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3. European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer

Author

Vergote, I, Gonzalez-Martin, A, Ray-Coquard, I, Harter, P, Colombo, N, Pujol, P, Lorusso, D, Mirza, M, Brasiuniene, B, Madry, R, Brenton, J, Ausems, M, Buttner, R, Lambrechts, D, Abreu, M, Balboni, S, Banerjee, S, Barberis, M, Barretina Ginesta, M, Baurain, J, Bignami, M, Bjorge, L, Blecharz, P, Bruchim, I, Capilna, M, Cerana, N, Cicchetti, A, Collins, D, Concin, N, D'Incalci, M, Davidson, B, de la Motte Rouge, T, De Iaco, P, Demirkiran, F, Denys, H, Doerk, T, Dorum, A, Ferrero, A, Fidalgo, A, Genuardi, M, Gladieff, L, Glasspool, R, Grimm, C, Gultekin, M, Hahnen, E, Hasenburg, A, Hegmane, A, Heinzelmann, V, Hogdall, E, Janavicius, R, Jarmalaite, S, Kalachand, R, Kaneva, R, Kilickap, S, Kocian, R, Kolencik, D, Kristeleit, R, Kryzhanivska, A, Leary, A, Lemley, B, Ligtenberg, M, Lopez-Guerrero, J, Lord, C, Avall-Lundqvist, E, Maenpaa, J, Mahner, S, Marme, F, Marth, C, Mcneish, I, Merkelbach-Bruse, S, Mourits, M, Normanno, N, Oaknin, A, Ojamaa, K, Papdimitriou, C, Penault-Llorca, F, Perrone, A, Pignata, S, Pikarsky, E, Rouleau, E, Rubio, M, Sapino, A, Schmalfeldt, B, Sehouli, J, Shapira, R, Steffensen, K, Sukhin, V, Syrios, J, Szallasi, Z, Taskiran, C, Terzic, M, Tischkowitz, M, Toth, I, Van de Vijver, K, Vardar, M, Wasag, B, Wimberger, P, Witteveen, E, Vergote I., Gonzalez-Martin A., Ray-Coquard I., Harter P., Colombo N., Pujol P., Lorusso D., Mirza M. R., Brasiuniene B., Madry R., Brenton J. D., Ausems M. G. E. M., Buttner R., Lambrechts D., Ausems M., Brenton J., Abreu M., Balboni S., Banerjee S., Barberis M., Barretina Ginesta M. P., Baurain J. -F., Bignami M., Bjorge L., Blecharz P., Bruchim I., Capilna M., Cerana N., Cicchetti A., Collins D., Concin N., D'Incalci M., Davidson B., de la Motte Rouge T., De Iaco P., Demirkiran F., Denys H., Doerk T., Dorum A., Ferrero A., Fidalgo A. P., Genuardi M., Gladieff L., Glasspool R., Grimm C., Gultekin M., Hahnen E., Hasenburg A., Hegmane A., Heinzelmann V., Hogdall E., Janavicius R., Jarmalaite S., Kalachand R., Kaneva R., Kilickap S., Kocian R., Kolencik D., Kristeleit R., Kryzhanivska A., Leary A., Lemley B., Ligtenberg M., Lopez-Guerrero J. A., Lord C. J., Avall-Lundqvist E., Maenpaa J., Mahner S., Marme F., Marth C., McNeish I., Merkelbach-Bruse S., Mourits M., Normanno N., Oaknin A., Ojamaa K., Papdimitriou C., Penault-Llorca F., Perrone A. M., Pignata S., Pikarsky E., Rouleau E., Rubio M., Sapino A., Schmalfeldt B., Sehouli J., Shapira R., Steffensen K. D., Sukhin V., Syrios J., Szallasi Z., Taskiran C., Terzic M., Tischkowitz M., Toth I., Van de Vijver K., Vardar M. A., Wasag B., Wimberger P., Witteveen E., Vergote, I, Gonzalez-Martin, A, Ray-Coquard, I, Harter, P, Colombo, N, Pujol, P, Lorusso, D, Mirza, M, Brasiuniene, B, Madry, R, Brenton, J, Ausems, M, Buttner, R, Lambrechts, D, Abreu, M, Balboni, S, Banerjee, S, Barberis, M, Barretina Ginesta, M, Baurain, J, Bignami, M, Bjorge, L, Blecharz, P, Bruchim, I, Capilna, M, Cerana, N, Cicchetti, A, Collins, D, Concin, N, D'Incalci, M, Davidson, B, de la Motte Rouge, T, De Iaco, P, Demirkiran, F, Denys, H, Doerk, T, Dorum, A, Ferrero, A, Fidalgo, A, Genuardi, M, Gladieff, L, Glasspool, R, Grimm, C, Gultekin, M, Hahnen, E, Hasenburg, A, Hegmane, A, Heinzelmann, V, Hogdall, E, Janavicius, R, Jarmalaite, S, Kalachand, R, Kaneva, R, Kilickap, S, Kocian, R, Kolencik, D, Kristeleit, R, Kryzhanivska, A, Leary, A, Lemley, B, Ligtenberg, M, Lopez-Guerrero, J, Lord, C, Avall-Lundqvist, E, Maenpaa, J, Mahner, S, Marme, F, Marth, C, Mcneish, I, Merkelbach-Bruse, S, Mourits, M, Normanno, N, Oaknin, A, Ojamaa, K, Papdimitriou, C, Penault-Llorca, F, Perrone, A, Pignata, S, Pikarsky, E, Rouleau, E, Rubio, M, Sapino, A, Schmalfeldt, B, Sehouli, J, Shapira, R, Steffensen, K, Sukhin, V, Syrios, J, Szallasi, Z, Taskiran, C, Terzic, M, Tischkowitz, M, Toth, I, Van de Vijver, K, Vardar, M, Wasag, B, Wimberger, P, Witteveen, E, Vergote I., Gonzalez-Martin A., Ray-Coquard I., Harter P., Colombo N., Pujol P., Lorusso D., Mirza M. R., Brasiuniene B., Madry R., Brenton J. D., Ausems M. G. E. M., Buttner R., Lambrechts D., Ausems M., Brenton J., Abreu M., Balboni S., Banerjee S., Barberis M., Barretina Ginesta M. P., Baurain J. -F., Bignami M., Bjorge L., Blecharz P., Bruchim I., Capilna M., Cerana N., Cicchetti A., Collins D., Concin N., D'Incalci M., Davidson B., de la Motte Rouge T., De Iaco P., Demirkiran F., Denys H., Doerk T., Dorum A., Ferrero A., Fidalgo A. P., Genuardi M., Gladieff L., Glasspool R., Grimm C., Gultekin M., Hahnen E., Hasenburg A., Hegmane A., Heinzelmann V., Hogdall E., Janavicius R., Jarmalaite S., Kalachand R., Kaneva R., Kilickap S., Kocian R., Kolencik D., Kristeleit R., Kryzhanivska A., Leary A., Lemley B., Ligtenberg M., Lopez-Guerrero J. A., Lord C. J., Avall-Lundqvist E., Maenpaa J., Mahner S., Marme F., Marth C., McNeish I., Merkelbach-Bruse S., Mourits M., Normanno N., Oaknin A., Ojamaa K., Papdimitriou C., Penault-Llorca F., Perrone A. M., Pignata S., Pikarsky E., Rouleau E., Rubio M., Sapino A., Schmalfeldt B., Sehouli J., Shapira R., Steffensen K. D., Sukhin V., Syrios J., Szallasi Z., Taskiran C., Terzic M., Tischkowitz M., Toth I., Van de Vijver K., Vardar M. A., Wasag B., Wimberger P., and Witteveen E.

