased mutation burden after transplantation. This increase could be attributed to a unique mutational signature caused by the antiviral drug ganciclovir. Using a machine learning approach, we detected this signature in cancer genomes of individuals who received HSCT or solid organ transplantation earlier in life. Antiviral treatment with nucleoside analogs can cause enhanced mutagenicity in transplant recipients, which may ultimately contribute to therapy-related carcinogenesis.

Published
2021

37. Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli

Author

Pleguezuelos-Manzano, Cayetano, Puschhof, Jens, Rosendahl Huber, Axel, van Hoeck, Arne, Wood, Henry M, Nomburg, Jason, Gurjao, Carino, Manders, Freek, Dalmasso, Guillaume, Stege, Paul B, Paganelli, Fernanda L, Geurts, Maarten H, Beumer, Joep, Mizutani, Tomohiro, Miao, Yi, van der Linden, Reinier, van der Elst, Stefan, Garcia, K Christopher, Top, Janetta, Willems, Rob J L, Giannakis, Marios, Bonnet, Richard, Quirke, Phil, Meyerson, Matthew, Cuppen, Edwin, van Boxtel, Ruben, Clevers, Hans, Pleguezuelos-Manzano, Cayetano, Puschhof, Jens, Rosendahl Huber, Axel, van Hoeck, Arne, Wood, Henry M, Nomburg, Jason, Gurjao, Carino, Manders, Freek, Dalmasso, Guillaume, Stege, Paul B, Paganelli, Fernanda L, Geurts, Maarten H, Beumer, Joep, Mizutani, Tomohiro, Miao, Yi, van der Linden, Reinier, van der Elst, Stefan, Garcia, K Christopher, Top, Janetta, Willems, Rob J L, Giannakis, Marios, Bonnet, Richard, Quirke, Phil, Meyerson, Matthew, Cuppen, Edwin, van Boxtel, Ruben, and Clevers, Hans

Abstract

Various species of the intestinal microbiota have been associated with the development of colorectal cancer1,2, but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin3. This compound is believed to alkylate DNA on adenine residues4,5 and induces double-strand breaks in cultured cells3. Here we expose human intestinal organoids to genotoxic pks+ E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.

Published
2020

41. Mutational signature in colorectal cancer caused by genotoxic pks+E. coli.

Author

Pleguezuelos-Manzano, Cayetano, Puschhof, Jens, Rosendahl Huber, Axel, van Hoeck, Arne, Wood, Henry M., Nomburg, Jason, Gurjao, Carino, Manders, Freek, Dalmasso, Guillaume, Stege, Paul B., Paganelli, Fernanda L., Geurts, Maarten H., Beumer, Joep, Mizutani, Tomohiro, Miao, Yi, van der Linden, Reinier, van der Elst, Stefan, Genomics England Research Consortium, Ambrose, J. C., and Arumugam, P.

Abstract

Various species of the intestinal microbiota have been associated with the development of colorectal cancer1,2, but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin3. This compound is believed to alkylate DNA on adenine residues4,5 and induces double-strand breaks in cultured cells3. Here we expose human intestinal organoids to genotoxic pks+E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island. Organoids derived from human intestinal cells that are co-cultured with bacteria carrying the genotoxic pks+ island develop a distinct mutational signature associated with colorectal cancer. [ABSTRACT FROM AUTHOR]

Published
2020
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42. Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes.

Author

Meister MT, Groot Koerkamp MJA, de Souza T, Breunis WB, Frazer-Mendelewska E, Brok M, DeMartino J, Manders F, Calandrini C, Kerstens HHD, Janse A, Dolman MEM, Eising S, Langenberg KPS, van Tuil M, Knops RRG, van Scheltinga ST, Hiemcke-Jiwa LS, Flucke U, Merks JHM, van Noesel MM, Tops BBJ, Hehir-Kwa JY, Kemmeren P, Molenaar JJ, van de Wetering M, van Boxtel R, Drost J, and Holstege FCP

Subjects
Child, Humans, Organoids pathology, Rhabdomyosarcoma diagnosis, Rhabdomyosarcoma pathology
Abstract

Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here, we describe the generation of a collection of 19 pediatric RMS tumor organoid (tumoroid) models (success rate of 41%) comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within 4-8 weeks, indicating the feasibility of personalized drug screening. Molecular, genetic, and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to 6 months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Published
2022
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43. Mutational signature in colorectal cancer caused by genotoxic pks + E. coli.

Author

Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A, van Hoeck A, Wood HM, Nomburg J, Gurjao C, Manders F, Dalmasso G, Stege PB, Paganelli FL, Geurts MH, Beumer J, Mizutani T, Miao Y, van der Linden R, van der Elst S, Garcia KC, Top J, Willems RJL, Giannakis M, Bonnet R, Quirke P, Meyerson M, Cuppen E, van Boxtel R, and Clevers H

Subjects
Coculture Techniques, Cohort Studies, Consensus Sequence, DNA Damage, Gastrointestinal Microbiome, Humans, Organoids cytology, Organoids metabolism, Organoids microbiology, Peptides genetics, Polyketides, Colorectal Neoplasms genetics, Colorectal Neoplasms microbiology, Escherichia coli genetics, Escherichia coli pathogenicity, Genomic Islands genetics, Mutagenesis, Mutation
Abstract

Various species of the intestinal microbiota have been associated with the development of colorectal cancer 1,2 , but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin 3 . This compound is believed to alkylate DNA on adenine residues 4,5 and induces double-strand breaks in cultured cells 3 . Here we expose human intestinal organoids to genotoxic pks + E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.

Published
2020
Full Text
View/download PDF

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