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125 results on '"Brinkman, A.B."'

1. Author Correction: Pan-cancer analysis of whole genomes

Author

Aaltonen, L.A., Abeshouse, A., Brinkman, A.B., Span, P.N., Sweep, F.C.G.J., et al., Aaltonen, L.A., Abeshouse, A., Brinkman, A.B., Span, P.N., Sweep, F.C.G.J., and et al.

Abstract

Item does not contain fulltext

Published
2023

5. Terminal keratinocyte differentiation in vitro is associated with a stable DNA methylome

Author

Smits, J.P., Dirks, R.A.M., Qu, J., Oortveld, M.A.W., Brinkman, A.B., Zeeuwen, P.L., Schalkwijk, J., Zhou, H., Marks, H., Bogaard, E.H.J. van den, Smits, J.P., Dirks, R.A.M., Qu, J., Oortveld, M.A.W., Brinkman, A.B., Zeeuwen, P.L., Schalkwijk, J., Zhou, H., Marks, H., and Bogaard, E.H.J. van den

Abstract

29 maart 2021, Contains fulltext : 235970.pdf (Publisher’s version ) (Open Access)

Published
2021

6. Clonotypic Features of Rearranged Immunoglobulin Genes Yield Personalized Biomarkers for Minimal Residual Disease Monitoring in Multiple Myeloma

Author

Langerhorst, P., Brinkman, A.B., VanDuijn, M.M., Wessels, H.J., Groenen, P.J.T.A., Joosten, I., Gool, A.J. van, Gloerich, J., Scheijen, B., Jacobs, J.F.M., Langerhorst, P., Brinkman, A.B., VanDuijn, M.M., Wessels, H.J., Groenen, P.J.T.A., Joosten, I., Gool, A.J. van, Gloerich, J., Scheijen, B., and Jacobs, J.F.M.

Abstract

Contains fulltext : 235603.pdf (Publisher’s version ) (Closed access)

Published
2021

7. Pan-cancer analysis of whole genomes

Author

Campbell, P.J., Getz, G., Korbel, J.O., Stuart, J.M., Jennings, J.L., Stein, L.D., Brinkman, A.B., Span, P.N., Sweep, F.C.G.J., Campbell, P.J., Getz, G., Korbel, J.O., Stuart, J.M., Jennings, J.L., Stein, L.D., Brinkman, A.B., Span, P.N., and Sweep, F.C.G.J.

Abstract

Contains fulltext : 217736.pdf (publisher's version ) (Open Access)

Published
2020

8. Comprehensive evaluation of methods to assess overall and cell-specific immune infiltrates in breast cancer

Author

Nederlof, Iris, Bortoli, Davide De, Bareche, Yacine, Nguyen, Bastien, Maaker, Michiel de, Hooijer, Gerrit K.J., Brinkman, A.B., Buisseret, L., Kok, M, Smid, M, Eynden, G.G. Van den, Hudecek, J., Sotiriou, C., Larsimont, D., Biganzoli, Elia, Salgado, R., Desmedt, Christine, Nederlof, Iris, Bortoli, Davide De, Bareche, Yacine, Nguyen, Bastien, Maaker, Michiel de, Hooijer, Gerrit K.J., Brinkman, A.B., Buisseret, L., Kok, M, Smid, M, Eynden, G.G. Van den, Hudecek, J., Sotiriou, C., Larsimont, D., Biganzoli, Elia, Salgado, R., and Desmedt, Christine

Abstract

Contains fulltext : 227297.pdf (publisher's version ) (Open Access)

Published
2019

9. Integrative Proteomic Profiling Reveals PRC2-Dependent Epigenetic Crosstalk Maintains Ground-State Pluripotency

Author

Mierlo, G. van, Dirks, R.A.M., Clerck, Laura De, Brinkman, A.B., Huth, Michelle, Kloet, S.L., Kroeze, L., Jansen, J.H., Vermeulen, Michiel, Dhaenens, Maarten, Marks, Hendrik, Mierlo, G. van, Dirks, R.A.M., Clerck, Laura De, Brinkman, A.B., Huth, Michelle, Kloet, S.L., Kroeze, L., Jansen, J.H., Vermeulen, Michiel, Dhaenens, Maarten, and Marks, Hendrik

Abstract

Contains fulltext : 200091.pdf (Publisher’s version ) (Open Access)

