77 results on '"Stelloo, E"'
Search Results
2. OC-0508 Molecular classification of endometrial cancer is predictive of response to adjuvant radiotherapy
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Horeweg, N., primary, Nout, R.A., additional, Jobsen, J.J., additional, Lutgens, J.C., additional, Jürgenliemk-Schulz, I.M., additional, Haverkort, D.M., additional, Mens, J.W.M., additional, de Jong, M.A., additional, Wortman, B.G., additional, de Boer, S.M., additional, Putter, H., additional, Stelloo, E., additional, Smit, V.T., additional, Bosse, T., additional, and Creutzberg, C.L., additional
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- 2023
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3. Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy
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Wortman, B. G., Creutzberg, C. L., Putter, H., Jürgenliemk-Schulz, I. M., Jobsen, J. J., Lutgens, L. C. H. W., van der Steen-Banasik, E. M., Mens, J. W. M., Slot, A., Kroese, M. C. Stenfert, van Triest, B., Nijman, H. W., Stelloo, E., Bosse, T., de Boer, S. M., van Putten, W. L. J., Smit, V. T. H. B. M, Nout, R. A., and for the PORTEC Study Group
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- 2018
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4. Markers of the p53 pathway further refine molecular profiling in high-risk endometrial cancer: A TransPORTEC initiative
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Edmondson, R.J., Crosbie, E.J., Nickkho-Amiry, M., Kaufmann, A., Stelloo, E., Nijman, H.W., Leary, A., Auguste, A., Mileshkin, L., Pollock, P., MacKay, H.J., Powell, M.E., Bosse, T., Creutzberg, C.L., and Kitchener, H.C.
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- 2017
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5. Practical guidance for mismatch repair-deficiency testing in endometrial cancer
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Stelloo, E., Jansen, A.M.L., Osse, E.M., Nout, R.A., Creutzberg, C.L., Ruano, D., Church, D.N., Morreau, H., Smit, V.T.H.B.M., van Wezel, T., and Bosse, T.
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- 2017
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6. PATIENT-DERIVED OVARIAN CANCER ORGANOIDS RESEMBLE CLINICAL RESPONSE TO CHEMOTHERAPEUTICS AND PROVIDE INSIGHTS INTO RESPONSE MECHANISMS: EP1118
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de Witte, C J, Stelloo, E, Hami, N, Valle-Inclan, Espejo J, Lõhmussaar, K, Kopper, O, Vreuls, C, Jonges, T, van Diest, P J, Clevers, H, Snippert, H JG, Kloosterman, W P, Zweemer, R P, and Witteveen, P O
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- 2019
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7. Whole genome sequencing of ovarian granulosa cell tumours show heterogeneity, genomic instability and tumour evolution
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Roze, J F, Monroe, G M, Groeneweg, J W, Stelloo, E, Paijens, S T, Nijman, H W, van Meurs, H S, van Lonkhuijzen, L RCW, Piek, J MJ, Lok, C AR, Jonges, G N, and Zweemer, R P
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- 2019
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8. The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis
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AbuAli, G, Chaisaklert, W, Stelloo, E, Pazarentzos, E, Hwang, M-S, Qize, D, Harding, S V, Al-Rubaish, A, Alzahrani, A J, Al-Ali, A, Sanders, T A B, Aboagye, E O, and Grimm, S
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- 2015
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9. 28 Prevalence and prognosis of lynch syndrome and sporadic mismatch repair deficiency in the combined PORTEC-1,-2 and -3 endometrial cancer trials
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Post, C, primary, Stelloo, E, additional, Smit, V, additional, Ruano, D, additional, Tops, CM, additional, Vermij, L, additional, Rutten, TA, additional, Jürgenliemk-Schulz, IM, additional, Lutgens, LC, additional, Jobsen, JJ, additional, Nout, RA, additional, Crosbie, EJ, additional, Powell, ME, additional, Mileshkin, L, additional, Leary, A, additional, Bessette, P, additional, de Boer, SM, additional, Horeweg, N, additional, van Wezel, T, additional, Bosse, T, additional, and Creutzberg, CL, additional
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- 2020
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10. GENERATION OF ORGANOIDS FROM OVARIAN ADULT GRANULOSA CELL TUMOURS FOR INDIVIDUALIZED DRUG SCREENING
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Monroe, G., Roze, J., Stelloo, E., Stangl, C., Sereno, F., Groeneweg, J., Paijens, S., Nijman, H., van Meurs, H., van Lonkhuijzen, L., Piek, J., Lok, C., Jonges, G., Witteveen, P., Zweemer, R., Obstetrics and Gynaecology, CCA - Cancer Treatment and Quality of Life, ACS - Atherosclerosis & ischemic syndromes, ACS - Microcirculation, Cardiology, and Radiology and Nuclear Medicine
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- 2019
11. Whole genome sequencing of ovarian granulosa cell tumors reveals tumor heterogeneity and a high-grade TP53-specific subgroup
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Roze, JF, primary, Monroe, GR, additional, Kutzera, J, additional, Groeneweg, JW, additional, Stelloo, E, additional, Paijens, ST, additional, Nijman, HW, additional, van Meurs, HS, additional, van Lonkhuijzen, LRCW, additional, Piek, JMJ, additional, Lok, CAR, additional, Jonges, GN, additional, Witteveen, PO, additional, Verheijen, RHM, additional, van Haaften, G, additional, and Zweemer, RP, additional
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- 2020
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12. P174 Generation of organoids from ovarian adult granulosa cell tumours for individualized drug screening
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Monroe, G, primary, Roze, J, additional, Stelloo, E, additional, Stangl, C, additional, Sereno, F, additional, Groeneweg, J, additional, Paijens, S, additional, Nijman, H, additional, van Meurs, H, additional, van Lonkhuijzen, L, additional, Piek, J, additional, Lok, C, additional, Jonges, G, additional, Witteveen, P, additional, and Zweemer, R, additional
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- 2019
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13. EP1118 Patient-derived ovarian cancer organoids resemble clinical response to chemotherapeutics and provide insights into response mechanisms
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de Witte, CJ, primary, Stelloo, E, additional, Hami, N, additional, Espejo Valle-Inclan, J, additional, Lõhmussaar, K, additional, Kopper, O, additional, Vreuls, C, additional, Jonges, T, additional, van Diest, PJ, additional, Clevers, H, additional, Snippert, HJG, additional, Kloosterman, WP, additional, Zweemer, RP, additional, and Witteveen, PO, additional
- Published
- 2019
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14. Whole genome sequencing of ovarian granulosa cell tumours show heterogeneity, genomic instability and tumour evolution
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Roze, JF, primary, Monroe, GM, additional, Groeneweg, JW, additional, Stelloo, E, additional, Paijens, ST, additional, Nijman, HW, additional, van Meurs, HS, additional, Lonkhuijzen, LRCW van, additional, Piek, JMJ, additional, Lok, CAR, additional, Jonges, GN, additional, and Zweemer, RP, additional
- Published
- 2019
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15. Molecular alterations in endometrial cancer: implications for clinical management
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Stelloo, E., Smit, V.T.H.B.M., Creutzberg, C.L., Bosse, T., Marijnen, C.A.M., Hollema, H., Nijman, H.W., Vijver, M.J. van de, and Leiden University
- Subjects
Polymerase epsilon ,p53 ,Endometrial cancer ,Microsatellite instability ,Adjuvant therapy - Abstract
Over the last decades, advances have been made in the treatment of endometrial cancer. The clinicopathological risk stratification for postoperative therapy has considerably reduced overtreatment by refining indications and introducing treatment with fewer side effects. Despite refinement in the use of postoperative radiation therapy in EC, over- and under- treatment remain a clinical problem. This may be caused by the limited accuracy of the clinicopathological risk stratification to select patients of higher risk of recurrence. The lack of reproducibility of pathologists to diagnose tumor type and grade may also limit the accuracy of the clinicopathological risk stratification. Expert gyneco-pathology review and a two-tiered grading system will lead to more accurate and reproducible diagnoses. Nonetheless, there is pressing need to understand tumor behavior and design tailored treatments to further improve risk stratification. The identification of molecular markers predictive of recurrence risk or treatment benefit beyond current clinicopathological factors would represent a major advance. The aims of this thesis were to gain insight in the molecular alterations of endometrial cancer and to identify prognostic markers in endometrial cancer to refine clinicopathological risk assessment and direct adjuvant therapy.
