68 results on '"Hoogstraat M"'
Search Results
2. Functional mapping of androgen receptor enhancer activity
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Department of Computational Sciences and Engineering; Department of Molecular Biology and Genetics, Özturan, Doğancan; Altıntaş, Berkay Umut; Gökbayrak, Bengül; Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842), Huang, Flora Chia-Chi; Morova, Tunç; Hu, Eugene; Yu, Lok Pak Ivan; Linder, Simon; Hoogstraat, M.; Stelloo, Suzan; Sar, Funda; Van der Poel, Henk; Saffarzadeh, Mohammadali; Le Bihan, Stephane; McConegy, Brian; Y Feng, Felix; Gleave, E. Martin; Bergman, M. Andries; Collins, Colin; Hach, Faraz; Zwart, Wilbert; Emberly, Eldon, Department of Computational Sciences and Engineering; Department of Molecular Biology and Genetics, Özturan, Doğancan; Altıntaş, Berkay Umut; Gökbayrak, Bengül; Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842), and Huang, Flora Chia-Chi; Morova, Tunç; Hu, Eugene; Yu, Lok Pak Ivan; Linder, Simon; Hoogstraat, M.; Stelloo, Suzan; Sar, Funda; Van der Poel, Henk; Saffarzadeh, Mohammadali; Le Bihan, Stephane; McConegy, Brian; Y Feng, Felix; Gleave, E. Martin; Bergman, M. Andries; Collins, Colin; Hach, Faraz; Zwart, Wilbert; Emberly, Eldon
- Abstract
Background: androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10-100x more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription. Results: to characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity. Conclusions: using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters.
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- 2021
3. Functional mapping of androgen receptor enhancer activity
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Özturan, Doğancan; Altıntaş, Berkay Umut; Gökbayrak, Bengül; Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842), Huang, Flora Chia-Chi; Morova, Tunç; Hu, Eugene; Yu, Lok Pak Ivan; Linder, Simon; Hoogstraat, M.; Stelloo, Suzan; Sar, Funda; Van der Poel, Henk; Saffarzadeh, Mohammadali; Le Bihan, Stephane; McConegy, Brian; Y Feng, Felix; Gleave, E. Martin; Bergman, M. Andries; Collins, Colin; Hach, Faraz; Zwart, Wilbert; Emberly, Eldon, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), Graduate School of Health Sciences; Graduate School of Sciences and Engineering, Department of Computational Sciences and Engineering; Department of Molecular Biology and Genetics, Özturan, Doğancan; Altıntaş, Berkay Umut; Gökbayrak, Bengül; Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842), Huang, Flora Chia-Chi; Morova, Tunç; Hu, Eugene; Yu, Lok Pak Ivan; Linder, Simon; Hoogstraat, M.; Stelloo, Suzan; Sar, Funda; Van der Poel, Henk; Saffarzadeh, Mohammadali; Le Bihan, Stephane; McConegy, Brian; Y Feng, Felix; Gleave, E. Martin; Bergman, M. Andries; Collins, Colin; Hach, Faraz; Zwart, Wilbert; Emberly, Eldon, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), Graduate School of Health Sciences; Graduate School of Sciences and Engineering, and Department of Computational Sciences and Engineering; Department of Molecular Biology and Genetics
- Abstract
Background: androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10-100x more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription. Results: to characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity. Conclusions: using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters., KWF Dutch Cancer Society; Scientific and Technological Research Council of Turkey (TÜBİTAK); 1001 Projects; NSERC; Prostate Cancer Foundation BC; Astellas Pharma Inc.
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- 2021
4. Abstract PD8-09: Approximately 40% of invasive recurrences after treatment of ductal carcinoma in situ is likely to be a second primary tumor
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Visser, LL, primary, Hoogstraat, M, additional, Elshof, LE, additional, van de Vijver, K, additional, Groen, EJ, additional, Almekinders, MM, additional, Bierman, C, additional, Nieboer, F, additional, de Maaker, M, additional, Kristel, P, additional, Mulder, L, additional, Schaapveld, M, additional, Schmidt, MK, additional, Lips, E, additional, and Wesseling, J, additional
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- 2019
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5. Enrichment of high-grade tumors in breast cancer gene expression studies
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van Seijen, M, Mooyaart, Antien, Mulder, L, Hoogstraat, M, Drukker, CA, Loo, CE, Pouw, B, Sonke, GS, Wesseling, J, Lips, EH, van Seijen, M, Mooyaart, Antien, Mulder, L, Hoogstraat, M, Drukker, CA, Loo, CE, Pouw, B, Sonke, GS, Wesseling, J, and Lips, EH
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- 2018
6. Tumor infiltrating lymphocytes predict benefit from TAC but not from ddAC in triple negative breast cancer in the randomized MATADOR trial (BOOG 2004-04)
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van Rossum, A.G.J., primary, Hoogstraat, M., additional, Opdam, M., additional, Horlings, H., additional, Wessels, L., additional, Kerkhoven, R.M., additional, van Leeuwen - Stok, A.E., additional, Oosterkamp, H.M., additional, Kok, M., additional, and Linn, S.C., additional
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- 2018
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7. PO-070 Identification of risk factors for subsequent invasive breast cancer after primary DCIS by transcriptomic profiling
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Visser, L., primary, Hoogstraat, M., additional, Elshof, L., additional, Leeuwen, F. Van, additional, Rutgers, E., additional, Schaapveld, M., additional, Schmidt, M., additional, Lips, E., additional, and Wesseling, J., additional
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- 2018
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8. Long-term prognosis of young breast cancer patients (<= 40 years) who did not receive adjuvant systemic treatment
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Dackus, G.M.H.E. (Gwen), Hoeve, N.D. (Natalie) ter, Opdam, M. (Mark), Vreuls, W. (Willem), Varga, Z. (Zsuzsanna), Koop, E. (Esther), Willems, S.M. (Stefan Martin), Deurzen, C.H.M. (Carolien) van, Groen, E.J. (Emilie), Cordoba, A. (Alicia), Bart, J. (Jos), Mooyaart, A.L. (Antien), Tweel, J.G. (Jan) van den, Zolota, V. (Vicky), Wesseling, J. (Jelle), Sapino, A. (Anna), Chmielik, E. (Ewa), Ryska, A. (Ales), Amant, F. (Frédéric), Broeks, A. (Annegien), Kerkhoven, R.M. (Ron), Stathonikos, N. (Nikolas), Veta, M. (Mitko), Voogd, A.C. (Adri), Jóźwiak, K. (Katarzyna), Hauptmann, M. (Michael), Hoogstraat, M. (Marlous), Schmidt, M.K. (Marjanka), Sonke, G.S. (Gabe), Wall, E. (Elsken) van der, Siesling, S. (Sabine), Diest, P.J. (Paul) van, Linn, S.C. (Sabine), Dackus, G.M.H.E. (Gwen), Hoeve, N.D. (Natalie) ter, Opdam, M. (Mark), Vreuls, W. (Willem), Varga, Z. (Zsuzsanna), Koop, E. (Esther), Willems, S.M. (Stefan Martin), Deurzen, C.H.M. (Carolien) van, Groen, E.J. (Emilie), Cordoba, A. (Alicia), Bart, J. (Jos), Mooyaart, A.L. (Antien), Tweel, J.G. (Jan) van den, Zolota, V. (Vicky), Wesseling, J. (Jelle), Sapino, A. (Anna), Chmielik, E. (Ewa), Ryska, A. (Ales), Amant, F. (Frédéric), Broeks, A. (Annegien), Kerkhoven, R.M. (Ron), Stathonikos, N. (Nikolas), Veta, M. (Mitko), Voogd, A.C. (Adri), Jóźwiak, K. (Katarzyna), Hauptmann, M. (Michael), Hoogstraat, M. (Marlous), Schmidt, M.K. (Marjanka), Sonke, G.S. (Gabe), Wall, E. (Elsken) van der, Siesling, S. (Sabine), Diest, P.J. (Paul) van, and Linn, S.C. (Sabine)
- Abstract
__Introduction__ Currently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient’s prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged ≤40 years. __Methods and analysis__ All young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online im
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- 2017
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9. Enrichment of high-grade tumors in breast cancer gene expression studies
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van Seijen, M. (M.), Mooyaart, A.L. (A. L.), Mulder, L. (L.), Hoogstraat, M. (Marlous), Drukker, C.A. (C. A.), Loo, C.E. (Claudette), Pouw, B. (B.), Sonke, G.S. (Gabe), Wesseling, J. (Jelle), Lips, E.H. (Esther), van Seijen, M. (M.), Mooyaart, A.L. (A. L.), Mulder, L. (L.), Hoogstraat, M. (Marlous), Drukker, C.A. (C. A.), Loo, C.E. (Claudette), Pouw, B. (B.), Sonke, G.S. (Gabe), Wesseling, J. (Jelle), and Lips, E.H. (Esther)
- Abstract
Purpose: Gene expression (GE) profiling for breast cancer classification and prognostication has become increasingly used in clinical diagnostics. GE profiling requires a reasonable tumor cell percentage and high-quality RNA. As a consequence, a certain amount of samples drop out. If tumor characteristics are different between samples included and excluded from GE profiling, this can lead to bias. Therefore, we assessed whether patient and tumor characteristics differ between tumors suitable or unsuitable for generating GE profiles in breast cancer. Methods: In a consecutive cohort of 738 breast cancer patients who received neoadjuvant chemotherapy at the Netherlands Cancer Institute, GE profiling was performed. We compared tumor characteristics and treatment outcome between patients included and excluded from GE profiling. Results were validated in an independent cohort of 812 patients treated with primary surgery. Results: GE analysis could be performed in 53% of the samples. Patients with tumor GE profiles more often had high-grade tumors [odds ratio 2.57 (95%CI 1.77–3.72), p < 0.001] and were more often lymph node positive [odds ratio 1.50 (95%CI 1.03–2.19), p = 0.035] compared to the group for which GE profiling was not possible. In the validation cohort, tumors suitable for gene expression analysis were more often high grade. Conclusions: In our gene expression studies, tumors suitable for GE profiling had more often an unfavorable prognostic profile. Due to selection of samples with a high tumor percentage, we automatically select for tumors with specific features, i.e., tumors with a higher grade and lymph node involvement. It is important to be aware of this phenomenon when performing gene expression analysis in a research or clinical context.