Published
2019

11. Comprehensive evaluation of methods to assess overall and cell-specific immune infiltrates in breast cancer

Author

Nederlof, I. (Iris), De Bortoli, D. (Davide), Bareche, Y. (Yacine), Nguyen, B. (Bastien), De Maaker, M. (Michiel), Hooijer, J., Buisseret, L. (Laurence), Kok, M. (Marleen), Smid, M. (Marcel), Eynden, G. van den, Brinkman, A.B. (Arie B.), Hudecek, J. (Jan), Koster, J. (Jan), Sotiriou, C. (Christos), Larsimont, D. (Denis), Martens, J.W.M. (John), Vijver, M.J. (Marc ), Horlings, H.M. (Hugo M.), Salgado, R. (Roberto), Biganzoli, L. (Laura), Desmedt, C. (Christine), Nederlof, I. (Iris), De Bortoli, D. (Davide), Bareche, Y. (Yacine), Nguyen, B. (Bastien), De Maaker, M. (Michiel), Hooijer, J., Buisseret, L. (Laurence), Kok, M. (Marleen), Smid, M. (Marcel), Eynden, G. van den, Brinkman, A.B. (Arie B.), Hudecek, J. (Jan), Koster, J. (Jan), Sotiriou, C. (Christos), Larsimont, D. (Denis), Martens, J.W.M. (John), Vijver, M.J. (Marc ), Horlings, H.M. (Hugo M.), Salgado, R. (Roberto), Biganzoli, L. (Laura), and Desmedt, C. (Christine)

Abstract

Background: Breast cancer (BC) immune infiltrates play a critical role in tumor progression and response to treatment. Besides stromal tumor infiltrating lymphocytes (sTILs) which have recently reached level 1B evidence as a prognostic marker in triple negative BC, a plethora of methods to assess immune infiltration exists, and it is unclear how these compare to each other and if they can be used interchangeably. Methods: Two experienced pathologists scored sTIL, intra-tumoral TIL (itTIL), and 6 immune cell types (CD3+, CD4+, CD8+, CD20+, CD68+, FOXP3+) in the International Cancer Genomics Consortium breast cancer cohort using hematoxylin and eosin-stained (n = 243) and immunohistochemistry-stained tissue microarrays (n = 254) and whole slides (n = 82). The same traits were evaluated using transcriptomic- and methylomic-based deconvolution methods or signatures. Results: The concordance correlation coefficient (CCC) between pathologists for sTIL was very good (0.84) and for cell-specific immune infiltrates slightly lower (0.63-0.66). Comparison between tissue microarray and whole slide pathology scores revealed systematically higher values in whole slides (ratio 2.60-5.98). The Spearman correlations between microscopic sTIL and transcriptomic- or methylomic-based assessment of immune infiltr

Published
2019
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12. Mutational signatures impact the breast cancer transcriptome and distinguish mitotic from immune response pathways

Author

Martens, J.W.M., Smid, M., Rodriguez-Gonzalez, G., Sieuwerts, A.M., Prager-Van der Smissen, W.J.C., Van der Vlugt-Daane, M.V., Van Galen, A., Nik-Zainal, S., Staaf, J., Brinkman, A.B., Van De Vijver, M.J., Richardson, A.L., Berentsen, K., Caldas, C., Butler, A., Martin, S., Davies, H.D., Debets, R., Meijer-Van Gelder, M.E., Van Deurzen, C.H.M., Ramakrishna, M.R., Ringner, M., Viari, A., Birney, E., Borresen-Dale, A.L., Stunnenberg, H.G., Stratton, M., and Foekens, J.A.