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- 2017
16. Comprehensive analysis of microsatellite instability and mismatch repair protein expression in nearly 700 endometrial cancers
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Stelloo, E., Jansen, A., Osse, E., Nout, R., Ruano, D., Wezel, T., Creutzberg, C., Vincent THBM Smit, Morreau, H., and Bosse, E.
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- 2016
17. Markers of the p53 pathway further refine molecular profiling in high-risk endometrial cancer: A Trans PORTEC initiative
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Edmondson, R.J., primary, Crosbie, E.J., additional, Nickkho-Amiry, M., additional, Kaufmann, A., additional, Stelloo, E., additional, Nijman, H.W., additional, Leary, A., additional, Auguste, A., additional, Mileshkin, L., additional, Pollock, P., additional, MacKay, H.J., additional, Powell, M.E., additional, Bosse, T., additional, Creutzberg, C.L., additional, and Kitchener, H.C., additional
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- 2017
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18. Prognostic Significance of POLE Proofreading Mutations in Endometrial Cancer
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Church, D.N., Stelloo, E., Nout, R.A., Valtcheva, N., Depreeuw, J., Haar, N. ter, Noske, A., Amant, F., Tomlinson, I.P.M., Wild, P.J., Lambrechts, D., Jurgenliemk-Schulz, I.M., Jobsen, J.J., Smit, V.T.H.B.M., Creutzberg, C.L., and Bosse, T.
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- 2015
19. PROGNOSTIC SIGNIFICANCE OF POLE EXONUCLEASE DOMAIN MUTATION IN EARLY STAGE ENDOMETRIAL CANCER
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Church, D., Stelloo, E., Nout, R.A., Valtcheva, N., Depreeuw, J., Haar, N. ter, Amant, F., Tomlinson, I.P.M., Wild, P., Smit, V., Creutzberg, C.L., and Bosse, T.
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- 2014
20. MOLECULAR PROFILING OF HIGH-RISK ENDOMETRIAL CANCER; A TRANSPORTEC PILOT STUDY
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Bosse, T., Nout, R. A., Stelloo, E., Mackay, H. J., Church, D., Powell, M., Leary, A., Mileshkin, L., Kitchener, H., Vincent THBM Smit, and Creutzberg, C. L.
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- 2014
21. Quantification of LVSI Improves Its Strength as Prognostic Factor for Recurrence in Stage I Endometrial Cancer Patients Treated in the PORTEC Trials
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Nout, R.A., Peters, E.E.M., Jurgenlienik-Schulz, I.M., Jobsen, J.J., Mens, J.W.M., Stelloo, E., Smit, V.T.H., Bosse, T., and Creutzberg, C.L.
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- 2014
22. HIGH CORRELATION OF MOLECULAR TUMOR ALTERATIONS IN ENDOMETRIAL CURRETAGE AND HYSTERECTOMY-SPECIMENS IN PATIENTS WITH ENDOMETRIAL CARCINOMA
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Stelloo, E., Nout, R.A., Naves, L.C.L.M., Haar, N.T. ter, Creutzberg, C.L., Smit, T.H.B.M., and Bosse, T.
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- 2013
23. 207 POLE proofreading mutations elicit an anti-tumor immune response in endometrial cancer
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Van Gool, I., primary, Eggink, F., additional, Freeman-Mills, L., additional, Stelloo, E., additional, Marchi, E., additional, Palles, C., additional, De Bruyn, M., additional, Nout, R., additional, De Kroon, C., additional, Osse, M., additional, Klenerman, P., additional, Creutzberg, C., additional, Tomlinson, I., additional, Smit, V., additional, Nijman, H., additional, Bosse, T., additional, and Church, D., additional
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- 2015
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24. L1 cell adhesion molecule is a strong predictor for distant recurrence and overall survival in early stage endometrial cancer: Pooled PORTEC trial results
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Bosse, T., primary, Nout, R.A., additional, Stelloo, E., additional, Dreef, E., additional, Nijman, H.W., additional, Jürgenliemk-Schulz, I.M., additional, Jobsen, J.J., additional, Creutzberg, C.L., additional, and Smit, V.T.H.B.M., additional
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- 2014
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25. Quantification of LVSI Improves Its Strength as Prognostic Factor for Recurrence in Stage I Endometrial Cancer Patients Treated in the PORTEC Trials
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Nout, R.A., primary, Peters, E.E.M., additional, Jürgenliemk-Schulz, Ì.M., additional, Jobsen, J.J., additional, Mens, J.W.M., additional, Stelloo, E., additional, Smit, V.T.H., additional, Bosse, T., additional, and Creutzberg, C.L., additional
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- 2014
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26. The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis
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AbuAli, G, primary, Chaisaklert, W, additional, Stelloo, E, additional, Pazarentzos, E, additional, Hwang, M-S, additional, Qize, D, additional, Harding, S V, additional, Al-Rubaish, A, additional, Alzahrani, A J, additional, Al-Ali, A, additional, Sanders, T A B, additional, Aboagye, E O, additional, and Grimm, S, additional
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- 2014
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27. Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases.
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Bootsma S, Dings MPG, Kesselaar J, Helderman RFCPA, van Megesen K, Constantinides A, Moreno LF, Stelloo E, Scutigliani EM, Bokan B, Torang A, van Hooff SR, Zwijnenburg DA, Wouters VM, van de Vlasakker VCJ, Galanos LJK, Nijman LE, Logiantara A, Veenstra VL, Schlingemann S, van Piggelen S, van der Wel N, Krawczyk PM, Platteeuw JJ, Tuynman JB, de Hingh IH, Klomp JPG, Oubrie A, Snaebjornsson P, Medema JP, Oei AL, Kranenburg O, Elbers CC, Lenos KJ, Vermeulen L, and Bijlsma MF
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- Animals, Humans, Mice, Cell Line, Tumor, Rats, Female, Hyperthermic Intraperitoneal Chemotherapy methods, Colorectal Neoplasms pathology, Colorectal Neoplasms drug therapy, Peritoneal Neoplasms secondary, Peritoneal Neoplasms drug therapy, Peritoneal Neoplasms therapy, Mitochondria metabolism, Mitochondria drug effects
- Abstract
Peritoneal metastases (PMs) from colorectal cancer (CRC) respond poorly to treatment and are associated with unfavorable prognosis. For example, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery in resectable patients shows limited benefit, and novel treatments are urgently needed. The majority of CRC-PMs represent the CMS4 molecular subtype of CRC, and here we queried the vulnerabilities of this subtype in pharmacogenomic databases to identify novel therapies. This reveals the copper ionophore elesclomol (ES) as highly effective against CRC-PMs. ES exhibits rapid cytotoxicity against CMS4 cells by targeting mitochondria. We find that a markedly reduced mitochondrial content in CMS4 cells explains their vulnerability to ES. ES demonstrates efficacy in preclinical models of PMs, including CRC-PMs and ovarian cancer organoids, mouse models, and a HIPEC rat model of PMs. The above proposes ES as a promising candidate for the local treatment of CRC-PMs, with broader implications for other PM-prone cancers., Competing Interests: Declaration of interests L.V. is an employee and shareholder of Genentech-Roche. M.F.B. has received research funding from Celgene, Frame Therapeutics, and Lead Pharma and has acted as a consultant to Servier and Olympus., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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28. Non-IG::MYC in diffuse large B-cell lymphoma confers variable genomic configurations and MYC transactivation potential.