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- 2017
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10. Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study
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Weeber, F. (Fleur), Cirkel, G.A. (Geert), Hoogstraat, M. (Marlous), Bins, S. (Sander), Gadellaa-Van Hooijdonk, C.G.M. (C. G M), Ooft, S.N. (Salo), Werkhoven, E.D. (E.) van, Willems, S.M. (Stefan Martin), van Stralen, M. (Marijn), Veldhuis, W.B. (Wouter), Besselink, N. (Nicolle), Horlings, H.M. (Hugo M.), Steeghs, N. (Neeltje), Jonge, M.J.A. (Maja) de, Langenberg, M.H. (Marlies), Wessels, L. (Lodewyk), Cuppen, E. (Edwin), Schellens, J.H.M. (Jan), Sleijfer, S. (Stefan), Lolkema, M.P. (Martijn), Voest, E.E. (Emile), Weeber, F. (Fleur), Cirkel, G.A. (Geert), Hoogstraat, M. (Marlous), Bins, S. (Sander), Gadellaa-Van Hooijdonk, C.G.M. (C. G M), Ooft, S.N. (Salo), Werkhoven, E.D. (E.) van, Willems, S.M. (Stefan Martin), van Stralen, M. (Marijn), Veldhuis, W.B. (Wouter), Besselink, N. (Nicolle), Horlings, H.M. (Hugo M.), Steeghs, N. (Neeltje), Jonge, M.J.A. (Maja) de, Langenberg, M.H. (Marlies), Wessels, L. (Lodewyk), Cuppen, E. (Edwin), Schellens, J.H.M. (Jan), Sleijfer, S. (Stefan), Lolkema, M.P. (Martijn), and Voest, E.E. (Emile)
- Abstract
Background: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type. Methods: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK. Treatment benefit was determined according to TTP ratio and RECIST. We tested for associations between treatment benefit and single molecular aberrations, clusters of aberrations and pathway perturbation. Results: Cell line screens indicated several genes, such as PTEN (P = 0.016; Wald test), to be associated with sensitivity to mTOR inhibition. Subsequently 73 patients were included, of which 59 started treatment with everolimus. Response and molecular data were available from 43 patients. PTEN aberrations, i.e. copy number loss or mutation, were associated with treatment benefit (P = 0.046; Fisher's exact test). Conclusion: Loss-of-function aberrations in PTEN potentially represent a tumor type agnostic biomarker for benefit from everolimus and warrants further confirmation in subsequent studies.
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- 2017
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11. Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study
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Weeber, F, Cirkel, GA, Hoogstraat, M, Bins, Sander, Gadellaa-van Hooijdonk, CGM, Veldhuis, WB, Ooft, S, van Werkhoven, E, Williems, SM, van Stralen, M, Besselink, N J M, Horlings, HM, Steeghs, N, de Jonge, Maja, Langenberg, M H G, Wessels, LFA, Cuppen, E, Schellens, JH, Sleijfer, Stefan, Lolkema, Martijn, Voest, EE, Weeber, F, Cirkel, GA, Hoogstraat, M, Bins, Sander, Gadellaa-van Hooijdonk, CGM, Veldhuis, WB, Ooft, S, van Werkhoven, E, Williems, SM, van Stralen, M, Besselink, N J M, Horlings, HM, Steeghs, N, de Jonge, Maja, Langenberg, M H G, Wessels, LFA, Cuppen, E, Schellens, JH, Sleijfer, Stefan, Lolkema, Martijn, and Voest, EE
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- 2017
12. Abstract PD1-07: Comprehensive characterization of matched pre-treatment biopsies and residual disease of doxorubicin treated breast cancer
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Lips, EH, primary, Hoogstraat, M, additional, Mulder, L, additional, Nederlof, PM, additional, Sonke, GS, additional, Rodenhuis, S, additional, Wesseling, J, additional, and Wessels, LFA, additional
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- 2017
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13. TP53 mutated glioblastoma stem-like cell cultures are sensitive to dual mTORC1/2 inhibition while resistance in TP53 wild type cultures can be overcome by combined inhibition of mTORC1/2 and Bcl-2
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Venkatesan, S. (Subramanian), Hoogstraat, M. (Marlous), Caljouw, E. (Ester), Pierson, T. (Tessa), Spoor, J.K.H. (Jochem), Zeneyedpour, L. (Lona), Dubbink, H.J. (Erik Jan), Dekker, L.J.M. (Lennard J. M.), Kaaij, M. (Mariëlle) van der, Kloezeman, J.J. (Jenneke), Pont, L.M.E.B. (L.M.E. Berghauser), Besselink, N. (Nicolle), Luider, T.M. (Theo), Joore, J. (Jos), Martens, J.W.M. (John), Lamfers, M.L.M. (Martine), Sleijfer, S. (Stefan), Leenstra, S. (Sieger), Venkatesan, S. (Subramanian), Hoogstraat, M. (Marlous), Caljouw, E. (Ester), Pierson, T. (Tessa), Spoor, J.K.H. (Jochem), Zeneyedpour, L. (Lona), Dubbink, H.J. (Erik Jan), Dekker, L.J.M. (Lennard J. M.), Kaaij, M. (Mariëlle) van der, Kloezeman, J.J. (Jenneke), Pont, L.M.E.B. (L.M.E. Berghauser), Besselink, N. (Nicolle), Luider, T.M. (Theo), Joore, J. (Jos), Martens, J.W.M. (John), Lamfers, M.L.M. (Martine), Sleijfer, S. (Stefan), and Leenstra, S. (Sieger)
- Abstract
Background: Glioblastoma is the most malignant tumor of the central nervous system and still lacks effective treatment. This study explores mutational biomarkers of 11 drugs targeting either the RTK/Ras/PI3K, the p53 or the Rb pathway using 25 patient-derived glioblastoma stem-like cell cultures (GSCs). Results: We found that TP53 mutated GSCs were approximately 3.5 fold more sensitive to dual inhibition of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) compared to wild type GSCs. We identified that Bcl-2(Thr56/Ser70) phosphorylation contributed to the resistance of TP53 wild type GSCs against dual mTORC1/2 inhibition. The Bcl-2 inhibitor ABT-263 (navitoclax) increased sensitivity to the mTORC1/2 inhibitor AZD8055 in TP53 wild type GSCs, while sensitivity to AZD8055 in TP53 mutated GSCs remained unchanged. Conclusion: Our data suggest that Bcl-2 confers resistance to mTORC1/2 inhibitors in TP53 wild type GSCs and that combined inhibition of both mTORC1/2 and Bcl-2 is worthwhile to explore further in TP53 wild type glioblastomas, whereas in TP53 mutated glioblastomas dual mTORC1/2 inhibitors should be explored.
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- 2016
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14. RUBIC identifies driver genes by detecting recurrent DNA copy number breaks
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Van Dyk, H.O. (author), Hoogstraat, M (author), ten Hoeve, J (author), Reinders, M.J.T. (author), Wessels, L.F.A. (author), Van Dyk, H.O. (author), Hoogstraat, M (author), ten Hoeve, J (author), Reinders, M.J.T. (author), and Wessels, L.F.A. (author)
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The frequent recurrence of copy number aberrations across tumour samples is a reliable hallmark of certain cancer driver genes. However, state-of-the-art algorithms for detecting recurrent aberrations fail to detect several known drivers. In this study, we propose RUBIC, an approach that detects recurrent copy number breaks, rather than recurrently amplified or deleted regions. This change of perspective allows for a simplified approach as recursive peak splitting procedures and repeated re-estimation of the background model are avoided. Furthermore, we control the false discovery rate on the level of called regions, rather than at the probe level, as in competing algorithms. We benchmark RUBIC against GISTIC2 (a stateof- the-art approach) and RAIG (a recently proposed approach) on simulated copy number data and on three SNP6 and NGS copy number data sets from TCGA. We show that RUBIC calls more focal recurrent regions and identifies a much larger fraction of known cancer genes., Pattern Recognition and Bioinformatics
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- 2016
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15. TP53 mutated glioblastoma stem-like cell cultures are sensitive to dual mTORC1/2 inhibition while resistance in TP53 wild type cultures can be overcome by combined inhibition of mTORC1/2 and Bcl-2
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Venkatesan, S, Hoogstraat, M, Caljouw, E, Pierson, T, Spoor, Jochem, Moradi - Zeneyedpour, Lona, Dubbink, Erik jan, Dekker, Lennard, van der Kaaij, Mariëlle, Kloezeman, Jenneke, Berghauser Pont, Lotte, Besselink, N J M, Luider, Theo, Joore, J, Martens, John, Lamfers, Martine, Sleijfer, Stefan, Leenstra, Sieger, Venkatesan, S, Hoogstraat, M, Caljouw, E, Pierson, T, Spoor, Jochem, Moradi - Zeneyedpour, Lona, Dubbink, Erik jan, Dekker, Lennard, van der Kaaij, Mariëlle, Kloezeman, Jenneke, Berghauser Pont, Lotte, Besselink, N J M, Luider, Theo, Joore, J, Martens, John, Lamfers, Martine, Sleijfer, Stefan, and Leenstra, Sieger
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- 2016
16. Comprehensive characterization of matched pre-treatment biopsies and residual disease of chemotherapy treated breast cancer
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Hoogstraat, M., primary, Lips, E., additional, Mulder, L., additional, Nederlof, P., additional, Sonke, G., additional, Rodenhuis, S., additional, Wesseling, J., additional, and Wessels, L.F.A., additional
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- 2016
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17. Robust BRCA1-like classification of copy number profiles of samples repeated across different datasets and platforms
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Schouten, P.C., Grigoriadis, A., Kuilman, T., Mirza, H., Watkins, J.A., Cooke, S.A., Dyk, E. van, Severson, T.M., Rueda, O.M., Hoogstraat, M., Verhagen, C.V.M., Natrajan, R., Chin, S.F., Lips, E.H., Kruizinga, J., Velds, A., Nieuwland, M., Kerkhoven, R.M., Krijgsman, O., Vens, C., Peeper, D., Nederlof, P.M., Caldas, C., Tutt, A.N., Wessels, L.F., Linn, S.C., Schouten, P.C., Grigoriadis, A., Kuilman, T., Mirza, H., Watkins, J.A., Cooke, S.A., Dyk, E. van, Severson, T.M., Rueda, O.M., Hoogstraat, M., Verhagen, C.V.M., Natrajan, R., Chin, S.F., Lips, E.H., Kruizinga, J., Velds, A., Nieuwland, M., Kerkhoven, R.M., Krijgsman, O., Vens, C., Peeper, D., Nederlof, P.M., Caldas, C., Tutt, A.N., Wessels, L.F., and Linn, S.C.