Abstract

Background: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. Design: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts’ consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. Conclusion: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR de

Published
2022

6. Reference standards for gene fusion molecular assays on cytological samples: an international validation study

Author

Malapelle, U, Pepe, F, Pisapia, P, Altimari, A, Bellevicine, C, Brunnström, H, Bruno, R, Büttner, R, Cirnes, L, De Andrea, C, de Biase, D, Dumur, C, Ericson Lindquist, K, Fontanini, G, Gautiero, E, Gentien, D, Hofman, P, Hofman, V, Iaccarino, A, Lozano, M, Mayo-de-Las-Casas, C, Merkelbach-Bruse, S, Pagni, F, Roman, R, Schmitt, F, Siemanowski, J, Roy-Chowdhuri, S, Tallini, G, Tresserra, F, Vander Borght, S, Vielh, P, Vigliar, E, Vita, G, Weynand, B, Rosell, R, Molina Vila, M, Troncone, G, Malapelle, Umberto, Pepe, Francesco, Pisapia, Pasquale, Altimari, Annalisa, Bellevicine, Claudio, Brunnström, Hans, Bruno, Rossella, Büttner, Reinhard, Cirnes, Luis, De Andrea, Carlos E, de Biase, Dario, Dumur, Catherine I, Ericson Lindquist, Kajsa, Fontanini, Gabriella, Gautiero, Eugenio, Gentien, David, Hofman, Paul, Hofman, Veronique, Iaccarino, Antonino, Lozano, Maria Dolores, Mayo-de-Las-Casas, Clara, Merkelbach-Bruse, Sabine, Pagni, Fabio, Roman, Ruth, Schmitt, Fernando C, Siemanowski, Janna, Roy-Chowdhuri, Sinchita, Tallini, Giovanni, Tresserra, Francesc, Vander Borght, Sara, Vielh, Philippe, Vigliar, Elena, Vita, Giulia Anna Carmen, Weynand, Birgit, Rosell, Rafael, Molina Vila, Miguel Angel, Troncone, Giancarlo, Malapelle, U, Pepe, F, Pisapia, P, Altimari, A, Bellevicine, C, Brunnström, H, Bruno, R, Büttner, R, Cirnes, L, De Andrea, C, de Biase, D, Dumur, C, Ericson Lindquist, K, Fontanini, G, Gautiero, E, Gentien, D, Hofman, P, Hofman, V, Iaccarino, A, Lozano, M, Mayo-de-Las-Casas, C, Merkelbach-Bruse, S, Pagni, F, Roman, R, Schmitt, F, Siemanowski, J, Roy-Chowdhuri, S, Tallini, G, Tresserra, F, Vander Borght, S, Vielh, P, Vigliar, E, Vita, G, Weynand, B, Rosell, R, Molina Vila, M, Troncone, G, Malapelle, Umberto, Pepe, Francesco, Pisapia, Pasquale, Altimari, Annalisa, Bellevicine, Claudio, Brunnström, Hans, Bruno, Rossella, Büttner, Reinhard, Cirnes, Luis, De Andrea, Carlos E, de Biase, Dario, Dumur, Catherine I, Ericson Lindquist, Kajsa, Fontanini, Gabriella, Gautiero, Eugenio, Gentien, David, Hofman, Paul, Hofman, Veronique, Iaccarino, Antonino, Lozano, Maria Dolores, Mayo-de-Las-Casas, Clara, Merkelbach-Bruse, Sabine, Pagni, Fabio, Roman, Ruth, Schmitt, Fernando C, Siemanowski, Janna, Roy-Chowdhuri, Sinchita, Tallini, Giovanni, Tresserra, Francesc, Vander Borght, Sara, Vielh, Philippe, Vigliar, Elena, Vita, Giulia Anna Carmen, Weynand, Birgit, Rosell, Rafael, Molina Vila, Miguel Angel, and Troncone, Giancarlo

Abstract

AIMS: Gene fusions assays are key for personalised treatments of advanced human cancers. Their implementation on cytological material requires a preliminary validation that may make use of cell line slides mimicking cytological samples. In this international multi-institutional study, gene fusion reference standards were developed and validated. METHODS: Cell lines harbouring EML4(13)-ALK(20) and SLC34A2(4)-ROS1(32) gene fusions were adopted to prepare reference standards. Eight laboratories (five adopting amplicon-based and three hybridisation-based platforms) received, at different dilution points two sets of slides (slide A 50.0%, slide B 25.0%, slide C 12.5% and slide D wild type) stained by Papanicolaou (Pap) and May Grunwald Giemsa (MGG). Analysis was carried out on a total of 64 slides. RESULTS: Four (50.0%) out of eight laboratories reported results on all slides and dilution points. While 12 (37.5%) out of 32 MGG slides were inadequate, 27 (84.4%) out of 32 Pap slides produced libraries adequate for variant calling. The laboratories using hybridisation-based platforms showed the highest rate of inadequate results (13/24 slides, 54.2%). Conversely, only 10.0% (4/40 slides) of inadequate results were reported by laboratories adopting amplicon-based platforms. CONCLUSIONS: Reference standards in cytological format yield better results when Pap staining and processed by amplicon-based assays. Further investigation is required to optimise these standards for MGG stained cells and for hybridisation-based approaches.

Published
2023

7. EGFR exon 20 insertions in non-small cell lung cancer (NSCLC): Impact of TP53 mutation status and value of immune checkpoint blockade (ICB)

Author

Kron, A., Scheffler, M., Ihle, M., Michels, S., Sueptitz, J., Prang, D., Jakobs, F., Nogova, L., Fischer, R. N., Eisert, A. K., Riedel, R., Kron, F., Hillmer, A., Loges, S., Merkelbach-Bruse, S., Buettner, R., Wolf, J., Kron, A., Scheffler, M., Ihle, M., Michels, S., Sueptitz, J., Prang, D., Jakobs, F., Nogova, L., Fischer, R. N., Eisert, A. K., Riedel, R., Kron, F., Hillmer, A., Loges, S., Merkelbach-Bruse, S., Buettner, R., and Wolf, J.

Published
2022

8. ROS1 aberrations in non-small cell lung cancer patients without rearrangements: Clinical and molecular characteristics

Author

Glaser, M., von Levetzow, C., Michels, S., Nogova, L., Katzenmeier, M., Woempner, C., Schmitz, J., Bitter, E., Terjung, I., Passmann, E., Schaufler, D., Eisert, A., Fischer, R., Riedel, R., Weber, J-P., Hahne, S., Merkelbach-Bruse, S., Buettner, R., Wolf, J., Scheffler, M., Glaser, M., von Levetzow, C., Michels, S., Nogova, L., Katzenmeier, M., Woempner, C., Schmitz, J., Bitter, E., Terjung, I., Passmann, E., Schaufler, D., Eisert, A., Fischer, R., Riedel, R., Weber, J-P., Hahne, S., Merkelbach-Bruse, S., Buettner, R., Wolf, J., and Scheffler, M.