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Zhang C, Stelloo E, Barrans S, Cucco F, Jiang D, Tzioni MM, Chen Z, Li Y, Swennenhuis JF, Makker J, Rásó-Barnett L, Liu H, El-Daly H, Soilleux E, Shah N, Nagumantry SK, Kyaw M, Prahladan MP, Tooze R, Westhead DR, Feitsma H, Davies AJ, Burton C, Johnson PWM, and Du MQ
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- Humans, Transcriptional Activation, Proto-Oncogene Proteins c-bcl-6 genetics, Translocation, Genetic, Genomics, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
MYC translocation occurs in 8-14% of diffuse large B-cell lymphoma (DLBCL), and may concur with BCL2 and/or BCL6 translocation, known as double-hit (DH) or triple-hit (TH). DLBCL-MYC/BCL2-DH/TH are largely germinal centre B-cell like subtype, but show variable clinical outcome, with IG::MYC fusion significantly associated with inferior survival. While DLBCL-MYC/BCL6-DH are variable in their cell-of-origin subtypes and clinical outcome. Intriguingly, only 40-50% of DLBCL with MYC translocation show high MYC protein expression (>70%). We studied 186 DLBCLs with MYC translocation including 32 MYC/BCL2/BCL6-TH, 75 MYC/BCL2-DH and 26 MYC/BCL6-DH. FISH revealed a MYC/BCL6 fusion in 59% of DLBCL-MYC/BCL2/BCL6-TH and 27% of DLBCL-MYC/BCL6-DH. Targeted NGS showed a similar mutation profile and LymphGen genetic subtype between DLBCL-MYC/BCL2/BCL6-TH and DLBCL-MYC/BCL2-DH, but variable LymphGen subtypes among DLBCL-MYC/BCL6-DH. MYC protein expression is uniformly high in DLBCL with IG::MYC, but variable in those with non-IG::MYC including MYC/BCL6-fusion. Translocation breakpoint analyses of 8 cases by TLC-based NGS showed no obvious genomic configuration that enables MYC transactivation in 3 of the 4 cases with non-IG::MYC, while a typical promoter substitution or IGH super enhancer juxtaposition in the remaining cases. The findings potentially explain variable MYC expression in DLBCL with MYC translocation, and also bear practical implications in its routine assessment., (© 2024. The Author(s).)
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- 2024
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29. Formalin-Fixed, Paraffin-Embedded-Targeted Locus Capture: A Next-Generation Sequencing Technology for Accurate DNA-Based Gene Fusion Detection in Bone and Soft Tissue Tumors.
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Stelloo E, Meijers RWJ, Swennenhuis JF, Allahyar A, Hajo K, Cangiano M, de Leng WWJ, van Helvert S, Van der Meulen J, Creytens D, van Kempen LC, Cleton-Jansen AM, Bovee JVMG, de Laat W, Splinter E, and Feitsma H
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- Humans, Paraffin Embedding methods, DNA genetics, Formaldehyde, Gene Fusion, Technology, Tissue Fixation, High-Throughput Nucleotide Sequencing methods, Soft Tissue Neoplasms diagnosis, Soft Tissue Neoplasms genetics
- Abstract
Chromosomal rearrangements are important drivers in cancer, and their robust detection is essential for diagnosis, prognosis, and treatment selection, particularly for bone and soft tissue tumors. Current diagnostic methods are hindered by limitations, including difficulties with multiplexing targets and poor quality of RNA. A novel targeted DNA-based next-generation sequencing method, formalin-fixed, paraffin-embedded-targeted locus capture (FFPE-TLC), has shown advantages over current diagnostic methods when applied on FFPE lymphomas, including the ability to detect novel rearrangements. We evaluated the utility of FFPE-TLC in bone and soft tissue tumor diagnostics. FFPE-TLC sequencing was successfully applied on noncalcified and decalcified FFPE samples (n = 44) and control samples (n = 19). In total, 58 rearrangements were identified in 40 FFPE tumor samples, including three previously negative samples, and none was identified in the FFPE control samples. In all five discordant cases, FFPE-TLC could identify gene fusions where other methods had failed due to either detection limits or poor sample quality. FFPE-TLC achieved a high specificity and sensitivity (no false positives and negatives). These results indicate that FFPE-TLC is applicable in cancer diagnostics to simultaneously analyze many genes for their involvement in gene fusions. Similar to the observation in lymphomas, FFPE-TLC is a good DNA-based alternative to the conventional methods for detection of rearrangements in bone and soft tissue tumors., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2023
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30. Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer.
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Horeweg N, Nout RA, Jürgenliemk-Schulz IM, Lutgens LCHW, Jobsen JJ, Haverkort MAD, Mens JWM, Slot A, Wortman BG, de Boer SM, Stelloo E, Verhoeven-Adema KW, Putter H, Smit VTHBM, Bosse T, and Creutzberg CL
- Subjects
- Female, Humans, Combined Modality Therapy, Radiation Oncology, Endometrial Neoplasms genetics, Endometrial Neoplasms radiotherapy, Brachytherapy
- Abstract
Purpose: The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC)., Methods: Data of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier's methodology and log-rank tests., Results: A total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε ( POLE mut EC). In mismatch repair-deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; P = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; P < .0001)., Conclusion: The molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in POLE mut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control.
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- 2023
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31. Comparison of NTRK fusion detection methods in microsatellite-instability-high metastatic colorectal cancer.
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Schraa SJ, Stelloo E, Laclé MM, Swennenhuis JF, Brosens LAA, Fijneman RJA, Feitsma H, Koopman M, de Leng WW, Vink GR, and Bol GM
- Subjects
- Humans, Receptor, trkA genetics, In Situ Hybridization, Fluorescence, Microsatellite Repeats, Oncogene Proteins, Fusion genetics, Gene Fusion, Neoplasms genetics, Colonic Neoplasms genetics
- Abstract
Tropomyosin receptor kinase (TRK) inhibitors have been approved for metastatic solid tumors harboring NTRK fusions, but the detection of NTRK fusions is challenging. International guidelines recommend pan-TRK immunohistochemistry (IHC) screening followed by next generation sequencing (NGS) in tumor types with low prevalence of NTRK fusions, including metastatic colorectal cancer (mCRC). RNA-based NGS is preferred, but is expensive, time-consuming, and extracting good-quality RNA from FFPE tissue is challenging. Alternatives in daily clinical practice are warranted. We assessed the diagnostic performance of RNA-NGS, FFPE-targeted locus capture (FFPE-TLC), fluorescence in situ hybridization (FISH), and the 5'/3' imbalance quantitative RT-PCR (qRT-PCR) after IHC screening in 268 patients with microsatellite-instability-high mCRC, the subgroup in which NTRK fusions are most prevalent (1-5%). A consensus result was determined after review of all assay results. In 16 IHC positive tumors, 10 NTRK fusions were detected. In 33 IHC negative samples, no additional transcribed NTRK fusions were found, underscoring the high sensitivity of IHC. Sensitivity of RNA-NGS, FFPE-TLC, FISH, and qRT-PCR was 90%, 90%, 78%, and 100%, respectively. Specificity was 100% for all assays. Robustness, defined as the percentage of samples that provided an interpretable result in the first run, was 100% for FFPE-TLC, yet more limited for RNA-NGS (85%), FISH (70%), and qRT-PCR (70%). Overall, we do not recommend FISH for the detection of NTRK fusions in mCRC due to its low sensitivity and limited robustness. We conclude that RNA-NGS, FFPE-TLC, and qRT-PCR are appropriate assays for NTRK fusion detection, after enrichment with pan-TRK IHC, in routine clinical practice., (© 2023. The Author(s).)
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- 2023
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32. Targeted locus amplification to develop robust patient-specific assays for liquid biopsies in pediatric solid tumors.