Subjects
Molecular Biology
Abstract

Item does not contain fulltext

Published
2016

13. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Author

Glodzik, D. (Dominik), Morganella, S. (Sandro), Davies, H. (Helen), Simpson, P.T. (Peter T.), Li, Y. (Yilong), Zou, X. (Xueqing), Diez-Perez, J. (Javier), Staaf, J. (Johan), Alexandrov, L.B. (Ludmil), Smid, M. (Marcel), Brinkman, A.B. (Arie B.), Rye, I.H. (Inga Hansine), Russnes, H. (Hege), Raine, (Keiran), Purdie, C.A. (Colin A.), Lakhani, S. (Sunil), Thompson, A.M. (Alastair M.), Birney, E. (Ewan), Stunnenberg, H. (Henk), Vijver, M.J. (Marc ), Martens, J.W.M. (John), Borresen-Dale, A.-L. (Anne-Lise), Richardson, A.L. (Andrea), Kong, G. (Gu), Viari, A. (Alain), Easton, D.F. (Douglas), Evan, G. (Gerard), Campbell, P.J. (Peter), Stratton, M.R. (Michael R.), Nik-Zainal, S. (Serena), Glodzik, D. (Dominik), Morganella, S. (Sandro), Davies, H. (Helen), Simpson, P.T. (Peter T.), Li, Y. (Yilong), Zou, X. (Xueqing), Diez-Perez, J. (Javier), Staaf, J. (Johan), Alexandrov, L.B. (Ludmil), Smid, M. (Marcel), Brinkman, A.B. (Arie B.), Rye, I.H. (Inga Hansine), Russnes, H. (Hege), Raine, (Keiran), Purdie, C.A. (Colin A.), Lakhani, S. (Sunil), Thompson, A.M. (Alastair M.), Birney, E. (Ewan), Stunnenberg, H. (Henk), Vijver, M.J. (Marc ), Martens, J.W.M. (John), Borresen-Dale, A.-L. (Anne-Lise), Richardson, A.L. (Andrea), Kong, G. (Gu), Viari, A. (Alain), Easton, D.F. (Douglas), Evan, G. (Gerard), Campbell, P.J. (Peter), Stratton, M.R. (Michael R.), and Nik-Zainal, S. (Serena)

Abstract

Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be

Published
2017
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14. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers

Author

Glodzik, D., Morganella, S., Davies, H., Simpson, P.T., Li, Y., Zou, X., Diez-Perez, J., Staaf, J., Alexandrov, L.B., Smid, M., Brinkman, A.B., Rye, I.H., Russnes, H., Raine, K., Purdie, C.A., Lakhani, S.R., Thompson, A.M., Birney, E., Stunnenberg, H.G, Van De Vijver, M.J., Martens, J.W.M., Borresen-Dale, A.-L., Richardson, A.L., Kong, G., Viari, A., Easton, D., Evan, G., Campbell, P.J., Stratton, M.R., Nik-Zainal, S., Glodzik, D., Morganella, S., Davies, H., Simpson, P.T., Li, Y., Zou, X., Diez-Perez, J., Staaf, J., Alexandrov, L.B., Smid, M., Brinkman, A.B., Rye, I.H., Russnes, H., Raine, K., Purdie, C.A., Lakhani, S.R., Thompson, A.M., Birney, E., Stunnenberg, H.G, Van De Vijver, M.J., Martens, J.W.M., Borresen-Dale, A.-L., Richardson, A.L., Kong, G., Viari, A., Easton, D., Evan, G., Campbell, P.J., Stratton, M.R., and Nik-Zainal, S.

Abstract

Contains fulltext : 168881.pdf (Publisher’s version ) (Closed access)

Published
2017

15. The topography of mutational processes in breast cancer genomes

Author

Morganella, S., Alexandrov, L.B., Glodzik, D., Zou, X.Q., Davies, H., Staaf, J., Sieuwerts, A.M., Brinkman, A.B., Martin, S., Ramakrishna, M., Butler, A., Kim, H.Y., Borg, A., Sotiriou, C., Futreal, P.A., Campbell, P.J., Span, P.N., Van Laere, S., Lakhani, S.R., Eyfjord, J.E., Thompson, A.M., Stunnenberg, H.G., de Vijver, M.J.V., Martens, J.W.M., Borresen-Dale, A.L., Richardson, A.L., Kong, G., Thomas, G, Sale, J., Rada, C., Stratton, M.R., Birney, E., Nik-Zainal, S., Morganella, S., Alexandrov, L.B., Glodzik, D., Zou, X.Q., Davies, H., Staaf, J., Sieuwerts, A.M., Brinkman, A.B., Martin, S., Ramakrishna, M., Butler, A., Kim, H.Y., Borg, A., Sotiriou, C., Futreal, P.A., Campbell, P.J., Span, P.N., Van Laere, S., Lakhani, S.R., Eyfjord, J.E., Thompson, A.M., Stunnenberg, H.G., de Vijver, M.J.V., Martens, J.W.M., Borresen-Dale, A.L., Richardson, A.L., Kong, G., Thomas, G, Sale, J., Rada, C., Stratton, M.R., Birney, E., and Nik-Zainal, S.