Published
2022

9. The biological effect of small-scale ROS1 aberrations: An in silico analysis

Author

Glaser, M., Von Levetzow, C., Michels, S., Nogova, L., Katzenmeier, M., Wompner, C., Schmitz, J., Bitter, E., Terjung, I., Passmann, E., Schaufler, D., Eisert, A. K., Fischer, R. N., Riedel, R., Weber, J-P., Hahne, S., Merkelbach-Bruse, S., Buttner, R., Wolf, J., Scheffler, M., Glaser, M., Von Levetzow, C., Michels, S., Nogova, L., Katzenmeier, M., Wompner, C., Schmitz, J., Bitter, E., Terjung, I., Passmann, E., Schaufler, D., Eisert, A. K., Fischer, R. N., Riedel, R., Weber, J-P., Hahne, S., Merkelbach-Bruse, S., Buttner, R., Wolf, J., and Scheffler, M.

Published
2022

10. Small-scale ROS1 aberrations: Functional impact and therapeutic potential

Author

Glaser, M., von Levetzow, C., Michels, S., Nogova, L., Katzenmeier, M., Woempner, C., Schmitz, J., Bitter, E., Terjung, I., Passmann, E., Schaufler, D., Eisert, A., Fischer, R. N., Riedel, R., Hahne, S., Merkelbach-Bruse, S., Buettner, R., Wolf, J., Scheffler, M., Glaser, M., von Levetzow, C., Michels, S., Nogova, L., Katzenmeier, M., Woempner, C., Schmitz, J., Bitter, E., Terjung, I., Passmann, E., Schaufler, D., Eisert, A., Fischer, R. N., Riedel, R., Hahne, S., Merkelbach-Bruse, S., Buettner, R., Wolf, J., and Scheffler, M.

Published
2022

11. Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNuM)

Author

Janning, M., Sueptitz, J., Albers-Leischner, C., Delpy, P., Tufman, A., Velthaus-Rusik, J-L, Reck, M., Jung, A., Kauffmann-Guerrero, D., Bonzheim, I, Braendlein, S., Hummel, H-D, Wiesweg, M., Schildhaus, H-U, Stratmann, J. A., Sebastian, M., Alt, J., Buth, J., Esposito, I, Berger, J., Toegel, L., Saalfeld, F. C., Wermke, M., Merkelbach-Bruse, S., Hillmer, A. M., Klauschen, F., Bokemeyer, C., Buettner, R., Wolf, J., Loges, S., Janning, M., Sueptitz, J., Albers-Leischner, C., Delpy, P., Tufman, A., Velthaus-Rusik, J-L, Reck, M., Jung, A., Kauffmann-Guerrero, D., Bonzheim, I, Braendlein, S., Hummel, H-D, Wiesweg, M., Schildhaus, H-U, Stratmann, J. A., Sebastian, M., Alt, J., Buth, J., Esposito, I, Berger, J., Toegel, L., Saalfeld, F. C., Wermke, M., Merkelbach-Bruse, S., Hillmer, A. M., Klauschen, F., Bokemeyer, C., Buettner, R., Wolf, J., and Loges, S.

Abstract

Background: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, 57681, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. Patients and methods: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, 57681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). Results: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and

Published
2022

12. High concordance of different molecular assays in the determination of HRD associated GIS in high grade epithelial ovarian cancer

Author

Weichert, W., Bartels, S., Braicu, I., Christinat, Y., Demes, M., Endris, V., Herold, S., Heukamp, L. C., Hummel, M., Lehmann, U., Merkelbach-Bruse, S., Pfarr, N., Rad, R., Sehouli, J., Siemanowski, J., Stenzinger, A., von Schwarzenberg, K., Vollbrecht, C., Wild, P. J., Zocholl, D., Weichert, W., Bartels, S., Braicu, I., Christinat, Y., Demes, M., Endris, V., Herold, S., Heukamp, L. C., Hummel, M., Lehmann, U., Merkelbach-Bruse, S., Pfarr, N., Rad, R., Sehouli, J., Siemanowski, J., Stenzinger, A., von Schwarzenberg, K., Vollbrecht, C., Wild, P. J., and Zocholl, D.

Published
2022

13. Prevalence and potential biological role of TERT amplifications in ALK translocated adenocarcinoma of the lung.

Author

Wolf J., Kron A., Schultheis A.M., Buettner R., Alidousty C., Duerbaum N., Wagener-Ryczek S., Baar T., Martelotto L.G., Heydt C., Siemanowski J., Holz B., Binot E., Fassunke J., Merkelbach-Bruse S., Wolf J., Kron A., Schultheis A.M., Buettner R., Alidousty C., Duerbaum N., Wagener-Ryczek S., Baar T., Martelotto L.G., Heydt C., Siemanowski J., Holz B., Binot E., Fassunke J., and Merkelbach-Bruse S.

Abstract

Aims: The advent of specific ALK-targeting drugs has radically changed the outcome of patients with ALK translocated non-small-cell lung cancer (NSCLC). However, emerging resistance to treatment with ALK inhibitors in these patients remains a major concern. In previous studies, we analysed two ALK+ patient cohorts (TP53 wild-type/TP53 mutated) in terms of copy number alterations. All patients belonging to the TP53 wild-type group had mainly genetically stable genomes, with one exception showing chromosomal instability and amplifications of several gene loci, including TERT. Here, we aimed to determine the prevalence of TERT amplifications in these ALK+ lung cancer patients by analysing an independent cohort of 109 ALK translocated cases. We further analysed the copy numbers of numerous cancer-relevant genes and other genetic aberrations. Methods and Results: The prevalence of TERT amplifications was determined by means of FISH analyses. Copy numbers of 87 cancer-relevant genes were determined by NanoString nCounter technology, FoundationOne and lung-specific NGS panels in some of these TERT-amplified samples, and clinical data on patients with TERT-amplified tumours were collected. Our data revealed that five (4.6%) of all 109 analysed ALK+ patients harboured amplification of TERT and that these patients had genetically unstable genomes. Conclusion(s): Our preliminary study shows that ALK+ adenocarcinomas should be evaluated in the context of their genomic background in order to more clearly understand and predict patients' individual course of disease.Copyright © 2020 The Authors. Histopathology published by John Wiley & Sons Ltd

Published
2021

14. Prevalence and potential biological role of TERT amplifications in ALK translocated adenocarcinoma of the lung.

Author

Wolf J., Kron A., Schultheis A.M., Buettner R., Alidousty C., Duerbaum N., Wagener-Ryczek S., Baar T., Martelotto L.G., Heydt C., Siemanowski J., Holz B., Binot E., Fassunke J., Merkelbach-Bruse S., Wolf J., Kron A., Schultheis A.M., Buettner R., Alidousty C., Duerbaum N., Wagener-Ryczek S., Baar T., Martelotto L.G., Heydt C., Siemanowski J., Holz B., Binot E., Fassunke J., and Merkelbach-Bruse S.