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van Zogchel LMJ, Lak NSM, Gelineau NU, Sergeeva I, Stelloo E, Swennenhuis J, Feitsma H, van Min M, Splinter E, Bleijs M, Groot Koerkamp M, Breunis W, Meister MT, Kholossy WH, Holstege FCP, Molenaar JJ, de Leng WWJ, Stutterheim J, van der Schoot CE, and Tytgat GAM
- Abstract
Background: Liquid biopsies combine minimally invasive sample collection with sensitive detection of residual disease. Pediatric malignancies harbor tumor-driving copy number alterations or fusion genes, rather than recurrent point mutations. These regions contain tumor-specific DNA breakpoint sequences. We investigated the feasibility to use these breakpoints to design patient-specific markers to detect tumor-derived cell-free DNA (cfDNA) in plasma from patients with pediatric solid tumors., Materials and Methods: Regions of interest (ROI) were identified through standard clinical diagnostic pipelines, using SNP array for CNAs, and FISH or RT-qPCR for fusion genes. Using targeted locus amplification (TLA) on tumor organoids grown from tumor material or targeted locus capture (TLC) on FFPE material, ROI-specific primers and probes were designed, which were used to design droplet digital PCR (ddPCR) assays. cfDNA from patient plasma at diagnosis and during therapy was analyzed., Results: TLA was performed on material from 2 rhabdomyosarcoma, 1 Ewing sarcoma and 3 neuroblastoma. FFPE-TLC was performed on 8 neuroblastoma tumors. For all patients, at least one patient-specific ddPCR was successfully designed and in all diagnostic plasma samples the patient-specific markers were detected. In the rhabdomyosarcoma and Ewing sarcoma patients, all samples after start of therapy were negative. In neuroblastoma patients, presence of patient-specific markers in cfDNA tracked tumor burden, decreasing during induction therapy, disappearing at complete remission and re-appearing at relapse., Conclusion: We demonstrate the feasibility to determine tumor-specific breakpoints using TLA/TLC in different pediatric solid tumors and use these for analysis of cfDNA from plasma. Considering the high prevalence of CNAs and fusion genes in pediatric solid tumors, this approach holds great promise and deserves further study in a larger cohort with standardized plasma sampling protocols., Competing Interests: IS, ESt, JSw, HF, MM, ESp are employees of Cergentis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 van Zogchel, Lak, Gelineau, Sergeeva, Stelloo, Swennenhuis, Feitsma, van Min, Splinter, Bleijs, Groot Koerkamp, Breunis, Meister, Kholossy, Holstege, Molenaar, de Leng, Stutterheim, van der Schoot and Tytgat.)
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- 2023
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33. Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study.
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Kemps PG, Zondag TCE, Arnardóttir HB, Solleveld-Westerink N, Borst J, Steenwijk EC, van Egmond D, Swennenhuis JF, Stelloo E, Trambusti I, Verdijk RM, van Noesel CJM, Cleven AHG, Scheijde-Vermeulen MA, Koudijs MJ, Krsková L, Hawkins C, Egeler RM, Brok J, von Bahr Greenwood T, Svojgr K, Beishuizen A, van Laar JAM, Pötschger U, Hutter C, Sieni E, Minkov M, Abla O, van Wezel T, van den Bos C, and van Halteren AGS
- Subjects
- Humans, Cohort Studies, Proto-Oncogene Proteins B-raf genetics, Mutation, Histiocytosis, Langerhans-Cell genetics, Neoplasms
- Abstract
Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for ∼80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)-risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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34. Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer.
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Post CCB, Stelloo E, Smit VTHBM, Ruano D, Tops CM, Vermij L, Rutten TA, Jürgenliemk-Schulz IM, Lutgens LCHW, Jobsen JJ, Nout RA, Crosbie EJ, Powell ME, Mileshkin L, Leary A, Bessette P, Putter H, de Boer SM, Horeweg N, Nielsen M, Wezel TV, Bosse T, and Creutzberg CL
- Subjects
- Brain Neoplasms, Colorectal Neoplasms, DNA Methylation, DNA Mismatch Repair genetics, Female, Humans, MutL Protein Homolog 1 genetics, Neoplastic Syndromes, Hereditary, Prevalence, Prognosis, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Endometrial Neoplasms epidemiology, Endometrial Neoplasms genetics
- Abstract
Background: Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction; however, the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis, and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined Post Operative Radiation Therapy in Endometrial Carcinoma-1, -2, and -3 trial cohort., Methods: After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into 3 groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test, and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were 2-sided., Results: Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged: 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to 60 years or younger or to 70 years or younger would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses, respectively. Five-year recurrence-free survival was 91.7% (95% confidence interval [CI] = 83.1% to 100%; hazard ratio = 0.45, 95% CI = 0.16 to 1.24, P = .12) for LS, 95.5% (95% CI = 90.7% to 100%; hazard ratio = 0.17, 95% CI = 0.05 to 0.55, P = .003) for "other" vs 78.6% (95% CI = 73.8% to 83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95% CI = 0.0% to 24.7%), 1.5% (95% CI = 0.0% to 4.3%), and 7.0% (95% CI = 3.0% to 10.9%) within the LS, "other," and MLH1-hypermethylated MMRd-EC groups, respectively., Conclusions: The LS prevalence in the Post Operative Radiation Therapy in Endometrial Carcinoma trial population was 2.8% and among MMRd-ECs was 9.5%. Patients with LS-associated ECs showed a trend towards better recurrence-free survival and higher risk for second cancers compared with patients with MLH1-hypermethylated MMRd-EC., (© The Author(s) 2021. Published by Oxford University Press.)
- Published
- 2021
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35. Reconstructing single-cell karyotype alterations in colorectal cancer identifies punctuated and gradual diversification patterns.
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Bollen Y, Stelloo E, van Leenen P, van den Bos M, Ponsioen B, Lu B, van Roosmalen MJ, Bolhaqueiro ACF, Kimberley C, Mossner M, Cross WCH, Besselink NJM, van der Roest B, Boymans S, Oost KC, de Vries SG, Rehmann H, Cuppen E, Lens SMA, Kops GJPL, Kloosterman WP, Terstappen LWMM, Barnes CP, Sottoriva A, Graham TA, and Snippert HJG
- Subjects
- Cell Proliferation genetics, Chromatin genetics, Chromosomes, Human, Gene Dosage, Humans, Karyotype, Karyotyping, Microscopy, Confocal, Mitosis, Organoids growth & development, Organoids pathology, Spindle Apparatus genetics, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Single-Cell Analysis methods
- Abstract
Central to tumor evolution is the generation of genetic diversity. However, the extent and patterns by which de novo karyotype alterations emerge and propagate within human tumors are not well understood, especially at single-cell resolution. Here, we present 3D Live-Seq-a protocol that integrates live-cell imaging of tumor organoid outgrowth and whole-genome sequencing of each imaged cell to reconstruct evolving tumor cell karyotypes across consecutive cell generations. Using patient-derived colorectal cancer organoids and fresh tumor biopsies, we demonstrate that karyotype alterations of varying complexity are prevalent and can arise within a few cell generations. Sub-chromosomal acentric fragments were prone to replication and collective missegregation across consecutive cell divisions. In contrast, gross genome-wide karyotype alterations were generated in a single erroneous cell division, providing support that aneuploid tumor genomes can evolve via punctuated evolution. Mapping the temporal dynamics and patterns of karyotype diversification in cancer enables reconstructions of evolutionary paths to malignant fitness., (© 2021. The Author(s).)
- Published
- 2021
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36. In Vitro Systematic Drug Testing Reveals Carboplatin, Paclitaxel, and Alpelisib as a Potential Novel Combination Treatment for Adult Granulosa Cell Tumors.
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Roze J, Sendino Garví E, Stelloo E, Stangl C, Sereno F, Duran K, Groeneweg J, Paijens S, Nijman H, van Meurs H, van Lonkhuijzen L, Piek J, Lok C, Jonges G, Witteveen P, Verheijen R, van Haaften G, Zweemer R, and Monroe G
- Abstract
Adult granulosa cell tumors (AGCTs) arise from the estrogen-producing granulosa cells. Treatment of recurrence remains a clinical challenge, as systemic anti-hormonal treatment or chemotherapy is only effective in selected patients. We established a method to rapidly screen for drug responses in vitro using direct patient-derived cell lines in order to optimize treatment selection. The response to 11 monotherapies and 12 combination therapies, including chemotherapeutic, anti-hormonal, and targeted agents, were tested in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN). Drug screens were performed within 3 weeks after tissue collection by measurement of cell viability 72 h after drug application. The potential synergy of drug combinations was assessed. The human maximum drug plasma concentration (Cmax) and steady state (Css) thresholds obtained from available phase I/II clinical trials were used to predict potential toxicity in patients. Patient-derived AGCT cell lines demonstrated resistance to all monotherapies. All cell lines showed synergistic growth inhibition by combination treatment with carboplatin, paclitaxel, and alpelisib at a concentration needed to obtain 50% cell death (IC50) that are below the maximum achievable concentration in patients (IC50 < Cmax). We show that AGCT cell lines can be rapidly established and used for patient-specific in vitro drug testing, which may guide treatment decisions. Combination treatment with carboplatin, paclitaxel, and alpelisib was consistently effective in AGCT cell lines and should be further studied as a potential effective combination for AGCT treatment in patients.