- Abstract
Contains fulltext : 153904.pdf (publisher's version ) (Open Access), Breast cancers with BRCA1 germline mutation have a characteristic DNA copy number (CN) pattern. We developed a test that assigns CN profiles to be 'BRCA1-like' or 'non-BRCA1-like', which refers to resembling a BRCA1-mutated tumor or resembling a tumor without a BRCA1 mutation, respectively. Approximately one third of the BRCA1-like breast cancers have a BRCA1 mutation, one third has hypermethylation of the BRCA1 promoter and one third has an unknown reason for being BRCA1-like. This classification is indicative of patients' response to high dose alkylating and platinum containing chemotherapy regimens, which targets the inability of BRCA1 deficient cells to repair DNA double strand breaks. We investigated whether this classification can be reliably obtained with next generation sequencing and copy number platforms other than the bacterial artificial chromosome (BAC) array Comparative Genomic Hybridization (aCGH) on which it was originally developed. We investigated samples from 230 breast cancer patients for which a CN profile had been generated on two to five platforms, comprising low coverage CN sequencing, CN extraction from targeted sequencing panels (CopywriteR), Affymetrix SNP6.0, 135K/720K oligonucleotide aCGH, Affymetrix Oncoscan FFPE (MIP) technology, 3K BAC and 32K BAC aCGH. Pairwise comparison of genomic position-mapped profiles from the original aCGH platform and other platforms revealed concordance. For most cases, biological differences between samples exceeded the differences between platforms within one sample. We observed the same classification across different platforms in over 80% of the patients and kappa values of at least 0.36. Differential classification could be attributed to CN profiles that were not strongly associated to one class. In conclusion, we have shown that the genomic regions that define our BRCA1-like classifier are robustly measured by different CN profiling technologies, providing the possibility to retro- and prospectively in
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- 2015
18. Robust BRCA1-like classification of copy number profiles of samples repeated across different datasets and platforms
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Schouten, P.C. (author), Grigoriadis, A. (author), Kuilman, T. (author), Mirza, H. (author), Watkins, J.A. (author), Cooke, S.A. (author), Van Dyk, E. (author), Severson, T.M. (author), Rueda, O.M. (author), Hoogstraat, M. (author), Verhagen, C. (author), Natrajan, R. (author), Chin, S.F. (author), Lips, E.H. (author), Kruizinga, J. (author), Velds, A. (author), Nieuwland, M. (author), Kerkhoven, R.M. (author), Krijgsman, O. (author), Vens, C. (author), Peeper, D. (author), Nederlof, P.M. (author), Caldas, C. (author), Tutt, A.N. (author), Wessels, L.F.A. (author), Linn, S.C. (author), Schouten, P.C. (author), Grigoriadis, A. (author), Kuilman, T. (author), Mirza, H. (author), Watkins, J.A. (author), Cooke, S.A. (author), Van Dyk, E. (author), Severson, T.M. (author), Rueda, O.M. (author), Hoogstraat, M. (author), Verhagen, C. (author), Natrajan, R. (author), Chin, S.F. (author), Lips, E.H. (author), Kruizinga, J. (author), Velds, A. (author), Nieuwland, M. (author), Kerkhoven, R.M. (author), Krijgsman, O. (author), Vens, C. (author), Peeper, D. (author), Nederlof, P.M. (author), Caldas, C. (author), Tutt, A.N. (author), Wessels, L.F.A. (author), and Linn, S.C. (author)
- Abstract
Breast cancers with BRCA1 germline mutation have a characteristic DNA copy number (CN) pattern. We developed a test that assigns CN profiles to be ‘BRCA1-like’ or ‘non-BRCA1-like’, which refers to resembling a BRCA1-mutated tumor or resembling a tumor without a BRCA1 mutation, respectively. Approximately one third of the BRCA1-like breast cancers have a BRCA1 mutation, one third has hypermethylation of the BRCA1 promoter and one third has an unknown reason for being BRCA1-like. This classification is indicative of patients' response to high dose alkylating and platinum containing chemotherapy regimens, which targets the inability of BRCA1 deficient cells to repair DNA double strand breaks. We investigated whether this classification can be reliably obtained with next generation sequencing and copy number platforms other than the bacterial artificial chromosome (BAC) array Comparative Genomic Hybridization (aCGH) on which it was originally developed. We investigated samples from 230 breast cancer patients for which a CN profile had been generated on two to five platforms, comprising low coverage CN sequencing, CN extraction from targeted sequencing panels (CopywriteR), Affymetrix SNP6.0, 135K/720K oligonucleotide aCGH, Affymetrix Oncoscan FFPE (MIP) technology, 3K BAC and 32K BAC aCGH. Pairwise comparison of genomic position-mapped profiles from the original aCGH platform and other platforms revealed concordance. For most cases, biological differences between samples exceeded the differences between platforms within one sample. We observed the same classification across different platforms in over 80% of the patients and kappa values of at least 0.36. Differential classification could be attributed to CN profiles that were not strongly associated to one class. In conclusion, we have shown that the genomic regions that define our BRCA1-like classifier are robustly measured by different CN profiling technologies, providing the possibility to retro- and prospectively in, Intelligent Systems, Electrical Engineering, Mathematics and Computer Science
- Published
- 2015
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19. 189PD - Tumor infiltrating lymphocytes predict benefit from TAC but not from ddAC in triple negative breast cancer in the randomized MATADOR trial (BOOG 2004-04)
- Author
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van Rossum, A.G.J., Hoogstraat, M., Opdam, M., Horlings, H., Wessels, L., Kerkhoven, R.M., van Leeuwen - Stok, A.E., Oosterkamp, H.M., Kok, M., and Linn, S.C.
- Published
- 2018
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20. Ovarian cancer cell line panel (OCCP): Clinical importance of in vitro morphological subtypes
- Author
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Beaufort, C.M. (Corine M.), Helmijr, J. (Jean), Piskorz, A.M. (Anna M.), Hoogstraat, M. (Marlous), Ruigrok-Ritstier, K. (Kirsten), Besselink, N. (Nicolle), Murtaza, M. (Muhammed), IJcken, W.F.J. (Wilfred) van, Heine, A.A.J. (Anouk), Smid, M. (Marcel), Koudijs, M.J. (Marco J.), Brenton, J.D. (James D.), Berns, P.M.J.J. (Els), Helleman, J. (Jozien), Beaufort, C.M. (Corine M.), Helmijr, J. (Jean), Piskorz, A.M. (Anna M.), Hoogstraat, M. (Marlous), Ruigrok-Ritstier, K. (Kirsten), Besselink, N. (Nicolle), Murtaza, M. (Muhammed), IJcken, W.F.J. (Wilfred) van, Heine, A.A.J. (Anouk), Smid, M. (Marcel), Koudijs, M.J. (Marco J.), Brenton, J.D. (James D.), Berns, P.M.J.J. (Els), and Helleman, J. (Jozien)
- Abstract
Epithelial ovarian cancer is a highly heterogeneous disease and remains the most lethal gynaecological malignancy in the Western world. Therapeutic approaches need to account for inter-patient and intra-tumoural heterogeneity and detailed characterization of in vitro models representing the different histological an
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- 2014
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21. Ovarian Cancer Cell Line Panel (OCCP): Clinical Importance of In Vitro Morphological Subtypes
- Author
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Beaufort, Corine, Helmijr, Jean, Piskorz, AM, Hoogstraat, M, Ritstier, Kirsten, Besselink, N, Murtaza, M, van Ijcken, Wilfred, Heine, Anouk, Smid, Marcel, Koudijs, MJ, Brenton, JD, Berns, Els, Helleman, Jozien, Beaufort, Corine, Helmijr, Jean, Piskorz, AM, Hoogstraat, M, Ritstier, Kirsten, Besselink, N, Murtaza, M, van Ijcken, Wilfred, Heine, Anouk, Smid, Marcel, Koudijs, MJ, Brenton, JD, Berns, Els, and Helleman, Jozien
- Abstract
Epithelial ovarian cancer is a highly heterogeneous disease and remains the most lethal gynaecological malignancy in the Western world. Therapeutic approaches need to account for inter-patient and intra-tumoural heterogeneity and detailed characterization of in vitro models representing the different histological and molecular ovarian cancer subtypes is critical to enable reliable preclinical testing. There are approximately 100 publicly available ovarian cancer cell lines but their cellular and molecular characteristics are largely undescribed. We have characterized 39 ovarian cancer cell lines under uniform conditions for growth characteristics, mRNA/microRNA expression, exon sequencing, drug response for clinically-relevant therapeutics and collated all available information on the original clinical features and site of origin. We tested for statistical associations between the cellular and molecular features of the lines and clinical features. Of the 39 ovarian cancer cell lines, 14 were assigned as high-grade serous, four serous-type, one low-grade serous and 20 non-serous type. Three morphological subtypes: Epithelial (n = 21), Round (n = 7) and Spindle (n = 12) were identified that showed distinct biological and molecular characteristics, including overexpression of cell movement and migration-associated genes in the Spindle subtype. Comparison with the original clinical data showed association of the spindle-like tumours with metastasis, advanced stage, suboptimal debulking and poor prognosis. In addition, the expression profiles of Spindle, Round and Epithelial morphologies clustered with the previously described C1-stromal, C5-mesenchymal and C4 ovarian subtype expression profiles respectively. Comprehensive profiling of 39 ovarian cancer cell lines under controlled, uniform conditions demonstrates clinically relevant cellular and genomic characteristics. This data provides a rational basis for selecting models to develop specific treatment approaches for
- Published
- 2014
22. Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer
- Author
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Kloosterman, W.P., Hoogstraat, M., Paling, O., Tavakoli-Yaraki, M., Renkens, I., Vermaat, J.E., van Roosmalen, M., van Lieshout, S., Nijman, I.J., Roessingh, W., Van't Slot, R., van de Belt, J., Guryev, V., Koudijs, M.J., Voest, E.E., Cuppen, E., Kloosterman, W.P., Hoogstraat, M., Paling, O., Tavakoli-Yaraki, M., Renkens, I., Vermaat, J.E., van Roosmalen, M., van Lieshout, S., Nijman, I.J., Roessingh, W., Van't Slot, R., van de Belt, J., Guryev, V., Koudijs, M.J., Voest, E.E., and Cuppen, E.