Abstract

Aims: The advent of specific ALK-targeting drugs has radically changed the outcome of patients with ALK translocated non-small-cell lung cancer (NSCLC). However, emerging resistance to treatment with ALK inhibitors in these patients remains a major concern. In previous studies, we analysed two ALK+ patient cohorts (TP53 wild-type/TP53 mutated) in terms of copy number alterations. All patients belonging to the TP53 wild-type group had mainly genetically stable genomes, with one exception showing chromosomal instability and amplifications of several gene loci, including TERT. Here, we aimed to determine the prevalence of TERT amplifications in these ALK+ lung cancer patients by analysing an independent cohort of 109 ALK translocated cases. We further analysed the copy numbers of numerous cancer-relevant genes and other genetic aberrations. Methods and Results: The prevalence of TERT amplifications was determined by means of FISH analyses. Copy numbers of 87 cancer-relevant genes were determined by NanoString nCounter technology, FoundationOne and lung-specific NGS panels in some of these TERT-amplified samples, and clinical data on patients with TERT-amplified tumours were collected. Our data revealed that five (4.6%) of all 109 analysed ALK+ patients harboured amplification of TERT and that these patients had genetically unstable genomes. Conclusion(s): Our preliminary study shows that ALK+ adenocarcinomas should be evaluated in the context of their genomic background in order to more clearly understand and predict patients' individual course of disease.Copyright © 2020 The Authors. Histopathology published by John Wiley & Sons Ltd

Published
2021

15. Concordance between multiple HRD assays is substantial in high-grade ovarian cancer

Author

Weichert, W., Bartels, S., Baretton, G., Braicu, E. I., Demes, M. C., Endris, V., Herold, S., Heukamp, L., Hummel, M., Lehmann, U., Merkelbach-Bruse, S., Pfarr, N., Rad, R., Sehouli, J., Siemanowski, J., Stenzinger, A., von Schwarzenberg, K., Vollbrecht, C., Wild, P., Zocholl, D., Weichert, W., Bartels, S., Baretton, G., Braicu, E. I., Demes, M. C., Endris, V., Herold, S., Heukamp, L., Hummel, M., Lehmann, U., Merkelbach-Bruse, S., Pfarr, N., Rad, R., Sehouli, J., Siemanowski, J., Stenzinger, A., von Schwarzenberg, K., Vollbrecht, C., Wild, P., and Zocholl, D.

Published
2021

16. Homologous recombination repair deficiency as a predictive biomarker Basic mechanisms and detection methods

Author

Pfarr, N., Merkelbach-Bruse, S., Pfarr, N., and Merkelbach-Bruse, S.

Abstract

Background DNA double-strand breaks may evoke cell death or cancer. Cells have developed two fundamentally different mechanisms of DNA double-strand repair: the accurate mechanism of homologous recombination repair and the error-prone nonhomologous end joining. The deficiency of homologous recombination repair (HRD) is a frequent feature of several solid tumor entities and is associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitor therapy. Objectives Among other biomarkers, HRD testing provides an opportunity to guide PARP inhibitor therapy in solid tumors, but the basic principles are complex and the use and benefits of the different methodologies remain controversial. Knowledge of the underlying mechanisms at the molecular level will advance our understanding and will pave the way to introduce the testing of new biomarkers. Methods An overview of the fundamental mechanisms of DNA repair is provided. Important terms like HRR, HRD, and BRCAness are defined, and analysis methods are described, especially with regard to their integration in molecular pathology routine diagnostics. Results Currently, at least testing of the BRCA mutation status and genomic instability using a composite HRD score should be implemented in laboratories to identify subgroups of patients who might benefit from PARP inhibitor therapies. A broad range of testing methods is available with pros and cons for introduction in the clinical setting. They have to be validated carefully to reliably inform treatment selection. Conclusions Biomarkers to identify current homologous recombination deficiency status are needed to predict the benefit from PARP inhibitors and stratify their use in clinical management. Besides commercial assays, different tests might be used for the analysis of HRD. The application depends, among other things, on the local situation and has to be extensively validated.

Published
2021

17. Multi-center real-world comparison of the fully automated Idylla™ microsatellite instability assay with routine molecular methods and immunohistochemistry on formalin-fixed paraffin-embedded tissue of colorectal cancer

Author

Velasco, A, Tokat, F, Bonde, J, Trim, N, Bauer, E, Meeney, A, de Leng, W, Chong, G, Dalstein, V, Kis, LL, Lorentzen, JA, Tomic, S, Thwaites, K, Putzova, M, Birnbaum, A, Qazi, R, Primmer, V, Dockhorn-Dworniczak, B, Hernandez-Losa, J, Soares, FA, Gertler, AA, Kalman, M, Wong, C, Carraro, DM, Sousa, AC, Reis, RM, Fox, SB, Fassan, M, Brevet, M, Merkelbach-Bruse, S, Colling, R, Soilleux, E, Teo, RYW, D'Haene, N, Nolet, S, Ristimaki, A, Vaisanen, T, Chapusot, C, Soruri, A, Unger, T, Wecgowiec, J, Biscuola, M, Frattini, M, Long, A, Campregher, P, Matias-Guiu, X, Velasco, A, Tokat, F, Bonde, J, Trim, N, Bauer, E, Meeney, A, de Leng, W, Chong, G, Dalstein, V, Kis, LL, Lorentzen, JA, Tomic, S, Thwaites, K, Putzova, M, Birnbaum, A, Qazi, R, Primmer, V, Dockhorn-Dworniczak, B, Hernandez-Losa, J, Soares, FA, Gertler, AA, Kalman, M, Wong, C, Carraro, DM, Sousa, AC, Reis, RM, Fox, SB, Fassan, M, Brevet, M, Merkelbach-Bruse, S, Colling, R, Soilleux, E, Teo, RYW, D'Haene, N, Nolet, S, Ristimaki, A, Vaisanen, T, Chapusot, C, Soruri, A, Unger, T, Wecgowiec, J, Biscuola, M, Frattini, M, Long, A, Campregher, P, and Matias-Guiu, X

Abstract

Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests.

Published
2021

18. Homologous recombination repair deficiency as a predictive biomarker Basic mechanisms and detection methods

Author

Pfarr, N., Merkelbach-Bruse, S., Pfarr, N., and Merkelbach-Bruse, S.

Abstract

Background DNA double-strand breaks may evoke cell death or cancer. Cells have developed two fundamentally different mechanisms of DNA double-strand repair: the accurate mechanism of homologous recombination repair and the error-prone nonhomologous end joining. The deficiency of homologous recombination repair (HRD) is a frequent feature of several solid tumor entities and is associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitor therapy. Objectives Among other biomarkers, HRD testing provides an opportunity to guide PARP inhibitor therapy in solid tumors, but the basic principles are complex and the use and benefits of the different methodologies remain controversial. Knowledge of the underlying mechanisms at the molecular level will advance our understanding and will pave the way to introduce the testing of new biomarkers. Methods An overview of the fundamental mechanisms of DNA repair is provided. Important terms like HRR, HRD, and BRCAness are defined, and analysis methods are described, especially with regard to their integration in molecular pathology routine diagnostics. Results Currently, at least testing of the BRCA mutation status and genomic instability using a composite HRD score should be implemented in laboratories to identify subgroups of patients who might benefit from PARP inhibitor therapies. A broad range of testing methods is available with pros and cons for introduction in the clinical setting. They have to be validated carefully to reliably inform treatment selection. Conclusions Biomarkers to identify current homologous recombination deficiency status are needed to predict the benefit from PARP inhibitors and stratify their use in clinical management. Besides commercial assays, different tests might be used for the analysis of HRD. The application depends, among other things, on the local situation and has to be extensively validated.