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- 2021
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37. Prognostic Integrated Image-Based Immune and Molecular Profiling in Early-Stage Endometrial Cancer.
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Horeweg N, de Bruyn M, Nout RA, Stelloo E, Kedziersza K, León-Castillo A, Plat A, Mertz KD, Osse M, Jürgenliemk-Schulz IM, Lutgens LCHW, Jobsen JJ, van der Steen-Banasik EM, Smit VT, Creutzberg CL, Bosse T, Nijman HW, Koelzer VH, and Church DN
- Subjects
- Aged, Aged, 80 and over, DNA Mismatch Repair, Female, Humans, Linear Models, Middle Aged, Multivariate Analysis, Mutation, Neoplasm Staging, Prognosis, Tumor Suppressor Protein p53 genetics, Antigens, CD immunology, Biomarkers, Tumor, CD8-Positive T-Lymphocytes immunology, Endometrial Neoplasms genetics, Endometrial Neoplasms immunology, Integrin alpha Chains immunology
- Abstract
Optimum risk stratification in early-stage endometrial cancer combines clinicopathologic factors and the molecular endometrial cancer classification defined by The Cancer Genome Atlas (TCGA). It is unclear whether analysis of intratumoral immune infiltrate improves this. We developed a machine-learning, image-based algorithm to quantify density of CD8
+ and CD103+ immune cells in tumor epithelium and stroma in 695 stage I endometrioid endometrial cancers from the PORTEC-1 and -2 trials. The relationship between immune cell density and clinicopathologic/molecular factors was analyzed by hierarchical clustering and multiple regression. The prognostic value of immune infiltrate by cell type and location was analyzed by univariable and multivariable Cox regression, incorporating the molecular endometrial cancer classification. Tumor-infiltrating immune cell density varied substantially between cases, and more modestly by immune cell type and location. Clustering revealed three groups with high, intermediate, and low densities, with highly significant variation in the proportion of molecular endometrial cancer subgroups between them. Univariable analysis revealed intraepithelial CD8+ cell density as the strongest predictor of endometrial cancer recurrence; multivariable analysis confirmed this was independent of pathologic factors and molecular subgroup. Exploratory analysis suggested this association was not uniform across molecular subgroups, but greatest in tumors with mutant p53 and absent in DNA mismatch repair-deficient cancers. Thus, this work identified that quantification of intraepithelial CD8+ cells improved upon the prognostic utility of the molecular endometrial cancer classification in early-stage endometrial cancer., (©2020 American Association for Cancer Research.)- Published
- 2020
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38. Patient-Derived Ovarian Cancer Organoids Mimic Clinical Response and Exhibit Heterogeneous Inter- and Intrapatient Drug Responses.
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de Witte CJ, Espejo Valle-Inclan J, Hami N, Lõhmussaar K, Kopper O, Vreuls CPH, Jonges GN, van Diest P, Nguyen L, Clevers H, Kloosterman WP, Cuppen E, Snippert HJG, Zweemer RP, Witteveen PO, and Stelloo E
- Subjects
- Carcinoma, Ovarian Epithelial pathology, Drug Screening Assays, Antitumor methods, Female, Humans, Paclitaxel pharmacology, Pharmaceutical Preparations metabolism, Precision Medicine, Antineoplastic Agents pharmacology, Carcinoma, Ovarian Epithelial drug therapy, Drug Resistance, Neoplasm drug effects, Organoids pathology, Ovarian Neoplasms pathology
- Abstract
There remains an unmet need for preclinical models to enable personalized therapy for ovarian cancer (OC) patients. Here we evaluate the capacity of patient-derived organoids (PDOs) to predict clinical drug response and functional consequences of tumor heterogeneity. We included 36 whole-genome-characterized PDOs from 23 OC patients with known clinical histories. OC PDOs maintain the genomic features of the original tumor lesion and recapitulate patient response to neoadjuvant carboplatin/paclitaxel combination treatment. PDOs display inter- and intrapatient drug response heterogeneity to chemotherapy and targeted drugs, which can be partially explained by genetic aberrations. PDO drug screening identifies high responsiveness to at least one drug for 88% of patients. PDOs are valuable preclinical models that can provide insights into drug response for individual patients with OC, complementary to genetic testing. Generating PDOs of multiple tumor locations can improve clinical decision making and increase our knowledge of genetic and drug response heterogeneity., Competing Interests: Declaration of Interests H.C. is an inventor listed on several patents related to organoid technology. H.C. is the founder of OrganoidZ, which employs organoids for drug development. H.C. is the (unpaid) Chief Scientific Officer of Hubrecht Organoid Technology (HUB), a cofounder of Surrozen, and a scientific advisory board member for Kallyope, Merus, and Decibel. H.C. is a nonexecutive board member of Roche and Genentech and a scientific advisor for Life Sciences Partners. His full disclosure is given at https://www.uu.nl/staff/JCClevers/., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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39. Whole Genome Analysis of Ovarian Granulosa Cell Tumors Reveals Tumor Heterogeneity and a High-Grade TP53-Specific Subgroup.
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Roze J, Monroe G, Kutzera J, Groeneweg J, Stelloo E, Paijens S, Nijman H, Meurs HV, Lonkhuijzen LV, Piek J, Lok C, Jonges G, Witteveen P, Verheijen R, Haaften GV, and Zweemer R
- Abstract
Adult granulosa cell tumors (AGCTs) harbor a somatic FOXL2 c.402C>G mutation in ~95% of cases and are mainly surgically removed due to limited systemic treatment effect. In this study, potentially targetable genomic alterations in AGCTs were investigated by whole genome sequencing on 46 tumor samples and matched normal DNA. Copy number variant (CNV) analysis confirmed gain of chromosome 12 and 14, and loss of 22. Pathogenic TP53 mutations were identified in three patients with highest tumor mutational burden and mitotic activity, defining a high-grade AGCT subgroup. Within-patient tumor comparisons showed 29-80% unique somatic mutations per sample, suggesting tumor heterogeneity. A higher mutational burden was found in recurrent tumors, as compared to primary AGCTs. FOXL2 -wildtype AGCTs harbored DICER1 , TERT (C228T) and TP53 mutations and similar CNV profiles as FOXL2 -mutant tumors. Our study confirms that absence of the FOXL2 c.402C>G mutation does not exclude AGCT diagnosis. The lack of overlapping variants in targetable cancer genes indicates the need for personalized treatment for AGCT patients.
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- 2020
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40. Blinded histopathological characterisation of POLE exonuclease domain-mutant endometrial cancers: sheep in wolf's clothing.