- Abstract
BACKGROUND: Structural rearrangements form a major class of somatic variation in cancer genomes. Local chromosome shattering, termed chromothripsis, is a mechanism proposed to be the cause of clustered chromosomal rearrangements and was recently described to occur in a small percentage of tumors. The significance of these clusters for tumor development or metastatic spread is largely unclear. RESULTS: We used genome-wide long mate-pair sequencing and SNP array profiling to reveal that chromothripsis is a widespread phenomenon in primary colorectal cancer and metastases. We find large and small chromothripsis events in nearly every colorectal tumor sample and show that several breakpoints of chromothripsis clusters and isolated rearrangements affect cancer genes, including NOTCH2, EXO1 and MLL3. We complemented the structural variation studies by sequencing the coding regions of a cancer exome in all colorectal tumor samples and found somatic mutations in 24 genes, including APC, KRAS, SMAD4 and PIK3CA. A pairwise comparison of somatic variations in primary and metastatic samples indicated that many chromothripsis clusters, isolated rearrangements and point mutations are exclusively present in either the primary tumor or the metastasis and may affect cancer genes in a lesion-specific manner. CONCLUSIONS: We conclude that chromothripsis is a prevalent mechanism driving structural rearrangements in colorectal cancer and show that a complex interplay between point mutations, simple copy number changes and chromothripsis events drive colorectal tumor development and metastasis., BACKGROUND: Structural rearrangements form a major class of somatic variation in cancer genomes. Local chromosome shattering, termed chromothripsis, is a mechanism proposed to be the cause of clustered chromosomal rearrangements and was recently described to occur in a small percentage of tumors. The significance of these clusters for tumor development or metastatic spread is largely unclear. RESULTS: We used genome-wide long mate-pair sequencing and SNP array profiling to reveal that chromothripsis is a widespread phenomenon in primary colorectal cancer and metastases. We find large and small chromothripsis events in nearly every colorectal tumor sample and show that several breakpoints of chromothripsis clusters and isolated rearrangements affect cancer genes, including NOTCH2, EXO1 and MLL3. We complemented the structural variation studies by sequencing the coding regions of a cancer exome in all colorectal tumor samples and found somatic mutations in 24 genes, including APC, KRAS, SMAD4 and PIK3CA. A pairwise comparison of somatic variations in primary and metastatic samples indicated that many chromothripsis clusters, isolated rearrangements and point mutations are exclusively present in either the primary tumor or the metastasis and may affect cancer genes in a lesion-specific manner. CONCLUSIONS: We conclude that chromothripsis is a prevalent mechanism driving structural rearrangements in colorectal cancer and show that a complex interplay between point mutations, simple copy number changes and chromothripsis events drive colorectal tumor development and metastasis.
- Published
- 2011
23. PRI-CAT: a web-tool for the analysis, storage and visualization of plant ChIP-seq experiments.
- Author
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Muino, J.M., Hoogstraat, M., van Ham, R.C.H.J., van Dijk, A.D.J., Muino, J.M., Hoogstraat, M., van Ham, R.C.H.J., and van Dijk, A.D.J.
- Abstract
Although several tools for the analysis of ChIP-seq data have been published recently, there is a growing demand, in particular in the plant research community, for computational resources with which such data can be processed, analyzed, stored, visualized and integrated within a single, user-friendly environment. To accommodate this demand, we have developed PRI-CAT (Plant Research International ChIP-seq analysis tool), a web-based workflow tool for the management and analysis of ChIP-seq experiments. PRI-CAT is currently focused on Arabidopsis, but will be extended with other plant species in the near future. Users can directly submit their sequencing data to PRI-CAT for automated analysis. A QuickLoad server compatible with genome browsers is implemented for the storage and visualization of DNA-binding maps. Submitted datasets and results can be made publicly available through PRI-CAT, a feature that will enable community-based integrative analysis and visualization of ChIP-seq experiments. Secondary analysis of data can be performed with the aid of GALAXY, an external framework for tool and data integration. PRI-CAT is freely available at http://www.ab.wur.nl/pricat. No login is required.
- Published
- 2011
24. 177 - Comprehensive characterization of matched pre-treatment biopsies and residual disease of chemotherapy treated breast cancer
- Author
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Hoogstraat, M., Lips, E., Mulder, L., Nederlof, P., Sonke, G., Rodenhuis, S., Wesseling, J., and Wessels, L.F.A.
- Published
- 2016
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25. Effective therapeutic intervention and comprehensive genetic analysis of mTOR signaling in PEComa: A case report
- Author
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Weeber, F., Koudijs, M. J., Hoogstraat, M., Besselink, N. J. M., Lieshout, S., Nijman, I. J., Edwin Cuppen, Offerhaus, G. J., Voest, E. E., Pathology, and CCA - Disease profiling
26. 189PDTumor infiltrating lymphocytes predict benefit from TAC but not from ddAC in triple negative breast cancer in the randomized MATADOR trial (BOOG 2004-04).
- Author
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Rossum, A G J van, Hoogstraat, M, Opdam, M, Horlings, H, Wessels, L, Kerkhoven, R M, Stok, A E van Leeuwen -, Oosterkamp, H M, Kok, M, and Linn, S C
- Subjects
- *
TRIPLE-negative breast cancer , *LYMPHOCYTES - Published
- 2018
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27. Predictive gene expression profile for adjuvant taxane benefit in breast cancer in the MATADOR trial.
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Opdam M, van Rossum AGJ, Hoogstraat M, Bounova G, Horlings HM, van Werkhoven E, Mandjes IAM, van Leeuwen-Stok AE, Canisius S, van Tinteren H, Imholz ALT, Portielje JEA, Bos MEMM, Bakker S, Wesseling J, Kester L, van Rheenen J, Rutgers EJ, de Menezes RX, Wessels LFA, Kok M, Oosterkamp HM, and Linn SC
- Abstract
The primary objective of the prospective, randomized, multicenter, phase 3 biomarker Microarray Analysis in breast cancer to Taylor Adjuvant Drugs Or Regimens trial (MATADOR: ISRCTN61893718) is to generate a gene expression profile that can predict benefit from either docetaxel, doxorubicin, and cyclophosphamide (TAC) or dose-dense scheduled doxorubicin and cyclophosphamide (ddAC). Patients with a pT1-3, pN0-3 tumor were randomized 1:1 between ddAC and TAC. The primary endpoint was a gene profile-treatment interaction for recurrence-free survival (RFS). We observed 117 RFS events in 664 patients with a median follow-up of 7 years. Hallmark gene set analyses showed significant association between enrichment in immune-related gene expression and favorable outcome after TAC in hormone receptor-negative, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) (triple-negative breast cancer [TNBC]). We validated this association in TNBC patients treated with TAC on H&E slides; stromal tumor-infiltrating lymphocytes (sTILs) ≥20% was associated with longer RFS (hazard ratio 0.18, p = 0.01), while in patients treated with ddAC no difference in RFS was seen (hazard ratio 0.92, p = 0.86, p
interaction = 0.02)., Competing Interests: S.C.L. and H.M.O. received an institutional unrestricted research grant from Sanofi and Amgen to conduct the MATADOR study (ISRCTN61893718); H.M.O. received institutional research support funding from Roche; M.K. received institutional research support funding from Roche, BMS, and AZ; S.C.L. received institutional research support funding from Agendia, Amgen, AstraZeneca, Eurocept, Genentech, Immunomedics (now Gilead), Roche, Sanofi, and TESARO (now GSK). S.C.L. is an advisory board member for AstraZeneca for which the institute receives compensation, and for Cergentis (pro bono). S.C.L. receives funding for educational activities from Daiichi Sankyo, paid to the institute. H.M.O. is an advisory board member for Roche, Pfizer, and Novartis. M.K. is an advisory board member for AZ, BMS, Roche, MSD, and Daiichi for which the institute receives compensation., (© 2024 The Authors.)- Published
- 2024
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28. Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence.
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Linder S, Hoogstraat M, Stelloo S, Eickhoff N, Schuurman K, de Barros H, Alkemade M, Bekers EM, Severson TM, Sanders J, Huang CF, Morova T, Altintas UB, Hoekman L, Kim Y, Baca SC, Sjöström M, Zaalberg A, Hintzen DC, de Jong J, Kluin RJC, de Rink I, Giambartolomei C, Seo JH, Pasaniuc B, Altelaar M, Medema RH, Feng FY, Zoubeidi A, Freedman ML, Wessels LFA, Butler LM, Lack NA, van der Poel H, Bergman AM, and Zwart W
- Subjects
- ARNTL Transcription Factors genetics, Cell Line, Tumor, Circadian Rhythm, Drug Resistance, Neoplasm genetics, Epigenomics, Humans, Male, Nitriles therapeutic use, Receptors, Androgen genetics, Androgens pharmacology, Androgens therapeutic use, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target., Significance: Understanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007., (©2022 American Association for Cancer Research.)
- Published
- 2022
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29. Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer.