Published
2021

19. Concordance between multiple HRD assays is substantial in high-grade ovarian cancer

Author

Weichert, W., Bartels, S., Baretton, G., Braicu, E. I., Demes, M. C., Endris, V., Herold, S., Heukamp, L., Hummel, M., Lehmann, U., Merkelbach-Bruse, S., Pfarr, N., Rad, R., Sehouli, J., Siemanowski, J., Stenzinger, A., von Schwarzenberg, K., Vollbrecht, C., Wild, P., Zocholl, D., Weichert, W., Bartels, S., Baretton, G., Braicu, E. I., Demes, M. C., Endris, V., Herold, S., Heukamp, L., Hummel, M., Lehmann, U., Merkelbach-Bruse, S., Pfarr, N., Rad, R., Sehouli, J., Siemanowski, J., Stenzinger, A., von Schwarzenberg, K., Vollbrecht, C., Wild, P., and Zocholl, D.

Published
2021

20. EATON: A phase I dose-escalation trial of nazartinib (EGF816) and trametinib in EGFR-mutant non-small cell lung cancer (NSCLC) - preliminary data

Author

Michels, S., Westphal, T., Nogova, L., Scheffler, M., Deschler-Baier, B., Sebastian, M., Schuler, M., Wermke, M., Abdulla, D. S. Y., Fischer, R. N., Koleczko, S., Kron, A., Pinto, A., Riedel, R., Weber, J. -P., Fassunke, J., Merkelbach-Bruse, S., Haverkamp, H., Hellmich, M., Buettner, R., Wolf, J., Michels, S., Westphal, T., Nogova, L., Scheffler, M., Deschler-Baier, B., Sebastian, M., Schuler, M., Wermke, M., Abdulla, D. S. Y., Fischer, R. N., Koleczko, S., Kron, A., Pinto, A., Riedel, R., Weber, J. -P., Fassunke, J., Merkelbach-Bruse, S., Haverkamp, H., Hellmich, M., Buettner, R., and Wolf, J.

Published
2020

21. Small Cell Lung Cancer - Filling the gap between science and patients

Author

Weber, J. -P., Fischer, R. N., George, J., Scheel, A., Westphal, T., Koleczko, S., Nogova, L., Riedel, R., Michels, S., Scheffler, M., Abdullah, D. S. Y., Sueptitz, J., Keser, E., Merkelbach-Bruse, S., Pinto, A., Buettner, R., Thomas, R., Wolf, J., Weber, J. -P., Fischer, R. N., George, J., Scheel, A., Westphal, T., Koleczko, S., Nogova, L., Riedel, R., Michels, S., Scheffler, M., Abdullah, D. S. Y., Sueptitz, J., Keser, E., Merkelbach-Bruse, S., Pinto, A., Buettner, R., Thomas, R., and Wolf, J.

Published
2020

22. Small Cell Lung Cancer - Filling the gap between science and patients

Author

Weber, J. -P., Fischer, R. N., George, J., Scheel, A., Westphal, T., Koleczko, S., Nogova, L., Riedel, R., Michels, S., Scheffler, M., Abdullah, D. S. Y., Sueptitz, J., Keser, E., Merkelbach-Bruse, S., Pinto, A., Buettner, R., Thomas, R., Wolf, J., Weber, J. -P., Fischer, R. N., George, J., Scheel, A., Westphal, T., Koleczko, S., Nogova, L., Riedel, R., Michels, S., Scheffler, M., Abdullah, D. S. Y., Sueptitz, J., Keser, E., Merkelbach-Bruse, S., Pinto, A., Buettner, R., Thomas, R., and Wolf, J.

Published
2020

23. Development of high-risk HPV associated cervical dysplasia despite HPV-vaccination: a regional dysplasia center cohort study

Author

Fischer, A. K., Reuter-Jessen, K., Schildhaus, H-U, Hugo, T., Scheel, A. H., Merkelbach-Bruse, S., Heinmoeller, E., Buettner, R., Jasani, B., Walbeck, J., Rueschoff, J., Middell, P., Fischer, A. K., Reuter-Jessen, K., Schildhaus, H-U, Hugo, T., Scheel, A. H., Merkelbach-Bruse, S., Heinmoeller, E., Buettner, R., Jasani, B., Walbeck, J., Rueschoff, J., and Middell, P.

Abstract

The present study was conducted to examine the frequency of CIN/squamous intraepithelial lesions in patients after vaccination and respective HPV types observed at their referral to a regional center for screening of cervical dysplasia.

Published
2020

24. Status of the availability and use of next generation sequencing (NGS) in bladder cancer-a questionnaire within the uropathology working group

Author

Ortiz-Bruechle, N., Muders, M., Toma, M., Esposito, I, Hartmann, A., Stoehr, R., Reis, H., Wild, P., Koellermann, J., Bremmer, F., Leichsenring, J., Stenzinger, A., Merkelbach-Bruse, S., Kirfel, S., Perner, S., Hartmann, N., Roth, W., Jung, A., Kirchner, T., Schwamborn, K., Pfarr, N., Dahl, E., Knuechel, R., Gaisa, N. T., Ortiz-Bruechle, N., Muders, M., Toma, M., Esposito, I, Hartmann, A., Stoehr, R., Reis, H., Wild, P., Koellermann, J., Bremmer, F., Leichsenring, J., Stenzinger, A., Merkelbach-Bruse, S., Kirfel, S., Perner, S., Hartmann, N., Roth, W., Jung, A., Kirchner, T., Schwamborn, K., Pfarr, N., Dahl, E., Knuechel, R., and Gaisa, N. T.

Abstract

Background Technical advancement and availability of high-throughput analysis has advanced molecular subtyping of most cancers. Thus, new possibilities for precision oncology have emerged. Aim Therefore, we aimed to collect data regarding availability and use of next generation sequencing (NGS) for urothelial cancer within the uropathology working group of the German Society of Pathology. Methods We collected data by questionnaires and additionally asked for sequencing results of bladder cancers in the participating institutions. Results A total of 13 university-affiliated institutes of pathology took part in the survey. All university institutes offer NGS-based molecular panel diagnostics and provide panels covering between 15 and 170 genes. Altogether, only 20 bladder cancers were sequenced in routine diagnostics and for 10 cancers potential targeted treatment options were available. Discussion So far, despite availability of NGS diagnostics at university institutes of pathology, only few bladder cancer samples have been sequenced. Based on current data from the molecular subtyping of bladder cancers, we recommend a step-by-step protocol with basic immunohistochemistry analysis and subsequent subtype-dependent analyses, e.g., alterations of the fibroblast growth factor receptors (FGFR) or comprehensive gene panel analyses.

Published
2020

25. GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma

Author

Livingstone, E., Zaremba, A., Horn, S., Ugurel, S., Casalini, B., Schlaak, M., Hassel, J. C., Herbst, R., Utikal, J. S., Weide, B., Gutzmer, R., Meier, F., Koelsche, C., Hadaschik, E., Sucker, A., Reis, H., Merkelbach-Bruse, S., Siewert, M., Sahm, F., von Deimling, A., Cosgarea, I., Zimmer, L., Schadendorf, D., Schilling, B., Griewank, K. G., Livingstone, E., Zaremba, A., Horn, S., Ugurel, S., Casalini, B., Schlaak, M., Hassel, J. C., Herbst, R., Utikal, J. S., Weide, B., Gutzmer, R., Meier, F., Koelsche, C., Hadaschik, E., Sucker, A., Reis, H., Merkelbach-Bruse, S., Siewert, M., Sahm, F., von Deimling, A., Cosgarea, I., Zimmer, L., Schadendorf, D., Schilling, B., and Griewank, K. G.