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Van Gool IC, Ubachs JEH, Stelloo E, de Kroon CD, Goeman JJ, Smit VTHBM, Creutzberg CL, and Bosse T
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- Adult, Aged, Aged, 80 and over, Female, Humans, Immunohistochemistry, Middle Aged, Mutation, Biomarkers, Tumor genetics, Carcinoma, Endometrioid genetics, Carcinoma, Endometrioid pathology, DNA Polymerase II genetics, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Poly-ADP-Ribose Binding Proteins genetics
- Abstract
Aims: POLE exonuclease domain mutations identify a subset of endometrial cancer (EC) patients with an excellent prognosis. The use of this biomarker has been suggested to refine adjuvant treatment decisions, but the necessary sequencing is not widely performed and is relatively expensive. Therefore, we aimed to identify histopathological and immunohistochemical characteristics to aid in the detection of POLE-mutant ECs., Methods and Results: Fifty-one POLE-mutant endometrioid, 67 POLE-wild-type endometrioid and 15 POLE-wild-type serous ECs were included (total N = 133). An expert gynaecopathologist, blinded to molecular features, evaluated each case (two or more slides) for 16 morphological characteristics. Immunohistochemistry was performed for p53, p16, MLH1, MSH2, MSH6, and PMS2. POLE-mutant ECs were characterised by a prominent immune infiltrate: 80% showed peritumoral lymphocytes and 59% showed tumour-infiltrating lymphocytes, as compared with 43% and 28% of POLE-wild-type endometrioid ECs, and 27% and 13% of their serous counterparts (P < 0.01, all comparisons). Of POLE-mutant ECs, 33% contained tumour giant cells; this proportion was significantly higher than that in POLE-wild-type endometrioid ECs (10%; P = 0.003), but not significantly different from that in serous ECs (53%). Serous-like features were as often (focally) present in POLE-mutant as in POLE-wild-type endometrioid ECs (6-24%, depending on the feature). The majority of POLE-mutant ECs showed wild-type p53 (86%), negative/focal p16 (82%) and normal mismatch repair protein expression (90%)., Conclusions: A simple combination of morphological and immunohistochemical characteristics (tumour type, grade, peritumoral lymphocytes, MLH1, and p53 expression) can assist in prescreening for POLE exonuclease domain mutations in EC, increasing the probability of a mutation being detected from 7% to 33%. This facilitates the use of this important prognostic biomarker in routine pathology., (© 2017 John Wiley & Sons Ltd.)
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- 2018
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41. Folate receptor-α targeted near-infrared fluorescence imaging in high-risk endometrial cancer patients: a tissue microarray and clinical feasibility study.
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Boogerd LSF, Hoogstins CES, Gaarenstroom KN, de Kroon CD, Beltman JJ, Bosse T, Stelloo E, Vuyk J, Low PS, Burggraaf J, and Vahrmeijer AL
- Abstract
Objective: Detection and resection of all malignant lesions is pivotal in staging and cytoreductive surgery (CRS) of endometrial cancer (EC). Intraoperative EC detection could be enhanced using OTL-38, a fluorescent-labelled folate receptor-α (FRα) targeted imaging agent. The objectives of this study were to investigate which subgroups of high-risk EC patients express FRα and assess feasibility of intraoperative EC detection using OTL-38., Results: FRα expression on TMA was significantly correlated with tumor type ( p < 0.01). Eighty-two percent of serous and clear cell carcinomas showed FRα expression. Four patients were enrolled in the clinical study. Using fluorescence imaging all omental ( n = 3) and lymph node (LN) metastases ( n = 16) could be clearly identified, including one otherwise undetected omental metastasis. However, false-positive fluorescence was identified in 17/50 non-metastatic LNs, caused by OTL-38 targeting of FRβ, expressed by tumor-associated activated macrophages., Conclusions: This study describes high FRα expression in serous and clear cell EC and demonstrates the first experience of intraoperative FRα-targeted tumor detection in patients with these subtypes of EC. Although all metastases could be clearly identified using OTL-38, the role of tumor-associated macrophages should be further evaluated., Methods: Immunohistochemical (IHC) staining of FRα expression was performed on tissue micro arrays (TMA) of 116 patients with high-risk EC features. Patients with either serous or clear cell EC, planned for staging or CRS, were eligible for inclusion in the clinical study and received an intravenous dose of 0.0125 mg/kg OTL-38, 2-3 hours prior to surgery. Resected lesions, identified by standard-of-care and/or fluorescence imaging, were histopathologically assessed for FRα and tumor status., Competing Interests: CONFLICTS OF INTEREST The Centre for Human Drug Research (a not-for-profit foundation) and the Leiden University Medical Center received financial compensation, study drug and equipment for the execution of this study from On Target Laboratories LLC.
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- 2017
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42. Amplification of 1q32.1 Refines the Molecular Classification of Endometrial Carcinoma.
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Depreeuw J, Stelloo E, Osse EM, Creutzberg CL, Nout RA, Moisse M, Garcia-Dios DA, Dewaele M, Willekens K, Marine JC, Matias-Guiu X, Amant F, Lambrechts D, and Bosse T
- Subjects
- Aged, Cell Line, Tumor, Cluster Analysis, Disease-Free Survival, Endometrial Neoplasms pathology, Endometrial Neoplasms therapy, Female, Gene Expression Profiling methods, Humans, Middle Aged, Neoplasm Recurrence, Local, Outcome Assessment, Health Care methods, Outcome Assessment, Health Care statistics & numerical data, Prognosis, Proportional Hazards Models, Chromosomes, Human, Pair 1 genetics, DNA Copy Number Variations genetics, Endometrial Neoplasms genetics, Gene Amplification
- Abstract
Purpose: Molecular classification of endometrial cancer identified distinct molecular subgroups. However, the largest subset of endometrial cancers remains poorly characterized and is referred to as the "nonspecific molecular profile" (NSMP) subgroup. Here, we aimed at refining the classification of this subgroup by profiling somatic copy-number aberrations (SCNAs). Experimental Design: SCNAs were analyzed in 141 endometrial cancers using whole-genome SNP arrays and pooled with 361 endometrial cancers from The Cancer Genome Atlas. Genomic Identification of Significant Targets in Cancer (GISTIC) identified statistically enriched SCNAs and penalized Cox regression assessed survival effects. The prognostic significance of relevant SCNAs was validated using multiplex ligation-dependent probe amplification in 840 endometrial cancers from the PORTEC-1/2 trials. Copy-number status of genes was correlated with gene expression to identify potential cancer drivers. One plausible oncogene was validated in vitro using antisense oligonucleotide-based strategy. Results: SCNAs affecting chromosome 1q32.1 significantly correlated with worse relapse-free survival (RFS) in the NSMP subgroup (HR, 2.12; 95% CI, 1.26-3.59; P = 0.005). This effect was replicated in NSMP endometrial cancers from PORTEC-1/2 (HR, 2.34; 95% CI, 1.17-4.70; P = 0.017). A new molecular classification including the 1q32.1 amplification improved risk prediction of recurrence. MDM4 gene expression strongly correlated with 1q32.1 amplification. Silencing MDM4 inhibited cell growth in cell lines carrying 1q32.1 amplification, but not in those without MDM4 amplification. Vice versa , increasing MDM4 expression in nonamplified cell lines stimulated cell proliferation. Conclusions: 1q32.1 amplification was identified as a prognostic marker for poorly characterized NSMP endometrial cancers, refining the molecular classification of this subgroup. We functionally validated MDM4 as a potential oncogenic driver in the 1q32.1 region. Clin Cancer Res; 23(23); 7232-41. ©2017 AACR ., (©2017 American Association for Cancer Research.)
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- 2017
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43. Limited impact of intratumour heterogeneity on molecular risk assignment in endometrial cancer.
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van Esterik M, Van Gool IC, de Kroon CD, Nout RA, Creutzberg CL, Smit VTHBM, Bosse T, and Stelloo E
- Subjects
- Aged, Endometrial Neoplasms metabolism, Exons, Female, Gene Expression, Humans, Middle Aged, MutL Protein Homolog 1 genetics, MutL Protein Homolog 1 metabolism, Mutation, Neoplasm Grading, Neoplasm Staging, Neural Cell Adhesion Molecule L1 genetics, Neural Cell Adhesion Molecule L1 metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, beta Catenin genetics, Biomarkers, Tumor, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Genetic Variation
- Abstract
Introduction: Individual prediction of tumour behaviour based on molecular markers may refine adjuvant treatment strategies in endometrial cancer (EC). As these molecular alterations are determined in a small tumour fraction, high intratumour heterogeneity may interfere with correct risk prediction. This study aimed to investigate to which extent intratumour heterogeneity exists for molecular markers and whether it affects the molecular risk assignment in EC., Methods: Forty-nine ECs (three tumour blocks/case) were selected with alterations in POLE (n=10), CTNNB1 (n=8), p53 (n=10), mismatch repair (n=11), L1CAM (n=10), and ECs without any of these markers (n=9). Nine ECs carried more than one molecular marker. All 147 blocks were analysed for POLE exonuclease domain and CTNNB1 exon 3 mutations, and for p53, mismatch repair and L1CAM protein expression. All blocks were assigned to a favourable, intermediate or unfavourable risk group, based on a molecular risk assignment., Results: Concordance between the three tumour blocks for POLE and CTNNB1 mutational status, and p53, mismatch repair and L1CAM protein expression was found in 100% (48/48), 95.9% (47/49), 93.9% (46/49), 98.0% (48/49), and 91.8% (45/49) of tumours, respectively. These discordances were found in a total of nine cases (18.4%). The intratumour heterogeneity impacted the risk assignment in five cases (10.2%)., Conclusion: Intratumour heterogeneity of prognostic molecular markers in EC without morphologic heterogeneity is uncommon among three tumour fractions, affecting the molecular risk allocation in a limited number of cases. This low intratumour heterogeneity facilitates the implementation of the molecular risk assignment, advocating its use in clinical decision making.