Abstract

Contains fulltext : 158784.pdf (publisher's version ) (Open Access), Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.

Published
2016

16. Landscape of somatic mutations in 560 breast cancer whole-genome sequences

Author

Nik-Zainal, S., Davies, H., Staaf, J., Ramakrishna, M., Glodzik, D., Zou, X., Martincorena, I., Alexandrov, L.B., Martin, S., Wedge, D.C., Loo, P. Van, Ju, Y.S., Smid, M., Brinkman, A.B., Morganella, S., Aure, M.R., Lingjaerde, O.C., Langerod, A., Ringner, M., Ahn, S.M., Boyault, S., Brock, J.E., Broeks, A., Butler, A., Desmedt, C., Dirix, L., Dronov, S., Fatima, A., Foekens, J.A., Gerstung, M., Hooijer, G.K.J., Jang, S.J., Jones, D.R., Kim, H.Y., King, T.A., Krishnamurthy, S., Lee, H.J., Lee, J.Y., Li, Y., McLaren, S., Menzies, A., Mustonen, V., O'Meara, S., Pauporte, I., Pivot, X., Purdie, C.A., Raine, K., Ramakrishnan, K., Rodriguez-Gonzalez, F.G., Romieu, G., Sieuwerts, A.M., Simpson, P.T., Shepherd, R., Stebbings, L., Stefansson, O.A., Teague, J., Tommasi, S., Treilleux, I., Eynden, G.G. Van den, Vermeulen, P., Vincent-Salomon, A., Yates, L., Caldas, C., Veer, L. van 't, Tutt, A., Knappskog, S., Tan, B.K.T., Jonkers, J., Borg, A., Ueno, N.T., Sotiriou, C., Viari, A., Futreal, P.A., Campbell, P.J., Span, P.N., Laere, S. van, Lakhani, S.R., Eyfjord, J.E., Thompson, A.M., Birney, E., Stunnenberg, H.G., Vijver, M.J. van de, Martens, J.W.M., Borresen-Dale, A.L., Richardson, A.L., Kong, G., Thomas, G, Stratton, M.R., Nik-Zainal, S., Davies, H., Staaf, J., Ramakrishna, M., Glodzik, D., Zou, X., Martincorena, I., Alexandrov, L.B., Martin, S., Wedge, D.C., Loo, P. Van, Ju, Y.S., Smid, M., Brinkman, A.B., Morganella, S., Aure, M.R., Lingjaerde, O.C., Langerod, A., Ringner, M., Ahn, S.M., Boyault, S., Brock, J.E., Broeks, A., Butler, A., Desmedt, C., Dirix, L., Dronov, S., Fatima, A., Foekens, J.A., Gerstung, M., Hooijer, G.K.J., Jang, S.J., Jones, D.R., Kim, H.Y., King, T.A., Krishnamurthy, S., Lee, H.J., Lee, J.Y., Li, Y., McLaren, S., Menzies, A., Mustonen, V., O'Meara, S., Pauporte, I., Pivot, X., Purdie, C.A., Raine, K., Ramakrishnan, K., Rodriguez-Gonzalez, F.G., Romieu, G., Sieuwerts, A.M., Simpson, P.T., Shepherd, R., Stebbings, L., Stefansson, O.A., Teague, J., Tommasi, S., Treilleux, I., Eynden, G.G. Van den, Vermeulen, P., Vincent-Salomon, A., Yates, L., Caldas, C., Veer, L. van 't, Tutt, A., Knappskog, S., Tan, B.K.T., Jonkers, J., Borg, A., Ueno, N.T., Sotiriou, C., Viari, A., Futreal, P.A., Campbell, P.J., Span, P.N., Laere, S. van, Lakhani, S.R., Eyfjord, J.E., Thompson, A.M., Birney, E., Stunnenberg, H.G., Vijver, M.J. van de, Martens, J.W.M., Borresen-Dale, A.L., Richardson, A.L., Kong, G., Thomas, G, and Stratton, M.R.