Abstract

Background GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. Objectives To characterize these tumours in terms of clinical behaviour and genetic characteristics. Methods Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. Results We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). Conclusions Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanom

Published
2020

28. KRAS mutations in never-smoker NSCLC patients: Defining a new patient subgroup

Author

Scheffler, M., Nogova, L., Michels, S., Holzem, A., Chanra, T., Abdulla, D. S. Y., Koleczko, S., Merkelbach-Bruse, S., Fassunke, J., Kron, A., Scheel, A. H., Ihle, M. A., Heydt, C., Westphal, T., Weber, J. -P., Fischer, R. N., Riedel, R., Kaminsky, B., Draube, A., Rothe, A., Kambartel, K. -O., Hillmer, A., Buettner, R., Wolf, J., Scheffler, M., Nogova, L., Michels, S., Holzem, A., Chanra, T., Abdulla, D. S. Y., Koleczko, S., Merkelbach-Bruse, S., Fassunke, J., Kron, A., Scheel, A. H., Ihle, M. A., Heydt, C., Westphal, T., Weber, J. -P., Fischer, R. N., Riedel, R., Kaminsky, B., Draube, A., Rothe, A., Kambartel, K. -O., Hillmer, A., Buettner, R., and Wolf, J.

Published
2020

29. ALK Mutations in Primary and Relapsed Neuroblastoma in a GPOH Cohort

Author

Rosswog, C., Fassunke, J., Schoemig-Markiefka, B., Merkelbach-Bruse, S., Ackermann, S., Ortmann, M., Schulte, J., Westermann, F., Berthold, F., Simon, T., Hero, B., Fischer, M., Rosswog, C., Fassunke, J., Schoemig-Markiefka, B., Merkelbach-Bruse, S., Ackermann, S., Ortmann, M., Schulte, J., Westermann, F., Berthold, F., Simon, T., Hero, B., and Fischer, M.

Published
2020

30. FIND: a phase II study to evaluate the efficacy of erdafitinib in FGFR-altered NSCLC

Author

Nogova, L., Malchers, F., Hillmer, A. M., Merkelbach-Bruse, S., Pinto, A., Scheel, A. H., Siemanowski, J., Ueckeroth, F., Scheffler, M., Hummel, H. -D., Kern, J., Wermke, M., Kolbe, M., Grohe, C., Stratmann, J., Sebastian, M., Trummer, A., Weber, J. -P., Westphal, T., Michels, S., Koleczko, S., Sueptitz, J., Keser, E., Kron, A., Riedel, R., Abdulla, D. S. Y., Zadoyan, G., Sweiti, H., Santiago-Walker, A., Rothe, A., Draube, A., Sandler, A., Rodermann, E., Linck, D., Thomas, R. K., Buettner, R., Wolf, J., Nogova, L., Malchers, F., Hillmer, A. M., Merkelbach-Bruse, S., Pinto, A., Scheel, A. H., Siemanowski, J., Ueckeroth, F., Scheffler, M., Hummel, H. -D., Kern, J., Wermke, M., Kolbe, M., Grohe, C., Stratmann, J., Sebastian, M., Trummer, A., Weber, J. -P., Westphal, T., Michels, S., Koleczko, S., Sueptitz, J., Keser, E., Kron, A., Riedel, R., Abdulla, D. S. Y., Zadoyan, G., Sweiti, H., Santiago-Walker, A., Rothe, A., Draube, A., Sandler, A., Rodermann, E., Linck, D., Thomas, R. K., Buettner, R., and Wolf, J.

Published
2020

32. Status of the availability and use of next generation sequencing (NGS) in bladder cancer-a questionnaire within the uropathology working group

Author

Ortiz-Bruechle, N., Muders, M., Toma, M., Esposito, I, Hartmann, A., Stoehr, R., Reis, H., Wild, P., Koellermann, J., Bremmer, F., Leichsenring, J., Stenzinger, A., Merkelbach-Bruse, S., Kirfel, S., Perner, S., Hartmann, N., Roth, W., Jung, A., Kirchner, T., Schwamborn, K., Pfarr, N., Dahl, E., Knuechel, R., Gaisa, N. T., Ortiz-Bruechle, N., Muders, M., Toma, M., Esposito, I, Hartmann, A., Stoehr, R., Reis, H., Wild, P., Koellermann, J., Bremmer, F., Leichsenring, J., Stenzinger, A., Merkelbach-Bruse, S., Kirfel, S., Perner, S., Hartmann, N., Roth, W., Jung, A., Kirchner, T., Schwamborn, K., Pfarr, N., Dahl, E., Knuechel, R., and Gaisa, N. T.

Abstract

Background Technical advancement and availability of high-throughput analysis has advanced molecular subtyping of most cancers. Thus, new possibilities for precision oncology have emerged. Aim Therefore, we aimed to collect data regarding availability and use of next generation sequencing (NGS) for urothelial cancer within the uropathology working group of the German Society of Pathology. Methods We collected data by questionnaires and additionally asked for sequencing results of bladder cancers in the participating institutions. Results A total of 13 university-affiliated institutes of pathology took part in the survey. All university institutes offer NGS-based molecular panel diagnostics and provide panels covering between 15 and 170 genes. Altogether, only 20 bladder cancers were sequenced in routine diagnostics and for 10 cancers potential targeted treatment options were available. Discussion So far, despite availability of NGS diagnostics at university institutes of pathology, only few bladder cancer samples have been sequenced. Based on current data from the molecular subtyping of bladder cancers, we recommend a step-by-step protocol with basic immunohistochemistry analysis and subsequent subtype-dependent analyses, e.g., alterations of the fibroblast growth factor receptors (FGFR) or comprehensive gene panel analyses.

Published
2020

33. Development of high-risk HPV associated cervical dysplasia despite HPV-vaccination: a regional dysplasia center cohort study

Author

Fischer, A. K., Reuter-Jessen, K., Schildhaus, H-U, Hugo, T., Scheel, A. H., Merkelbach-Bruse, S., Heinmoeller, E., Buettner, R., Jasani, B., Walbeck, J., Rueschoff, J., Middell, P., Fischer, A. K., Reuter-Jessen, K., Schildhaus, H-U, Hugo, T., Scheel, A. H., Merkelbach-Bruse, S., Heinmoeller, E., Buettner, R., Jasani, B., Walbeck, J., Rueschoff, J., and Middell, P.

Abstract

The present study was conducted to examine the frequency of CIN/squamous intraepithelial lesions in patients after vaccination and respective HPV types observed at their referral to a regional center for screening of cervical dysplasia.

Published
2020

35. GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma

Author

Livingstone, E., Zaremba, A., Horn, S., Ugurel, S., Casalini, B., Schlaak, M., Hassel, J. C., Herbst, R., Utikal, J. S., Weide, B., Gutzmer, R., Meier, F., Koelsche, C., Hadaschik, E., Sucker, A., Reis, H., Merkelbach-Bruse, S., Siewert, M., Sahm, F., von Deimling, A., Cosgarea, I., Zimmer, L., Schadendorf, D., Schilling, B., Griewank, K. G., Livingstone, E., Zaremba, A., Horn, S., Ugurel, S., Casalini, B., Schlaak, M., Hassel, J. C., Herbst, R., Utikal, J. S., Weide, B., Gutzmer, R., Meier, F., Koelsche, C., Hadaschik, E., Sucker, A., Reis, H., Merkelbach-Bruse, S., Siewert, M., Sahm, F., von Deimling, A., Cosgarea, I., Zimmer, L., Schadendorf, D., Schilling, B., and Griewank, K. G.