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Lips EH, Kumar T, Megalios A, Visser LL, Sheinman M, Fortunato A, Shah V, Hoogstraat M, Sei E, Mallo D, Roman-Escorza M, Ahmed AA, Xu M, van den Belt-Dusebout AW, Brugman W, Casasent AK, Clements K, Davies HR, Fu L, Grigoriadis A, Hardman TM, King LM, Krete M, Kristel P, de Maaker M, Maley CC, Marks JR, Menegaz BA, Mulder L, Nieboer F, Nowinski S, Pinder S, Quist J, Salinas-Souza C, Schaapveld M, Schmidt MK, Shaaban AM, Shami R, Sridharan M, Zhang J, Stobart H, Collyar D, Nik-Zainal S, Wessels LFA, Hwang ES, Navin NE, Futreal PA, Thompson AM, Wesseling J, and Sawyer EJ
- Subjects
- Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Female, Genomics, Humans, Neoplasm Recurrence, Local genetics, Breast Neoplasms genetics, Breast Neoplasms pathology, Carcinoma, Ductal, Breast genetics, Carcinoma, Intraductal, Noninfiltrating genetics, Carcinoma, Intraductal, Noninfiltrating pathology
- Abstract
Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers., (© 2022. The Author(s).)
- Published
- 2022
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30. Comprehensive characterization of pre- and post-treatment samples of breast cancer reveal potential mechanisms of chemotherapy resistance.
- Author
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Hoogstraat M, Lips EH, Mayayo-Peralta I, Mulder L, Kristel P, van der Heijden I, Annunziato S, van Seijen M, Nederlof PM, Sonke GS, Zwart W, Wesseling J, and Wessels LFA
- Abstract
When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome, and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response, and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p = 0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; p = 0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatment sample (CDKN1B) or in the post-treatment sample (TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes., (© 2022. The Author(s).)
- Published
- 2022
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31. Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments.
- Author
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Kester L, Seinstra D, van Rossum AGJ, Vennin C, Hoogstraat M, van der Velden D, Opdam M, van Werkhoven E, Hahn K, Nederlof I, Lips EH, Mandjes IAM, van Leeuwen-Stok AE, Canisius S, van Tinteren H, Imholz ALT, Portielje JEA, Bos MEMM, Bakker SD, Rutgers EJ, Horlings HM, Wesseling J, Voest EE, Wessels LFA, Kok M, Oosterkamp HM, van Oudenaarden A, Linn SC, and van Rheenen J
- Subjects
- Cellular Microenvironment, Endothelial Cells pathology, Female, Humans, Tumor Microenvironment genetics, Breast Neoplasms drug therapy, Breast Neoplasms therapy
- Abstract
Purpose: Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types., Experimental Design: Using single-cell sequencing data, we generated reference profiles for all these cell types. We used these reference profiles in deconvolution algorithms to optimally detangle the cellular composition of more than 3,500 primary breast tumors of patients that were enrolled in the SCAN-B and MATADOR clinical trials, and for which bulk mRNA sequencing data were available., Results: This large data set enables us to identify and subsequently validate the cellular composition of microenvironments that distinguish differential survival and treatment benefit for different treatment regimens in patients with primary breast cancer. In addition to immune cells, we have identified that survival and therapy benefit are characterized by various contributions of distinct epithelial cell types., Conclusions: From our study, we conclude that differential survival and therapy benefit of patients with breast cancer are characterized by distinct microenvironments that include specific populations of immune and epithelial cells., (©2021 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
- Full Text
- View/download PDF
32. Reduced NCOR2 expression accelerates androgen deprivation therapy failure in prostate cancer.
- Author
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Long MD, Jacobi JJ, Singh PK, Llimos G, Wani SA, Rowsam AM, Rosario SR, Hoogstraat M, Linder S, Kirk J, Affronti HC, Bergman A, Zwart W, Campbell MJ, and Smiraglia DJ
- Subjects
- Animals, Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, Humans, Male, Mice, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local metabolism, Nuclear Receptor Co-Repressor 2 genetics, Nuclear Receptor Co-Repressor 2 metabolism, Prognosis, Prostatic Neoplasms drug therapy, Prostatic Neoplasms metabolism, Survival Rate, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Androgen Antagonists pharmacology, Androgens deficiency, Biomarkers, Tumor metabolism, Gene Expression Regulation, Neoplastic drug effects, Neoplasm Recurrence, Local pathology, Nuclear Receptor Co-Repressor 2 antagonists & inhibitors, Prostatic Neoplasms pathology
- Abstract
This study addresses the roles of nuclear receptor corepressor 2 (NCOR2) in prostate cancer (PC) progression in response to androgen deprivation therapy (ADT). Reduced NCOR2 expression significantly associates with shorter disease-free survival in patients with PC receiving adjuvant ADT. Utilizing the CWR22 xenograft model, we demonstrate that stably reduced NCOR2 expression accelerates disease recurrence following ADT, associates with gene expression patterns that include neuroendocrine features, and induces DNA hypermethylation. Stably reduced NCOR2 expression in isogenic LNCaP (androgen-sensitive) and LNCaP-C4-2 (androgen-independent) cells revealed that NCOR2 reduction phenocopies the impact of androgen treatment and induces global DNA hypermethylation patterns. NCOR2 genomic binding is greatest in LNCaP-C4-2 cells and most clearly associates with forkhead box (FOX) transcription factor FOXA1 binding. NCOR2 binding significantly associates with transcriptional regulation most when in active enhancer regions. These studies reveal robust roles for NCOR2 in regulating the PC transcriptome and epigenome and underscore recent mutational studies linking NCOR2 loss of function to PC disease progression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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33. Corrigendum to "A case-control study to identify molecular risk factors for local recurrence in young breast cancer patients" [Radiother Oncol 156 (2021) 127-135].
- Author
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Bosma SCJ, Hoogstraat M, van Werkhoven E, de Maaker M, van der Leij F, Elkhuizen PHM, Fourquet A, Poortmans P, Boersma LJ, Bartelink H, and van de Vijver MJ
- Published
- 2021
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34. An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer.
- Author
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Davies A, Nouruzi S, Ganguli D, Namekawa T, Thaper D, Linder S, Karaoğlanoğlu F, Omur ME, Kim S, Kobelev M, Kumar S, Sivak O, Bostock C, Bishop J, Hoogstraat M, Talal A, Stelloo S, van der Poel H, Bergman AM, Ahmed M, Fazli L, Huang H, Tilley W, Goodrich D, Feng FY, Gleave M, He HH, Hach F, Zwart W, Beltran H, Selth L, and Zoubeidi A
- Subjects
- Cell Line, Tumor, Enhancer of Zeste Homolog 2 Protein genetics, Enhancer of Zeste Homolog 2 Protein metabolism, Gene Regulatory Networks physiology, Humans, Male, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Receptors, Androgen genetics, Signal Transduction physiology, Gene Expression Regulation, Neoplastic genetics, Gene Regulatory Networks genetics, Prostatic Neoplasms pathology, Receptors, Androgen metabolism
- Abstract
Cancers adapt to increasingly potent targeted therapies by reprogramming their phenotype. Here we investigated such a phenomenon in prostate cancer, in which tumours can escape epithelial lineage confinement and transition to a high-plasticity state as an adaptive response to potent androgen receptor (AR) antagonism. We found that AR activity can be maintained as tumours adopt alternative lineage identities, with changes in chromatin architecture guiding AR transcriptional rerouting. The epigenetic regulator enhancer of zeste homologue 2 (EZH2) co-occupies the reprogrammed AR cistrome to transcriptionally modulate stem cell and neuronal gene networks-granting privileges associated with both fates. This function of EZH2 was associated with T350 phosphorylation and establishment of a non-canonical polycomb subcomplex. Our study provides mechanistic insights into the plasticity of the lineage-infidelity state governed by AR reprogramming that enabled us to redirect cell fate by modulating EZH2 and AR, highlighting the clinical potential of reversing resistance phenotypes., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2021
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35. Functional mapping of androgen receptor enhancer activity.
- Author
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Huang CF, Lingadahalli S, Morova T, Ozturan D, Hu E, Yu IPL, Linder S, Hoogstraat M, Stelloo S, Sar F, van der Poel H, Altintas UB, Saffarzadeh M, Le Bihan S, McConeghy B, Gokbayrak B, Feng FY, Gleave ME, Bergman AM, Collins C, Hach F, Zwart W, Emberly E, and Lack NA
- Subjects
- Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Genome, Human, Humans, Male, Molecular Sequence Annotation, Mutation genetics, Polymorphism, Single Nucleotide genetics, Prostatic Neoplasms genetics, Reproducibility of Results, Enhancer Elements, Genetic, Receptors, Androgen genetics
- Abstract
Background: Androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10-100× more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription., Results: To characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity., Conclusions: Using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters.
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- 2021
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36. A case-control study to identify molecular risk factors for local recurrence in young breast cancer patients.
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Bosma SCJ, Hoogstraat M, van Werkhoven E, de Maaker M, van der Leij F, Elkhuizen PHM, Fourquet A, Poortmans P, Boersma LJ, Bartelink H, and van de Vijver MJ
- Subjects
- Case-Control Studies, DNA Copy Number Variations, Humans, Mastectomy, Segmental, Middle Aged, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Risk Factors, Breast Neoplasms pathology
- Abstract
Purpose: To investigate risk factors for local recurrence (LR) after breast conserving therapy in young breast cancer patients randomized in the "Young Boost Trial"., Material & Methods: In the "Young Boost Trial" 2421 patients ≤50 years old were randomized between a 16 Gy and 26 Gy boost after breast conserving surgery and whole breast radiation (50 Gy). We performed a case-control study comparing patients who developed a LR (cases) and for each of them three control patients free of recurrence (controls). Clinicopathological factors, copy number- and gene expression profiles of primary tumors were compared between cases and controls, and between primary tumors and local recurrences., Results: The cumulative 5-year LR rate was 1.07% (95% CI 0.72-1.59%) and 10-year LR rate 2.56% (1.81-3.62%). Analysis of a subset of primary tumors and local recurrences showed similar histopathological characteristics (n = 15), copy number (n = 13) and gene expression profiles (n = 14). Basal subtype was strongly associated with LR in univariable and multivariable analysis. Gains of CCND1 were identified more frequently among controls, while more frequent gains of FGFR1 and IGF1R were observed among cases. Upregulation of genes involved in the p53-pathway was observed in recurring tumors compared to non-recurring tumors. We could not identify a genomic classifier for LR., Conclusions: All investigated local recurrences were true genomic recurrences. Although differences in copy number variation and gene expression pathways were observed in recurring tumors compared to non-recurring tumors, no genomic classifier for LR could be identified., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2021
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37. Response to Preoperative Radiation Therapy in Relation to Gene Expression Patterns in Breast Cancer Patients.