Abstract

Item does not contain fulltext, We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

Published
2016

17. Landscape of somatic mutations in 560 breast cancer whole-genome sequences

Author

Nik-Zainal, S. (Serena), Davies, H. (Helen), Staaf, J. (Johan), Ramakrishna, M. (Manasa), Glodzik, D. (Dominik), Zou, X. (Xueqing), Martincorena, I. (Inigo), Alexandrov, L.B. (Ludmil), Martin, S. (Sandra), Wedge, D.C. (David), Loo, P. (Peter) van, Ju, Y.S. (Young Seok), Smid, M. (Marcel), Brinkman, A.B. (Arie B.), Morganella, S. (Sandro), Aure, M.R. (Miriam R.), Lingjærde, O.C. (Ole Christian), Langerød, A. (Anita), Ringnér, M. (Markus), Ahn, S.-M. (Sung-Min), Boyault, S. (Sandrine), Brock, J.E. (Jane E.), Broeks, A. (Annegien), Butler, A. (Adam), Desmedt, C. (Christine), Dirix, L.Y. (Luc), Dronov, S. (Serge), Fatima, A. (Aquila), Foekens, J.A. (John), Gerstung, M. (Moritz), Hooijer, J., Jang, S.J. (Se Jin), Jones, D.R. (David R.), Kim, H.-Y. (Hyung-Yong), King, T.A. (Tari A.), Krishnamurthy, S. (Savitri), Lee, H.J. (Hee Jin), Lee, J.-Y. (Jeong-Yeon), Li, Y. (Yilong), McLaren, S. (Stuart), Menzies, D., Mustonen, V. (Ville), O'Meara, S. (Sarah), Pauporté, I. (Iris), Pivot, X. (Xavier), Purdie, C.A. (Colin A.), Raine, (Keiran), Ramakrishnan, K. (Kamna), Rodriguez-Gonzalez, F.G. (F. German), Romieu, G. (Gilles), Sieuwerts, A.M. (Anieta), Simpson, P.T. (Peter T.), Shepherd, R. (Rebecca), Stebbings, L.A. (Lucy), Stefansson, O.A. (Olafur A.), Teague, J. (Jon), Tommasi, S. (Stefania), Treilleux, I. (Isabelle), Eynden, G. van den, Vermeulen, P.B. (Peter), Vincent-Salomon, A. (Anne), Yates, L.R. (Lucy), Caldas, C. (Carlos), Veer, L.J. (Laura) van 't, Tutt, A. (Andrew), Knappskog, S. (Stian), Tan, B.K.T. (Benita Kiat Tee), Jonkers, J. (Jos), Borg, Å. (Åke), Ueno, N.T. (Naoto T.), Sotiriou, C. (Christos), Viari, A. (Alain), Futreal, P.A. (Andrew), Campbell, P.J. (Peter), Span, P.N. (Paul), Laere, S.J. (Steven) van, Lakhani, S. (Sunil), Eyfjord, J., Thompson, A.M. (Alastair M.), Birney, E. (Ewan), Stunnenberg, H. (Henk), Vijver, M.J. (Marc ), Martens, J.W.M. (John), Borresen-Dale, A.-L. (Anne-Lise), Richardson, A.L. (Andrea), Kong, G. (Gu), Thomas, G. (Gilles), Stratton, M.R. (Michael), Nik-Zainal, S. (Serena), Davies, H. (Helen), Staaf, J. (Johan), Ramakrishna, M. (Manasa), Glodzik, D. (Dominik), Zou, X. (Xueqing), Martincorena, I. (Inigo), Alexandrov, L.B. (Ludmil), Martin, S. (Sandra), Wedge, D.C. (David), Loo, P. (Peter) van, Ju, Y.S. (Young Seok), Smid, M. (Marcel), Brinkman, A.B. (Arie B.), Morganella, S. (Sandro), Aure, M.R. (Miriam R.), Lingjærde, O.C. (Ole Christian), Langerød, A. (Anita), Ringnér, M. (Markus), Ahn, S.-M. (Sung-Min), Boyault, S. (Sandrine), Brock, J.E. (Jane E.), Broeks, A. (Annegien), Butler, A. (Adam), Desmedt, C. (Christine), Dirix, L.Y. (Luc), Dronov, S. (Serge), Fatima, A. (Aquila), Foekens, J.A. (John), Gerstung, M. (Moritz), Hooijer, J., Jang, S.J. (Se Jin), Jones, D.R. (David R.), Kim, H.-Y. (Hyung-Yong), King, T.A. (Tari A.), Krishnamurthy, S. (Savitri), Lee, H.J. (Hee Jin), Lee, J.-Y. (Jeong-Yeon), Li, Y. (Yilong), McLaren, S. (Stuart), Menzies, D., Mustonen, V. (Ville), O'Meara, S. (Sarah), Pauporté, I. (Iris), Pivot, X. (Xavier), Purdie, C.A. (Colin A.), Raine, (Keiran), Ramakrishnan, K. (Kamna), Rodriguez-Gonzalez, F.G. (F. German), Romieu, G. (Gilles), Sieuwerts, A.M. (Anieta), Simpson, P.T. (Peter T.), Shepherd, R. (Rebecca), Stebbings, L.A. (Lucy), Stefansson, O.A. (Olafur A.), Teague, J. (Jon), Tommasi, S. (Stefania), Treilleux, I. (Isabelle), Eynden, G. van den, Vermeulen, P.B. (Peter), Vincent-Salomon, A. (Anne), Yates, L.R. (Lucy), Caldas, C. (Carlos), Veer, L.J. (Laura) van 't, Tutt, A. (Andrew), Knappskog, S. (Stian), Tan, B.K.T. (Benita Kiat Tee), Jonkers, J. (Jos), Borg, Å. (Åke), Ueno, N.T. (Naoto T.), Sotiriou, C. (Christos), Viari, A. (Alain), Futreal, P.A. (Andrew), Campbell, P.J. (Peter), Span, P.N. (Paul), Laere, S.J. (Steven) van, Lakhani, S. (Sunil), Eyfjord, J., Thompson, A.M. (Alastair M.), Birney, E. (Ewan), Stunnenberg, H. (Henk), Vijver, M.J. (Marc ), Martens, J.W.M. (John), Borresen-Dale, A.-L. (Anne-Lise), Richardson, A.L. (Andrea), Kong, G. (Gu), Thomas, G. (Gilles), and Stratton, M.R. (Michael)