Abstract

Background GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. Objectives To characterize these tumours in terms of clinical behaviour and genetic characteristics. Methods Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. Results We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). Conclusions Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanom

Published
2020

37. EATON: A phase I dose-escalation trial of nazartinib (EGF816) and trametinib in EGFR-mutant non-small cell lung cancer (NSCLC) - preliminary data

Author

Michels, S., Westphal, T., Nogova, L., Scheffler, M., Deschler-Baier, B., Sebastian, M., Schuler, M., Wermke, M., Abdulla, D. S. Y., Fischer, R. N., Koleczko, S., Kron, A., Pinto, A., Riedel, R., Weber, J. -P., Fassunke, J., Merkelbach-Bruse, S., Haverkamp, H., Hellmich, M., Buettner, R., Wolf, J., Michels, S., Westphal, T., Nogova, L., Scheffler, M., Deschler-Baier, B., Sebastian, M., Schuler, M., Wermke, M., Abdulla, D. S. Y., Fischer, R. N., Koleczko, S., Kron, A., Pinto, A., Riedel, R., Weber, J. -P., Fassunke, J., Merkelbach-Bruse, S., Haverkamp, H., Hellmich, M., Buettner, R., and Wolf, J.

Published
2020

38. Small Cell Lung Cancer - Filling the gap between science and patients

Author

Weber, J. -P., Fischer, R. N., George, J., Scheel, A., Westphal, T., Koleczko, S., Nogova, L., Riedel, R., Michels, S., Scheffler, M., Abdullah, D. S. Y., Sueptitz, J., Keser, E., Merkelbach-Bruse, S., Pinto, A., Buettner, R., Thomas, R., Wolf, J., Weber, J. -P., Fischer, R. N., George, J., Scheel, A., Westphal, T., Koleczko, S., Nogova, L., Riedel, R., Michels, S., Scheffler, M., Abdullah, D. S. Y., Sueptitz, J., Keser, E., Merkelbach-Bruse, S., Pinto, A., Buettner, R., Thomas, R., and Wolf, J.

Published
2020

39. FIND: a phase II study to evaluate the efficacy of erdafitinib in FGFR-altered NSCLC

Author

Nogova, L., Malchers, F., Hillmer, A. M., Merkelbach-Bruse, S., Pinto, A., Scheel, A. H., Siemanowski, J., Ueckeroth, F., Scheffler, M., Hummel, H. -D., Kern, J., Wermke, M., Kolbe, M., Grohe, C., Stratmann, J., Sebastian, M., Trummer, A., Weber, J. -P., Westphal, T., Michels, S., Koleczko, S., Sueptitz, J., Keser, E., Kron, A., Riedel, R., Abdulla, D. S. Y., Zadoyan, G., Sweiti, H., Santiago-Walker, A., Rothe, A., Draube, A., Sandler, A., Rodermann, E., Linck, D., Thomas, R. K., Buettner, R., Wolf, J., Nogova, L., Malchers, F., Hillmer, A. M., Merkelbach-Bruse, S., Pinto, A., Scheel, A. H., Siemanowski, J., Ueckeroth, F., Scheffler, M., Hummel, H. -D., Kern, J., Wermke, M., Kolbe, M., Grohe, C., Stratmann, J., Sebastian, M., Trummer, A., Weber, J. -P., Westphal, T., Michels, S., Koleczko, S., Sueptitz, J., Keser, E., Kron, A., Riedel, R., Abdulla, D. S. Y., Zadoyan, G., Sweiti, H., Santiago-Walker, A., Rothe, A., Draube, A., Sandler, A., Rodermann, E., Linck, D., Thomas, R. K., Buettner, R., and Wolf, J.

Published
2020

40. KRAS mutations in never-smoker NSCLC patients: Defining a new patient subgroup

Author

Scheffler, M., Nogova, L., Michels, S., Holzem, A., Chanra, T., Abdulla, D. S. Y., Koleczko, S., Merkelbach-Bruse, S., Fassunke, J., Kron, A., Scheel, A. H., Ihle, M. A., Heydt, C., Westphal, T., Weber, J. -P., Fischer, R. N., Riedel, R., Kaminsky, B., Draube, A., Rothe, A., Kambartel, K. -O., Hillmer, A., Buettner, R., Wolf, J., Scheffler, M., Nogova, L., Michels, S., Holzem, A., Chanra, T., Abdulla, D. S. Y., Koleczko, S., Merkelbach-Bruse, S., Fassunke, J., Kron, A., Scheel, A. H., Ihle, M. A., Heydt, C., Westphal, T., Weber, J. -P., Fischer, R. N., Riedel, R., Kaminsky, B., Draube, A., Rothe, A., Kambartel, K. -O., Hillmer, A., Buettner, R., and Wolf, J.

Published
2020

41. ALK Mutations in Primary and Relapsed Neuroblastoma in a GPOH Cohort

Author

Rosswog, C., Fassunke, J., Schoemig-Markiefka, B., Merkelbach-Bruse, S., Ackermann, S., Ortmann, M., Schulte, J., Westermann, F., Berthold, F., Simon, T., Hero, B., Fischer, M., Rosswog, C., Fassunke, J., Schoemig-Markiefka, B., Merkelbach-Bruse, S., Ackermann, S., Ortmann, M., Schulte, J., Westermann, F., Berthold, F., Simon, T., Hero, B., and Fischer, M.

Published
2020

43. Detection and interpretation of somatic variants inmolecular pathology

Author

Merkelbach-Bruse, S., Rehker, J., Siemanowski, J., Klauschen, F., Merkelbach-Bruse, S., Rehker, J., Siemanowski, J., and Klauschen, F.

Abstract

BackgroundDue to the increasing amount of data and sources of information, data evaluation is acrucial step in parallel sequencing.ObjectivesIllustration of pitfalls in evaluating the variant list of parallel sequencing and recommendations regarding software tools and databases.MethodsDescription of filtering steps used, demonstration of criteria and recommendations for annotation by examples from everyday work, comparative analysis of databases with somatic variants, description of the installation of an individualized database.ResultsVariant filtering is amultistep process using information from different databases. The plausibility of variant calling should be verified using the Integrative Genomics Viewer and variants should be described according to the Human Genome Variation Society (HGVS) recommendations. Different databases, which all show advantages and disadvantages, are available for variant interpretation. An individualized database can be built up with the open-source tool cBioPortal.ConclusionsDifferent tools and databases might be used for the analysis of parallel sequencing data. The application depends on, amongst other things, the local situation and has to be extensively validated.

Published
2019

44. Detection and interpretation of somatic variants inmolecular pathology

Author

Merkelbach-Bruse, S., Rehker, J., Siemanowski, J., Klauschen, F., Merkelbach-Bruse, S., Rehker, J., Siemanowski, J., and Klauschen, F.