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- 2017
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44. Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer-Combined Analysis of the PORTEC Cohorts.
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Stelloo E, Nout RA, Osse EM, Jürgenliemk-Schulz IJ, Jobsen JJ, Lutgens LC, van der Steen-Banasik EM, Nijman HW, Putter H, Bosse T, Creutzberg CL, and Smit VT
- Subjects
- Adult, Aged, Aged, 80 and over, Area Under Curve, DNA Polymerase II genetics, Endometrial Neoplasms mortality, Endometrial Neoplasms therapy, Female, Genes, p53, Humans, Middle Aged, Mutation, Neoplasm Grading, Neoplasm Staging, Poly-ADP-Ribose Binding Proteins genetics, Prognosis, Randomized Controlled Trials as Topic, Recurrence, Risk Assessment, Survival Analysis, Biomarkers, Tumor, Endometrial Neoplasms diagnosis, Endometrial Neoplasms genetics
- Abstract
Purpose: Recommendations for adjuvant treatment for women with early-stage endometrial carcinoma are based on clinicopathologic features. Comprehensive genomic characterization defined four subgroups: p53-mutant, microsatellite instability (MSI), POLE-mutant, and no specific molecular profile (NSMP). We aimed to confirm the prognostic capacity of these subgroups in large randomized trial populations, investigate potential other prognostic classifiers, and integrate these into an integrated molecular risk assessment guiding adjuvant therapy., Experimental Design: Analysis of MSI, hotspot mutations in 14 genes including POLE, protein expression of p53, ARID1a, β-catenin, L1CAM, PTEN, ER, and PR was undertaken on 947 available early-stage endometrioid endometrial carcinomas from the PORTEC-1 and -2 trials, mostly high-intermediate risk (n = 614). Prognostic value was determined using univariable and multivariable Cox proportional hazard models. AUCs of different risk stratification models were compared., Results: Molecular analyses were feasible in >96% of the patients and confirmed the four molecular subgroups: p53-mutant (9%), MSI (26%), POLE-mutant (6%), and NSMP (59%). Integration of prognostic molecular alterations with established clinicopathologic factors resulted in a stronger model with improved risk prognostication. Approximately 15% of high-intermediate risk patients had unfavorable features (substantial lymphovascular space invasion, p53-mutant, and/or >10% L1CAM), 50% favorable features (POLE-mutant, NSMP being microsatellite stable, and CTNNB1 wild-type), and 35% intermediate features (MSI or CTNNB1-mutant)., Conclusions: Integrating clinicopathologic and molecular factors improves the risk assessment of patients with early-stage endometrial carcinoma. Assessment of this integrated risk profile is feasible in daily practice, and holds promise to reduce both overtreatment and undertreatment. Clin Cancer Res; 22(16); 4215-24. ©2016 AACR., (©2016 American Association for Cancer Research.)
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- 2016
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45. Microsatellite instability derived JAK1 frameshift mutations are associated with tumor immune evasion in endometrioid endometrial cancer.
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Stelloo E, Versluis MA, Nijman HW, de Bruyn M, Plat A, Osse EM, van Dijk RH, Nout RA, Creutzberg CL, de Bock GH, Smit VT, Bosse T, and Hollema H
- Subjects
- Aged, Antigen Presentation, Cohort Studies, DNA Methylation, DNA Mutational Analysis, DNA, Neoplasm, Endometrial Neoplasms metabolism, Female, Histocompatibility Antigens Class I metabolism, Humans, Microsatellite Repeats, Middle Aged, Neoplasm Recurrence, Local genetics, Prognosis, Proteasome Endopeptidase Complex metabolism, Sequence Analysis, RNA, Endometrial Neoplasms genetics, Frameshift Mutation, Janus Kinase 1 genetics, Microsatellite Instability
- Abstract
JAK1 frameshift mutations may promote cancer cell immune evasion by impeding upregulation of the antigen presentation pathway in microsatellite unstable endometrial cancers (ECs). This study investigated the JAK1 mutation frequency, its functional implication in immune evasion and its prognostic significance in microsatellite unstable EC. Microsatellite instability and three microsatellite repeats within JAK1 were analyzed in 181 ECs. Sixty-two (34%) ECs showed microsatellite instability, of which 22 (35%) had a JAK1 mutation. LMP7, TAP1 and HLA class I protein expression and the presence of CD8-positive T-cells were analyzed in the microsatellite unstable ECs. JAK1 mutant microsatellite unstable ECs showed impaired upregulation of LMP7 (P=0.074) and HLA class I (P<0.001), validated using RNAseq data of the TCGA. TAP1 expression and presence of CD8-positive T-cells were not related to JAK1 mutations. In 198 additional microsatellite unstable ECs, the JAK1 mutation frequency was confirmed but no prognostic significance was found. For, JAK1 wildtype (n=135, 72%) and mutant (n=52, 28%) ECs, 10-year recurrence free rates were 84% and 77% (P=0.301). These observations show that JAK1 mutations are highly frequent in microsatellite unstable EC, not associated with survival, but are associated with impaired upregulation of LMP7 and HLA class I and may therefore facilitate immune escape., Competing Interests: The authors declare no conflict of interest.
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- 2016
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46. Prognostic significance of L1CAM expression and its association with mutant p53 expression in high-risk endometrial cancer.
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Van Gool IC, Stelloo E, Nout RA, Nijman HW, Edmondson RJ, Church DN, MacKay HJ, Leary A, Powell ME, Mileshkin L, Creutzberg CL, Smit VT, and Bosse T
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Endometrioid mortality, Carcinoma, Endometrioid secondary, Carcinoma, Endometrioid therapy, DNA Mutational Analysis, Disease Progression, Disease-Free Survival, Endometrial Neoplasms mortality, Endometrial Neoplasms pathology, Endometrial Neoplasms therapy, Female, Genetic Predisposition to Disease, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Middle Aged, Neoplasm Grading, Neoplasm Invasiveness, Neoplasm Recurrence, Local, Neoplasm Staging, Phenotype, Pilot Projects, Retrospective Studies, Risk Assessment, Risk Factors, Treatment Outcome, Young Adult, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Carcinoma, Endometrioid chemistry, Carcinoma, Endometrioid genetics, Endometrial Neoplasms chemistry, Endometrial Neoplasms genetics, Mutation, Neural Cell Adhesion Molecule L1 analysis, Tumor Suppressor Protein p53 genetics
- Abstract
Studies in early-stage, predominantly low- and intermediate-risk endometrial cancer have demonstrated that L1 cell adhesion molecule (L1CAM) overexpression identifies patients at increased risk of recurrence, yet its prognostic significance in high-risk endometrial cancer is unclear. To evaluate this, its frequency, and the relationship of L1CAM with the established endometrial cancer biomarker p53, we analyzed the expression of both markers by immunohistochemistry in a pilot series of 116 endometrial cancers (86 endometrioid, 30 non-endometrioid subtype) with high-risk features (such as high tumor grade and deep myometrial invasion) and correlated results with clinical outcome. We used The Cancer Genome Atlas (TCGA) endometrial cancer series to validate our findings. Using the previously reported cutoff of 10% positive staining, 51/116 (44%) tumors were classified as L1CAM-positive, with no significant association between L1CAM positivity and the rate of distant metastasis (P=0.195). However, increasing the threshold for L1CAM positivity to 50% resulted in a reduction of the frequency of L1CAM-positive tumors to 24% (28/116), and a significant association with the rate of distant metastasis (P=0.018). L1CAM expression was strongly associated with mutant p53 in the high-risk and TCGA series (P<0.001), although a substantial fraction (36% of endometrioid, 10% of non-endometrioid morphology) of p53-mutant endometrial cancers displayed <10% L1CAM positivity. Moreover, 30% of p53-wild-type non-endometrioid endometrial cancers demonstrated diffuse L1CAM staining, suggesting p53-independent mechanisms of L1CAM overexpression. In conclusion, the previously proposed threshold for L1CAM positivity of >10% does not predict prognosis in high-risk endometrial cancer, whereas an alternative threshold (>50%) does. L1CAM expression is strongly, but not universally, associated with mutant p53, and may be strong enough for clinical implementation as prognostic marker in combination with p53. The high frequency of L1CAM expression in high-risk endometrial cancers suggests that it may also be a promising therapeutic target in this tumor subset.