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Bosma SCJ, Hoogstraat M, van der Leij F, de Maaker M, Wesseling J, Lips E, Loo CE, Rutgers EJ, Elkhuizen PHM, Bartelink H, and van de Vijver MJ
- Subjects
- Biopsy, Breast Neoplasms genetics, Breast Neoplasms pathology, Breast Neoplasms surgery, Carcinoma, Ductal, Breast genetics, Carcinoma, Ductal, Breast pathology, Carcinoma, Ductal, Breast surgery, Clinical Trials, Phase II as Topic statistics & numerical data, Female, Frozen Sections, Gene Expression Profiling methods, Humans, Mastectomy, Multicenter Studies as Topic statistics & numerical data, Precision Medicine, RNA, Messenger analysis, RNA, Messenger biosynthesis, RNA, Messenger genetics, RNA, Neoplasm biosynthesis, RNA, Neoplasm genetics, Radiation Tolerance genetics, Sequence Analysis, RNA, Treatment Outcome, Breast Neoplasms radiotherapy, Carcinoma, Ductal, Breast radiotherapy, Gene Expression Regulation, Neoplastic radiation effects, Neoadjuvant Therapy, RNA, Neoplasm analysis, Transcriptome
- Abstract
Purpose: We aimed to study radiation-induced gene expression changes and to identify differences in gene expression between patients with and without response to radiation therapy (RT) for invasive breast cancer with the purpose of exploring whether a predictive signature could be developed. Such a signature could assist in optimizing individualized locoregional treatment., Methods and Materials: RNA-seq using next-generation sequencing was performed on fresh frozen samples from pretreatment biopsies and post-RT surgery specimens from patients with low-risk breast cancer treated within the multicenter preoperative accelerated partial breast irradiation trial. Patients were treated with preoperative RT (10 × 4 Gy in 10 days or 5 × 6 Gy in 5 days) and a lumpectomy 6 weeks thereafter. The response of the tumor to RT was evaluated by pathologic assessment. To analyze the gene expression data, unsupervised and supervised clustering was performed. Gene expression profiles were compared between biopsies of responders and nonresponders and between samples before and after RT., Results: Ninety-four samples from 77 patients were analyzed: 68 pretreatment biopsies and 26 post-RT surgery specimens. Six patients had a (near) complete pathologic response, 3 patients had a good response, 32 patients had a partial response, and 22 patients had no or very limited response. Comparing patients with and without response to RT, 25 genes were significantly differentially expressed and were not linked to a pathway. Comparison of samples before and after RT identified significant changes in gene expression. Genes involved in p53 signaling, TNFA1 signaling, apoptosis, epithelial mesenchymal transition, and inflammatory response were upregulated. Genes involved in mitotic spindle, G2M checkpoint, and E2F targets were downregulated., Conclusions: Radiation-induced gene expression changes mainly involved p53 signaling, cell cycle regulation, DNA repair, and inflammatory response. No clinically significant differences could be identified in gene expression between patients with and without response to RT., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2020
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38. The molecular genetic make-up of male breast cancer.
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Moelans CB, de Ligt J, van der Groep P, Prins P, Besselink NJM, Hoogstraat M, Ter Hoeve ND, Lacle MM, Kornegoor R, van der Pol CC, de Leng WWJ, Barbé E, van der Vegt B, Martens J, Bult P, Smit VTHBM, Koudijs MJ, Nijman IJ, Voest EE, Selenica P, Weigelt B, Reis-Filho JS, van der Wall E, Cuppen E, and van Diest PJ
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Breast Neoplasms, Male pathology, DNA Copy Number Variations, Female, Gene Amplification, Genome, Human genetics, Humans, Male, Middle Aged, Mutation, Oncogenes genetics, Prognosis, Breast Neoplasms, Male genetics
- Abstract
Male breast cancer (MBC) is extremely rare and accounts for less than 1% of all breast malignancies. Therefore, clinical management of MBC is currently guided by research on the disease in females. In this study, DNA obtained from 45 formalin-fixed paraffin-embedded (FFPE) MBCs with and 90 MBCs (52 FFPE and 38 fresh-frozen) without matched normal tissues was subjected to massively parallel sequencing targeting all exons of 1943 cancer-related genes. The landscape of mutations and copy number alterations was compared to that of publicly available estrogen receptor (ER)-positive female breast cancers (smFBCs) and correlated to prognosis. From the 135 MBCs, 90% showed ductal histology, 96% were ER-positive, 66% were progesterone receptor (PR)-positive, and 2% HER2-positive, resulting in 50, 46 and 4% luminal A-like, luminal B-like and basal-like cases, respectively. Five patients had Klinefelter syndrome (4%) and 11% of patients harbored pathogenic BRCA2 germline mutations. The genomic landscape of MBC to some extent recapitulated that of smFBC, with recurrent PIK3CA (36%) and GATA3 (15%) somatic mutations, and with 40% of the most frequently amplified genes overlapping between both sexes. TP53 (3%) somatic mutations were significantly less frequent in MBC compared to smFBC, whereas somatic mutations in genes regulating chromatin function and homologous recombination deficiency-related signatures were more prevalent. MDM2 amplifications were frequent (13%), correlated with protein overexpression (P = 0.001) and predicted poor outcome (P = 0.007). In conclusion, despite similarities in the genomic landscape between MBC and smFBC, MBC is a molecularly unique and heterogeneous disease requiring its own clinical trials and treatment guidelines.
- Published
- 2019
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39. GPCR-SAS: A web application for statistical analyses on G protein-coupled receptors sequences.
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Gómez Tamayo JC, Olivella M, Ríos S, Hoogstraat M, Gonzalez A, Mayol E, Deupi X, Campillo M, and Cordomí A
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- Animals, Humans, Receptors, G-Protein-Coupled chemistry, Sequence Analysis, Protein methods, Software
- Abstract
G protein-coupled receptors (GPCRs) are one of the largest protein families in mammals. They mediate signal transduction across cell membranes and are important targets for the pharmaceutical industry. The G Protein-Coupled Receptors-Sequence Analysis and Statistics (GPCR-SAS) web application provides a set of tools to perform comparative analysis of sequence positions between receptors, based on a curated structural-informed multiple sequence alignment. The analysis tools include: (i) percentage of occurrence of an amino acid or motif and entropy at a position or range of positions, (ii) covariance of two positions, (iii) correlation between two amino acids in two positions (or two sequence motifs in two ranges of positions), and (iv) snake-plot representation for a specific receptor or for the consensus sequence of a group of selected receptors. The analysis of conservation of residues and motifs across transmembrane (TM) segments may guide the design of more selective ligands or help to rationalize activation mechanisms, among others. As an example, here we analyze the amino acids of the "transmission switch", that initiates receptor activation following ligand binding. The tool is freely accessible at http://lmc.uab.cat/gpcrsas/., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2018
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40. Enrichment of high-grade tumors in breast cancer gene expression studies.
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van Seijen M, Mooyaart AL, Mulder L, Hoogstraat M, Drukker CA, Loo CE, Pouw B, Sonke GS, Wesseling J, and Lips EH
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- Antineoplastic Agents therapeutic use, Biopsy, Large-Core Needle, Breast pathology, Breast surgery, Breast Neoplasms mortality, Breast Neoplasms pathology, Breast Neoplasms therapy, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Lymphatic Metastasis, Mastectomy, Middle Aged, Neoadjuvant Therapy methods, Netherlands epidemiology, Prognosis, Retrospective Studies, Sequence Analysis, RNA, Breast Neoplasms genetics, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Tissue Array Analysis methods
- Abstract
Purpose: Gene expression (GE) profiling for breast cancer classification and prognostication has become increasingly used in clinical diagnostics. GE profiling requires a reasonable tumor cell percentage and high-quality RNA. As a consequence, a certain amount of samples drop out. If tumor characteristics are different between samples included and excluded from GE profiling, this can lead to bias. Therefore, we assessed whether patient and tumor characteristics differ between tumors suitable or unsuitable for generating GE profiles in breast cancer., Methods: In a consecutive cohort of 738 breast cancer patients who received neoadjuvant chemotherapy at the Netherlands Cancer Institute, GE profiling was performed. We compared tumor characteristics and treatment outcome between patients included and excluded from GE profiling. Results were validated in an independent cohort of 812 patients treated with primary surgery., Results: GE analysis could be performed in 53% of the samples. Patients with tumor GE profiles more often had high-grade tumors [odds ratio 2.57 (95%CI 1.77-3.72), p < 0.001] and were more often lymph node positive [odds ratio 1.50 (95%CI 1.03-2.19), p = 0.035] compared to the group for which GE profiling was not possible. In the validation cohort, tumors suitable for gene expression analysis were more often high grade., Conclusions: In our gene expression studies, tumors suitable for GE profiling had more often an unfavorable prognostic profile. Due to selection of samples with a high tumor percentage, we automatically select for tumors with specific features, i.e., tumors with a higher grade and lymph node involvement. It is important to be aware of this phenomenon when performing gene expression analysis in a research or clinical context.
- Published
- 2018
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41. A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity.