Abstract

BackgroundDue to the increasing amount of data and sources of information, data evaluation is acrucial step in parallel sequencing.ObjectivesIllustration of pitfalls in evaluating the variant list of parallel sequencing and recommendations regarding software tools and databases.MethodsDescription of filtering steps used, demonstration of criteria and recommendations for annotation by examples from everyday work, comparative analysis of databases with somatic variants, description of the installation of an individualized database.ResultsVariant filtering is amultistep process using information from different databases. The plausibility of variant calling should be verified using the Integrative Genomics Viewer and variants should be described according to the Human Genome Variation Society (HGVS) recommendations. Different databases, which all show advantages and disadvantages, are available for variant interpretation. An individualized database can be built up with the open-source tool cBioPortal.ConclusionsDifferent tools and databases might be used for the analysis of parallel sequencing data. The application depends on, amongst other things, the local situation and has to be extensively validated.

Published
2019

45. Genetic instability and recurrent MYC amplification in ALK-translocated NSCLC: a central role of TP53 mutations.

Author

Buettner R., Kron A., Merkelbach-Bruse S., Ihle M.A., Wolf J., Schultheis A.M., Alidousty C., Baar T., Martelotto L.G., Heydt C., Wagener S., Fassunke J., Duerbaum N., Scheel A.H., Frank S., Holz B., Binot E., Buettner R., Kron A., Merkelbach-Bruse S., Ihle M.A., Wolf J., Schultheis A.M., Alidousty C., Baar T., Martelotto L.G., Heydt C., Wagener S., Fassunke J., Duerbaum N., Scheel A.H., Frank S., Holz B., and Binot E.

Abstract

The anaplastic lymphoma kinase (ALK) rearrangement defines a distinct molecular subtype of non-small cell lung cancer (NSCLC). Despite the excellent initial efficacy of ALK inhibitors in patients with ALK+ lung cancer, resistance occurs almost inevitably. To date, there is no reliable biomarker allowing the identification of patients at higher risk of relapse. Here, we analysed a subset of 53 ALK+ tumours with and without TP53 mutation and ALK+ NSCLC cell lines by NanoString nCounter technology. We found that the co-occurrence of early TP53 mutations in ALK+ NSCLC can lead to chromosomal instability: 24% of TP53-mutated patients showed amplifications of known cancer genes such as MYC (14%), CCND1 (10%), TERT (5%), BIRC2 (5%), ORAOV1 (5%), and YAP1 (5%). MYC-overexpressing ALK+ TP53-mutated cells had a proliferative advantage compared to wild-type cells. ChIP-Seq data revealed MYC-binding sites within the promoter region of EML4, and MYC overexpression in ALK+ TP53-mutated cells resulted in an upregulation of EML4-ALK, indicating a potential MYC-dependent resistance mechanism in patients with increased MYC copy number. Our study reveals that ALK+ NSCLC represents a more heterogeneous subgroup of tumours than initially thought, and that TP53 mutations in that particular cancer type define a subset of tumours that harbour chromosomal instability, leading to the co-occurrence of pathogenic aberrations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Published
2018

46. Genetic instability and recurrent MYC amplification in ALK-translocated NSCLC: a central role of TP53 mutations.

Author

Buettner R., Kron A., Merkelbach-Bruse S., Ihle M.A., Wolf J., Schultheis A.M., Alidousty C., Baar T., Martelotto L.G., Heydt C., Wagener S., Fassunke J., Duerbaum N., Scheel A.H., Frank S., Holz B., Binot E., Buettner R., Kron A., Merkelbach-Bruse S., Ihle M.A., Wolf J., Schultheis A.M., Alidousty C., Baar T., Martelotto L.G., Heydt C., Wagener S., Fassunke J., Duerbaum N., Scheel A.H., Frank S., Holz B., and Binot E.

Abstract

The anaplastic lymphoma kinase (ALK) rearrangement defines a distinct molecular subtype of non-small cell lung cancer (NSCLC). Despite the excellent initial efficacy of ALK inhibitors in patients with ALK+ lung cancer, resistance occurs almost inevitably. To date, there is no reliable biomarker allowing the identification of patients at higher risk of relapse. Here, we analysed a subset of 53 ALK+ tumours with and without TP53 mutation and ALK+ NSCLC cell lines by NanoString nCounter technology. We found that the co-occurrence of early TP53 mutations in ALK+ NSCLC can lead to chromosomal instability: 24% of TP53-mutated patients showed amplifications of known cancer genes such as MYC (14%), CCND1 (10%), TERT (5%), BIRC2 (5%), ORAOV1 (5%), and YAP1 (5%). MYC-overexpressing ALK+ TP53-mutated cells had a proliferative advantage compared to wild-type cells. ChIP-Seq data revealed MYC-binding sites within the promoter region of EML4, and MYC overexpression in ALK+ TP53-mutated cells resulted in an upregulation of EML4-ALK, indicating a potential MYC-dependent resistance mechanism in patients with increased MYC copy number. Our study reveals that ALK+ NSCLC represents a more heterogeneous subgroup of tumours than initially thought, and that TP53 mutations in that particular cancer type define a subset of tumours that harbour chromosomal instability, leading to the co-occurrence of pathogenic aberrations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Published
2018

47. Implementation of Next Generation Sequencing-based Molecular Diagnostics in a Lung Cancer Center Tumor Board

Author

Frangenberg, A., Starbatty, B., Berressem, S., Sueptitz, J., Hayn, A., Hagmeyer, L., Wragge, S., Hellmessen, K., Merkelbach-Bruse, S., Ueckeroth, F., Hekmat, K., Frank, K., Randerath, W., Buettner, R., Wolf, J., Frangenberg, A., Starbatty, B., Berressem, S., Sueptitz, J., Hayn, A., Hagmeyer, L., Wragge, S., Hellmessen, K., Merkelbach-Bruse, S., Ueckeroth, F., Hekmat, K., Frank, K., Randerath, W., Buettner, R., and Wolf, J.

Published
2018

48. FIND trial: a phase II study to evaluate the efficacy of the FGFR-inhibitor erdafitinib in FGFR-mutated and - translocated squamous NSCLC (trial in progress)

Author

Nogova, L., Malchers, F., Zadoyan, G., Hillmer, A., Merkelbach-Bruse, S., Riedel, R., Michels, S., Masouleh, Kharabi B., De Porre, P., Santiago-Walker, A., Scheffler, M., Fischer, R. N., Abdulla, D. S. Y., Thomas, R., Buettner, R., Wolf, J., Nogova, L., Malchers, F., Zadoyan, G., Hillmer, A., Merkelbach-Bruse, S., Riedel, R., Michels, S., Masouleh, Kharabi B., De Porre, P., Santiago-Walker, A., Scheffler, M., Fischer, R. N., Abdulla, D. S. Y., Thomas, R., Buettner, R., and Wolf, J.

Published
2018

50. Co-occurrence of targetable aberrations in non-small cell lung cancer patients harboring MAP2K1 mutations

Author

Holzem, A., Nogova, L., Ihle, M. A., Woempner, C., Bitter, E., Michels, S., Fischer, R. N., Kron, A., Gerigk, U., Kern, J., Kaminsky, B., Randerath, W. J., Lorenz, J., Kambartel, K., Merkelbach-Bruse, S., Buttner, R., Scheffler, M., Wolf, J., Holzem, A., Nogova, L., Ihle, M. A., Woempner, C., Bitter, E., Michels, S., Fischer, R. N., Kron, A., Gerigk, U., Kern, J., Kaminsky, B., Randerath, W. J., Lorenz, J., Kambartel, K., Merkelbach-Bruse, S., Buttner, R., Scheffler, M., and Wolf, J.

Published
2018

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