Abstract

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

Published
2016
Full Text
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18. The topography of mutational processes in breast cancer genomes

Author

Morganella, S. (Sandro), Alexandrov, L.B. (Ludmil), Glodzik, D. (Dominik), Zou, X. (Xueqing), Davies, H. (Helen), Staaf, J. (Johan), Sieuwerts, A.M. (Anieta), Brinkman, A.B. (Arie B.), Martin, S. (Sandra), Ramakrishna, M. (Manasa), Butler, A. (Adam), Kim, H.-Y. (Hyung-Yong), Borg, Å. (Åke), Sotiriou, C. (Christos), Futreal, P.A. (P. Andrew), Campbell, P.J. (Peter), Span, P.N. (Paul), Laere, S.J. (Steven) van, Lakhani, S. (Sunil), Eyfjord, J., Thompson, A.M. (Alastair M.), Stunnenberg, H. (Henk), Vijver, M.J. (Marc ), Martens, J.W.M. (John), Borresen-Dale, A.-L. (Anne-Lise), Richardson, A.L. (Andrea), Kong, G. (Gu), Thomas, G. (Gilles), Sale, J. (Julian), Rada, C. (Cristina), Stratton, M.R. (Michael), Birney, E. (Ewan), Nik-Zainal, S. (Serena), Morganella, S. (Sandro), Alexandrov, L.B. (Ludmil), Glodzik, D. (Dominik), Zou, X. (Xueqing), Davies, H. (Helen), Staaf, J. (Johan), Sieuwerts, A.M. (Anieta), Brinkman, A.B. (Arie B.), Martin, S. (Sandra), Ramakrishna, M. (Manasa), Butler, A. (Adam), Kim, H.-Y. (Hyung-Yong), Borg, Å. (Åke), Sotiriou, C. (Christos), Futreal, P.A. (P. Andrew), Campbell, P.J. (Peter), Span, P.N. (Paul), Laere, S.J. (Steven) van, Lakhani, S. (Sunil), Eyfjord, J., Thompson, A.M. (Alastair M.), Stunnenberg, H. (Henk), Vijver, M.J. (Marc ), Martens, J.W.M. (John), Borresen-Dale, A.-L. (Anne-Lise), Richardson, A.L. (Andrea), Kong, G. (Gu), Thomas, G. (Gilles), Sale, J. (Julian), Rada, C. (Cristina), Stratton, M.R. (Michael), Birney, E. (Ewan), and Nik-Zainal, S. (Serena)

Abstract

Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Furthermore, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.