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Sachs N, de Ligt J, Kopper O, Gogola E, Bounova G, Weeber F, Balgobind AV, Wind K, Gracanin A, Begthel H, Korving J, van Boxtel R, Duarte AA, Lelieveld D, van Hoeck A, Ernst RF, Blokzijl F, Nijman IJ, Hoogstraat M, van de Ven M, Egan DA, Zinzalla V, Moll J, Boj SF, Voest EE, Wessels L, van Diest PJ, Rottenberg S, Vries RGJ, Cuppen E, and Clevers H
- Subjects
- Animals, Antineoplastic Agents pharmacology, Breast Neoplasms genetics, Cells, Cultured, Drug Screening Assays, Antitumor methods, Female, Humans, Mice, Mice, Nude, Organoids drug effects, Precision Medicine methods, Breast Neoplasms pathology, Genetic Heterogeneity, Organoids pathology, Tissue Banks
- Abstract
Breast cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, >100 primary and metastatic BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. DNA copy number variations as well as sequence changes were consistent within tumor-organoid pairs and largely retained even after extended passaging. BC organoids furthermore populated all major gene-expression-based classification groups and allowed in vitro drug screens that were consistent with in vivo xeno-transplantations and patient response. This study describes a representative collection of well-characterized BC organoids available for cancer research and drug development, as well as a strategy to assess in vitro drug response in a personalized fashion., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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42. Long-term prognosis of young breast cancer patients (≤40 years) who did not receive adjuvant systemic treatment: protocol for the PARADIGM initiative cohort study.
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Dackus GM, Ter Hoeve ND, Opdam M, Vreuls W, Varga Z, Koop E, Willems SM, Van Deurzen CH, Groen EJ, Cordoba A, Bart J, Mooyaart AL, van den Tweel JG, Zolota V, Wesseling J, Sapino A, Chmielik E, Ryska A, Amant F, Broeks A, Kerkhoven R, Stathonikos N, Veta M, Voogd A, Jozwiak K, Hauptmann M, Hoogstraat M, Schmidt MK, Sonke G, van der Wall E, Siesling S, van Diest PJ, and Linn SC
- Subjects
- Adult, Breast Neoplasms genetics, Breast Neoplasms metabolism, Cohort Studies, Gene Expression, Humans, Prognosis, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Registries, Time Factors, Breast Neoplasms pathology, Breast Neoplasms surgery, Research Design
- Abstract
Introduction: Currently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient's prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged ≤ 40 years., Methods and Analysis: All young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online image database platform for clinicopathological revision by an international team of breast pathologists. Immunohistochemical subtype will be assessed using tissue microarrays. Tumour RNA will be isolated and subjected to next-generation sequencing. Differences in gene expression found between patients with a favourable and those with a less favourable prognosis will be used to establish a prognostic classifier, using the triple negative patients as proof of principle., Ethics and Dissemination: Observational data from the Netherlands Cancer Registry and left over archival patient material are used. Therefore, the Dutch law on Research Involving Human Subjects Act (WMO) is not applicable. The PARADIGM study received a 'non-WMO' declaration from the Medical Ethics Committee of the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, waiving individual patient consent. All data and material used are stored in a coded way. Study results will be presented at international (breast cancer) conferences and published in peer-reviewed, open-access journals., Competing Interests: Competing interests: All authors have completed the Unified Competing Interest form (). Forms are available on request from the corresponding author. Authors declare the following: SCL reports grants from The Netherlands Organization for Health Research and Development (ZonMW) and A Sister’s Hope during the conduct of the study. SCL also received non-financial support from AstraZeneca, grants from AstraZeneca,Roche and Genentech and other from Novartis, Cergentis, PhilipsHealth BV, Roche and Astra Zeneca outside the submitted work. In addition, SCL has two patents pending (WO/2015/080585,PCT/NL2014/050813). AR reports grants, personal fees and non-financial support from Pfizer, grants and personal fees from Roche, Astra Zeneca, MSD, BMS, Merck and grants from Boehringer Ingelheim and Novartis outside the submitted work. NS reports grants from University Medical Centre Utrecht during the conduct of the study. SMW reports grants and personal fees from Roche, Pfizer, AstraZeneca and personal fees from MSD outside the submitted work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2017
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43. Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1β in tumor-associated macrophages.
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Kersten K, Coffelt SB, Hoogstraat M, Verstegen NJM, Vrijland K, Ciampricotti M, Doornebal CW, Hau CS, Wellenstein MD, Salvagno C, Doshi P, Lips EH, Wessels LFA, and de Visser KE
- Abstract
Patients with primary solid malignancies frequently exhibit signs of systemic inflammation. Notably, elevated levels of neutrophils and their associated soluble mediators are regularly observed in cancer patients, and correlate with reduced survival and increased metastasis formation. Recently, we demonstrated a mechanistic link between mammary tumor-induced IL17-producing γδ T cells, systemic expansion of immunosuppressive neutrophils and metastasis formation in a genetically engineered mouse model for invasive breast cancer. How tumors orchestrate this systemic inflammatory cascade to facilitate dissemination remains unclear. Here we show that activation of this cascade relies on CCL2-mediated induction of IL1β in tumor-associated macrophages. In line with these findings, expression of CCL2 positively correlates with IL1Β and macrophage markers in human breast tumors. We demonstrate that blockade of CCL2 in mammary tumor-bearing mice results in reduced IL17 production by γδ T cells, decreased neutrophil expansion and enhanced CD8
+ T cell activity. These results highlight a new role for CCL2 in facilitating the breast cancer-induced pro-metastatic systemic inflammatory γδ T cell - IL17 - neutrophil axis.- Published
- 2017
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44. Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study.
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Weeber F, Cirkel GA, Hoogstraat M, Bins S, Gadellaa-van Hooijdonk CGM, Ooft S, van Werkhoven E, Willems SM, van Stralen M, Veldhuis WB, Besselink NJM, Horlings HM, Steeghs N, de Jonge MJ, Langenberg MHG, Wessels LFA, Cuppen EPJG, Schellens JH, Sleijfer S, Lolkema MP, and Voest EE
- Abstract
Background: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type., Methods: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK. Treatment benefit was determined according to TTP ratio and RECIST. We tested for associations between treatment benefit and single molecular aberrations, clusters of aberrations and pathway perturbation., Results: Cell line screens indicated several genes, such as PTEN ( P = 0.016; Wald test), to be associated with sensitivity to mTOR inhibition. Subsequently 73 patients were included, of which 59 started treatment with everolimus. Response and molecular data were available from 43 patients. PTEN aberrations, i.e. copy number loss or mutation, were associated with treatment benefit ( P = 0.046; Fisher's exact test)., Conclusion: Loss-of-function aberrations in PTEN potentially represent a tumor type agnostic biomarker for benefit from everolimus and warrants further confirmation in subsequent studies., Competing Interests: CONFLICTS OF INTEREST The authors report no conflict of interest.
- Published
- 2017
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45. TP53 mutated glioblastoma stem-like cell cultures are sensitive to dual mTORC1/2 inhibition while resistance in TP53 wild type cultures can be overcome by combined inhibition of mTORC1/2 and Bcl-2.
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Venkatesan S, Hoogstraat M, Caljouw E, Pierson T, Spoor JK, Zeneyedpour L, Dubbink HJ, Dekker LJ, van der Kaaij M, Kloezeman J, Berghauser Pont LM, Besselink NJ, Luider TM, Joore J, Martens JW, Lamfers ML, Sleijfer S, and Leenstra S
- Subjects
- Aniline Compounds pharmacology, Biomarkers, Tumor, Brain Neoplasms drug therapy, Brain Neoplasms metabolism, Cell Line, Tumor, Cell Survival, Cohort Studies, DNA Mutational Analysis, Drug Screening Assays, Antitumor, Glioblastoma drug therapy, Glioblastoma metabolism, High-Throughput Nucleotide Sequencing, Humans, Morpholines chemistry, Mutation, Neoplastic Stem Cells cytology, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation, Proteome, Sulfonamides pharmacology, TOR Serine-Threonine Kinases metabolism, Brain Neoplasms genetics, Drug Resistance, Neoplasm, Glioblastoma genetics, Mechanistic Target of Rapamycin Complex 1 antagonists & inhibitors, Mechanistic Target of Rapamycin Complex 2 antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Tumor Suppressor Protein p53 metabolism
- Abstract
Background: Glioblastoma is the most malignant tumor of the central nervous system and still lacks effective treatment. This study explores mutational biomarkers of 11 drugs targeting either the RTK/Ras/PI3K, the p53 or the Rb pathway using 25 patient-derived glioblastoma stem-like cell cultures (GSCs)., Results: We found that TP53 mutated GSCs were approximately 3.5 fold more sensitive to dual inhibition of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) compared to wild type GSCs. We identified that Bcl-2(Thr56/Ser70) phosphorylation contributed to the resistance of TP53 wild type GSCs against dual mTORC1/2 inhibition. The Bcl-2 inhibitor ABT-263 (navitoclax) increased sensitivity to the mTORC1/2 inhibitor AZD8055 in TP53 wild type GSCs, while sensitivity to AZD8055 in TP53 mutated GSCs remained unchanged., Conclusion: Our data suggest that Bcl-2 confers resistance to mTORC1/2 inhibitors in TP53 wild type GSCs and that combined inhibition of both mTORC1/2 and Bcl-2 is worthwhile to explore further in TP53 wild type glioblastomas, whereas in TP53 mutated glioblastomas dual mTORC1/2 inhibitors should be explored., Competing Interests: The authors declare no competing financial interests.
- Published
- 2016
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46. RUBIC identifies driver genes by detecting recurrent DNA copy number breaks.
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van Dyk E, Hoogstraat M, Ten Hoeve J, Reinders MJ, and Wessels LF
- Subjects
- Chromosome Fragile Sites, Humans, Models, Genetic, Algorithms, DNA Copy Number Variations, Neoplasms genetics
- Abstract
The frequent recurrence of copy number aberrations across tumour samples is a reliable hallmark of certain cancer driver genes. However, state-of-the-art algorithms for detecting recurrent aberrations fail to detect several known drivers. In this study, we propose RUBIC, an approach that detects recurrent copy number breaks, rather than recurrently amplified or deleted regions. This change of perspective allows for a simplified approach as recursive peak splitting procedures and repeated re-estimation of the background model are avoided. Furthermore, we control the false discovery rate on the level of called regions, rather than at the probe level, as in competing algorithms. We benchmark RUBIC against GISTIC2 (a state-of-the-art approach) and RAIG (a recently proposed approach) on simulated copy number data and on three SNP6 and NGS copy number data sets from TCGA. We show that RUBIC calls more focal recurrent regions and identifies a much larger fraction of known cancer genes.