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- 2016
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47. POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer.
- Author
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van Gool IC, Eggink FA, Freeman-Mills L, Stelloo E, Marchi E, de Bruyn M, Palles C, Nout RA, de Kroon CD, Osse EM, Klenerman P, Creutzberg CL, Tomlinson IP, Smit VT, Nijman HW, Bosse T, and Church DN
- Subjects
- Cohort Studies, DNA Mutational Analysis, DNA Polymerase II immunology, Female, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Lymphocytes, Tumor-Infiltrating immunology, Poly-ADP-Ribose Binding Proteins, Polymerase Chain Reaction, DNA Polymerase II genetics, Endometrial Neoplasms genetics, Endometrial Neoplasms immunology, Mutation
- Abstract
Purpose: Recent studies have shown that 7% to 12% of endometrial cancers are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response, and clinical outcome in cancer, we investigated whether POLE-mutant endometrial cancers showed evidence of increased immunogenicity., Experimental Design: We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined endometrial cancer cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA endometrial cancer series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant endometrial cancers., Results: Compared with other endometrial cancers, POLE mutants displayed an enhanced cytotoxic T-cell response, evidenced by increased numbers of CD8(+) tumor-infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T-cell gene signature, and strong upregulation of the T-cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF, and granzyme B. This was accompanied by upregulation of T-cell exhaustion markers, consistent with chronic antigen exposure. In silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neoepitopes than other endometrial cancers, providing a potential explanation for our findings., Conclusions: Ultramutated POLE proofreading-mutant endometrial cancers are characterized by a robust intratumoral T-cell response, which correlates with, and may be caused by an enrichment of antigenic neopeptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers., (©2015 American Association for Cancer Research.)
- Published
- 2015
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48. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative.
- Author
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Stelloo E, Bosse T, Nout RA, MacKay HJ, Church DN, Nijman HW, Leary A, Edmondson RJ, Powell ME, Crosbie EJ, Kitchener HC, Mileshkin L, Pollock PM, Smit VT, and Creutzberg CL
- Subjects
- Adult, Aged, DNA Mutational Analysis, Female, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Middle Aged, Polymerase Chain Reaction, Prognosis, Risk Factors, Tissue Array Analysis, Biomarkers, Tumor analysis, Endometrial Neoplasms classification, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology
- Abstract
This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence-free, and overall survival were calculated using the Kaplan-Meier method and log-rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P=0.014) and distant metastasis rates 23%, 64%, and 50% (P=0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53-mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n=14) and group 2 (microsatellite instable; n=19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n=36) and 39% in group 4 (NSMP; P<0.001). Five-year recurrence-free survival was 93% and 95% for group 3 (POLE-mutant) and group 2 (microsatellite instable) vs 42% (group 1, p53-mutant) and 52% (group 4, NSMP; P<0.001). Targetable FBXW7 and FGFR2 mutations (6%), alterations in the PI3K-AKT pathway (60%) and hormone receptor positivity (45%) were frequently found. In conclusion, molecular analysis of high-risk endometrial cancer identifies four distinct prognostic subgroups, with potential therapeutic implications. High frequencies of targetable alterations were identified and may serve as targets for individualized treatment.
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- 2015
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49. Prognostic significance of POLE proofreading mutations in endometrial cancer.
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Church DN, Stelloo E, Nout RA, Valtcheva N, Depreeuw J, ter Haar N, Noske A, Amant F, Tomlinson IP, Wild PJ, Lambrechts D, Jürgenliemk-Schulz IM, Jobsen JJ, Smit VT, Creutzberg CL, and Bosse T
- Subjects
- Adult, Disease-Free Survival, Endometrial Neoplasms pathology, Female, Humans, Kaplan-Meier Estimate, Neoplasm Grading, Odds Ratio, Poly-ADP-Ribose Binding Proteins, Predictive Value of Tests, Prognosis, Biomarkers, Tumor genetics, DNA Polymerase II genetics, Endometrial Neoplasms genetics, Endometrial Neoplasms mortality, Mutation
- Abstract
Background: Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis., Methods: We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided., Results: POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06)., Conclusion: POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC., (© The Author 2014. Published by Oxford University Press.)
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- 2014
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50. High concordance of molecular tumor alterations between pre-operative curettage and hysterectomy specimens in patients with endometrial carcinoma.
- Author
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Stelloo E, Nout RA, Naves LC, Ter Haar NT, Creutzberg CL, Smit VT, and Bosse T
- Subjects
- Aged, Aged, 80 and over, Biomarkers, Tumor metabolism, Biopsy, Carcinoma, Endometrioid metabolism, Carcinoma, Endometrioid pathology, Carcinoma, Endometrioid surgery, Endometrial Neoplasms metabolism, Endometrial Neoplasms pathology, Endometrial Neoplasms surgery, Female, Genes, p53 genetics, Genetic Markers, Humans, Immunohistochemistry, Microsatellite Instability, Middle Aged, Mutation, PTEN Phosphohydrolase metabolism, Reproducibility of Results, beta Catenin metabolism, Biomarkers, Tumor genetics, Carcinoma, Endometrioid genetics, Curettage, DNA, Neoplasm analysis, Endometrial Neoplasms genetics, Hysterectomy, Tumor Suppressor Protein p53 metabolism
- Abstract
Objective: Molecular alterations in endometrial cancer have been shown to be prognostically significant but have not yet been implemented in the current clinical risk assessment. Few studies have investigated the reliability of molecular alterations in pre-operative specimens. Therefore, the objective was to determine whether molecular analysis of pre-operative endometrial cancer samples accurately reflects those alterations in the subsequent hysterectomy specimens., Methods: Paired pre-operative and hysterectomy specimens of 48 patients diagnosed with endometrial carcinoma, 42 endometrioid (EEC) and 6 non-endometrioid (NEEC) carcinomas, were analyzed for immunohistochemical expression of p53, PTEN and β-catenin. Tumor DNA was isolated and analyzed for microsatellite instability (MSI), TP53 mutations and somatic hot spot mutations in 13 genes., Results: In EEC patients, loss of PTEN, nuclear β-catenin and p53-mutant expression was found in 43%, 7% and 12%, respectively. No nuclear β-catenin was found in 5 of 6 NEEC patients, all serous cancers, whereas a p53-mutant expression was present in all serous cases. MSI was found in 19.5%, all EEC. Concordance for PTEN, β-catenin, p53 expression and MSI status was found in 79%, 92%, 79% and 93.5%, respectively. We detected 65 hot spot mutations in 39/48 (81%) tumors. Overall concordance of the GynCarta multigene analysis was 99.8%., Conclusions: The results confirm the reliability of immunohistochemical and DNA-based techniques in the evaluation of molecular alterations in pre-operative endometrial specimens and high concordance rates with the definitive hysterectomy specimens. The resulting molecular signature provides initial pre-operative diagnostic information on the status of oncogenic pathways, which may contribute to individualized treatment strategies., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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