- Published
- 2016
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47. Preserved genetic diversity in organoids cultured from biopsies of human colorectal cancer metastases.
- Author
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Weeber F, van de Wetering M, Hoogstraat M, Dijkstra KK, Krijgsman O, Kuilman T, Gadellaa-van Hooijdonk CG, van der Velden DL, Peeper DS, Cuppen EP, Vries RG, Clevers H, and Voest EE
- Subjects
- Antineoplastic Protocols standards, Base Sequence, Colorectal Neoplasms drug therapy, Genes, Neoplasm genetics, Humans, Molecular Sequence Data, Organoids chemistry, Precision Medicine methods, Sequence Analysis, DNA, Cell Culture Techniques methods, Colorectal Neoplasms genetics, Genetic Variation genetics, Neoplasm Metastasis genetics, Organoids cytology, Organoids growth & development
- Abstract
Tumor organoids are 3D cultures of cancer cells. They can be derived from the tumor of each individual patient, thereby providing an attractive ex vivo assay to tailor treatment. Using patient-derived tumor organoids for this purpose requires that organoids derived from biopsies maintain the genetic diversity of the in vivo tumor. In this study tumor biopsies were obtained from 14 patients with metastatic colorectal cancer (i) to test the feasibility of organoid culture from metastatic biopsy specimens and (ii) to compare the genetic diversity of patient-derived tumor organoids and the original tumor biopsy. Genetic analysis was performed using SOLiD sequencing for 1,977 cancer-relevant genes. Copy number profiles were generated from sequencing data using CopywriteR. Here we demonstrate that organoid cultures can be established from tumor biopsies of patients with metastatic colorectal cancer with a success rate of 71%. Genetic analysis showed that organoids reflect the metastasis from which they were derived. Ninety percent of somatic mutations were shared between organoids and biopsies from the same patient, and the DNA copy number profiles of organoids and the corresponding original tumor show a correlation of 0.89. Most importantly, none of the mutations that were found exclusively in either the tumor or organoid culture are in driver genes or genes amenable for drug targeting. These findings support further exploration of patient-derived organoids as an ex vivo platform to personalize anticancer treatment.
- Published
- 2015
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48. Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response.
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Lips EH, Michaut M, Hoogstraat M, Mulder L, Besselink NJ, Koudijs MJ, Cuppen E, Voest EE, Bernards R, Nederlof PM, Wesseling J, Rodenhuis S, and Wessels LF
- Subjects
- Adult, Aged, Antineoplastic Agents therapeutic use, Class I Phosphatidylinositol 3-Kinases, Connectin genetics, DNA Mutational Analysis, Drug Resistance, Neoplasm, Female, Gene Dosage, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Humans, Middle Aged, Phosphatidylinositol 3-Kinases genetics, Signal Transduction, Triple Negative Breast Neoplasms drug therapy, Tumor Suppressor Protein p53 genetics, Young Adult, Antineoplastic Agents pharmacology, Triple Negative Breast Neoplasms genetics
- Abstract
Introduction: In triple negative breast cancers (TNBC) the initial response to chemotherapy is often favorable, but relapse and chemotherapy resistance frequently occur in advanced disease. Hence there is an urgent need for targeted treatments in this breast cancer subtype. In the current study we deep sequenced DNA of tumors prior to chemotherapy to search for predictors of response or resistance., Methods: Next generation sequencing (NGS) was performed for 1,977 genes involved in tumorigenesis. DNA from 56 pre-treatment TNBC-biopsies was sequenced, as well as matched normal DNA. Following their tumor biopsy, patients started neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. We studied associations between genetic alterations and three clinical variables: chemotherapy response, relapse-free survival and BRCA proficiency., Results: The mutations observed were diverse and few recurrent mutations were detected. Most mutations were in TP53, TTN, and PIK3CA (55 %, 14 %, and 9 %, respectively). The mutation rates were similar between responders and non-responders (average mutation rate 9 vs 8 mutations). No recurrent mutations were associated with chemotherapy response or relapse. Interestingly, PIK3CA mutations were exclusively observed in patients proficient for BRCA1. Samples with a relapse had a higher copy number alteration rate, and amplifications of TTK and TP53BP2 were associated with a poor chemotherapy response., Conclusions: In this homogenous cohort of TNBCs few recurrent mutations were found. However, PIK3CA mutations were associated with BRCA proficiency, which can have clinical consequences in the near future.
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- 2015
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49. Genome-Wide Identification and Characterization of Novel Factors Conferring Resistance to Topoisomerase II Poisons in Cancer.
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Wijdeven RH, Pang B, van der Zanden SY, Qiao X, Blomen V, Hoogstraat M, Lips EH, Janssen L, Wessels L, Brummelkamp TR, and Neefjes J
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Apoptosis Regulatory Proteins genetics, CRISPR-Cas Systems, Capecitabine administration & dosage, Carcinoma drug therapy, Carcinoma genetics, Carcinoma metabolism, Chromosomal Proteins, Non-Histone genetics, Cyclophosphamide administration & dosage, DNA Helicases analysis, DNA-Binding Proteins genetics, Docetaxel, Doxorubicin administration & dosage, Doxorubicin pharmacology, Etoposide pharmacology, Female, Gene Expression Profiling, Humans, Intracellular Signaling Peptides and Proteins genetics, Kelch-Like ECH-Associated Protein 1, Neoplasm Proteins analysis, Nuclear Proteins analysis, Nuclear Proteins genetics, RNA Interference, RNA, Small Interfering pharmacology, SMARCB1 Protein, Sarcoma metabolism, Sarcoma pathology, Taxoids administration & dosage, Topotecan pharmacology, Transcription Factors analysis, Transcription Factors genetics, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms metabolism, Apoptosis Regulatory Proteins physiology, Chromosomal Proteins, Non-Histone physiology, DNA-Binding Proteins physiology, Drug Resistance, Neoplasm genetics, Genome-Wide Association Study, Intracellular Signaling Peptides and Proteins physiology, Neoplasm Proteins antagonists & inhibitors, Nuclear Proteins physiology, Topoisomerase II Inhibitors pharmacology, Transcription Factors physiology
- Abstract
The topoisomerase II poisons doxorubicin and etoposide constitute longstanding cornerstones of chemotherapy. Despite their extensive clinical use, many patients do not respond to these drugs. Using a genome-wide gene knockout approach, we identified Keap1, the SWI/SNF complex, and C9orf82 (CAAP1) as independent factors capable of driving drug resistance through diverse molecular mechanisms, all converging on the DNA double-strand break (DSB) and repair pathway. Loss of Keap1 or the SWI/SNF complex inhibits generation of DSB by attenuating expression and activity of topoisomerase IIα, respectively, whereas deletion of C9orf82 augments subsequent DSB repair. Their corresponding genes, frequently mutated or deleted in human tumors, may impact drug sensitivity, as exemplified by triple-negative breast cancer patients with diminished SWI/SNF core member expression who exhibit reduced responsiveness to chemotherapy regimens containing doxorubicin. Collectively, our work identifies genes that may predict the response of cancer patients to the broadly used topoisomerase II poisons and defines alternative pathways that could be therapeutically exploited in treatment-resistant patients., (©2015 American Association for Cancer Research.)
- Published
- 2015
- Full Text
- View/download PDF
50. Robust BRCA1-like classification of copy number profiles of samples repeated across different datasets and platforms.
- Author
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Schouten PC, Grigoriadis A, Kuilman T, Mirza H, Watkins JA, Cooke SA, van Dyk E, Severson TM, Rueda OM, Hoogstraat M, Verhagen CV, Natrajan R, Chin SF, Lips EH, Kruizinga J, Velds A, Nieuwland M, Kerkhoven RM, Krijgsman O, Vens C, Peeper D, Nederlof PM, Caldas C, Tutt AN, Wessels LF, and Linn SC
- Subjects
- Cohort Studies, Comparative Genomic Hybridization, DNA Methylation, Female, Humans, Randomized Controlled Trials as Topic, Breast Neoplasms genetics, Datasets as Topic, Gene Dosage, Genes, BRCA1
- Abstract
Breast cancers with BRCA1 germline mutation have a characteristic DNA copy number (CN) pattern. We developed a test that assigns CN profiles to be 'BRCA1-like' or 'non-BRCA1-like', which refers to resembling a BRCA1-mutated tumor or resembling a tumor without a BRCA1 mutation, respectively. Approximately one third of the BRCA1-like breast cancers have a BRCA1 mutation, one third has hypermethylation of the BRCA1 promoter and one third has an unknown reason for being BRCA1-like. This classification is indicative of patients' response to high dose alkylating and platinum containing chemotherapy regimens, which targets the inability of BRCA1 deficient cells to repair DNA double strand breaks. We investigated whether this classification can be reliably obtained with next generation sequencing and copy number platforms other than the bacterial artificial chromosome (BAC) array Comparative Genomic Hybridization (aCGH) on which it was originally developed. We investigated samples from 230 breast cancer patients for which a CN profile had been generated on two to five platforms, comprising low coverage CN sequencing, CN extraction from targeted sequencing panels (CopywriteR), Affymetrix SNP6.0, 135K/720K oligonucleotide aCGH, Affymetrix Oncoscan FFPE (MIP) technology, 3K BAC and 32K BAC aCGH. Pairwise comparison of genomic position-mapped profiles from the original aCGH platform and other platforms revealed concordance. For most cases, biological differences between samples exceeded the differences between platforms within one sample. We observed the same classification across different platforms in over 80% of the patients and kappa values of at least 0.36. Differential classification could be attributed to CN profiles that were not strongly associated to one class. In conclusion, we have shown that the genomic regions that define our BRCA1-like classifier are robustly measured by different CN profiling technologies, providing the possibility to retro- and prospectively investigate BRCA1-like classification across a wide range of CN platforms., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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