Published
2016
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19. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration

Author

Smid, M., Rodriguez-Gonzalez, F.G., Sieuwerts, A.M., Salgado, R., Smissen, W.J. Prager-Van der, Vlugt-Daane, M.V., Galen, A. van, Nik-Zainal, S., Staaf, J., Brinkman, A.B., Vijver, M.J. van de, Richardson, A.L., Fatima, A., Berentsen, K., Butler, A., Martin, S., Davies, H.R., Debets, R., Gelder, M.E. Meijer-van, Deurzen, C.H. van, MacGrogan, G., Eynden, G.G. Van den, Purdie, C., Thompson, A.M., Caldas, C., Span, P.N, Simpson, P.T., Lakhani, S.R., Laere, S. van, Desmedt, C., Ringner, M., Tommasi, S., Eyford, J., Broeks, A., Vincent-Salomon, A., Futreal, P.A., Knappskog, S., King, T., Thomas, G, Viari, A., Langerod, A., Borresen-Dale, A.L., Birney, E., Stunnenberg, H.G., Stratton, M., Foekens, J.A., Martens, J.W.M., Smid, M., Rodriguez-Gonzalez, F.G., Sieuwerts, A.M., Salgado, R., Smissen, W.J. Prager-Van der, Vlugt-Daane, M.V., Galen, A. van, Nik-Zainal, S., Staaf, J., Brinkman, A.B., Vijver, M.J. van de, Richardson, A.L., Fatima, A., Berentsen, K., Butler, A., Martin, S., Davies, H.R., Debets, R., Gelder, M.E. Meijer-van, Deurzen, C.H. van, MacGrogan, G., Eynden, G.G. Van den, Purdie, C., Thompson, A.M., Caldas, C., Span, P.N, Simpson, P.T., Lakhani, S.R., Laere, S. van, Desmedt, C., Ringner, M., Tommasi, S., Eyford, J., Broeks, A., Vincent-Salomon, A., Futreal, P.A., Knappskog, S., King, T., Thomas, G, Viari, A., Langerod, A., Borresen-Dale, A.L., Birney, E., Stunnenberg, H.G., Stratton, M., Foekens, J.A., and Martens, J.W.M.

Abstract

Contains fulltext : 163364.pdf (publisher's version ) (Open Access), A recent comprehensive whole genome analysis of a large breast cancer cohort was used to link known and novel drivers and substitution signatures to the transcriptome of 266 cases. Here, we validate that subtype-specific aberrations show concordant expression changes for, for example, TP53, PIK3CA, PTEN, CCND1 and CDH1. We find that CCND3 expression levels do not correlate with amplification, while increased GATA3 expression in mutant GATA3 cancers suggests GATA3 is an oncogene. In luminal cases the total number of substitutions, irrespective of type, associates with cell cycle gene expression and adverse outcome, whereas the number of mutations of signatures 3 and 13 associates with immune-response specific gene expression, increased numbers of tumour-infiltrating lymphocytes and better outcome. Thus, while earlier reports imply that the sheer number of somatic aberrations could trigger an immune-response, our data suggests that substitutions of a particular type are more effective in doing so than others.

Published
2016

20. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives

Author

Spruijt, C.G., Gnerlich, F., Smits, A.H., Pfaffeneder, T., Jansen, P.W.T.C., Bauer, C., Munzel, M., Wagner, M., Müller, M., Khan, F., Eberl, H.C., Mensinga, A., Brinkman, A.B., Lephikov, K., Muller, U., Walter, J., Boelens, R., van Ingen, H., Leonhardt, H., Carell, T., Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., and Sub NMR Spectroscopy

Subjects
DNA repair, DNA damage, Ubiquitin-Protein Ligases, Regulatory Factor X Transcription Factors, Biology, DNA-binding protein, General Biochemistry, Genetics and Molecular Biology, Mass Spectrometry, DNA Glycosylases, chemistry.chemical_compound, Cytosine, Kruppel-Like Factor 4, Mice, Proto-Oncogene Proteins, Animals, Molecular Biology, Embryonic Stem Cells, 5-Hydroxymethylcytosine, Biochemistry, Genetics and Molecular Biology(all), Stem Cells, Brain, DNA Methylation, Molecular biology, Chromatin, Cell biology, DNA-Binding Proteins, 5-Methylcytosine, DNA demethylation, chemistry, DNA methylation, Oxidation-Reduction, Transcription Factors
Abstract

SummaryTet proteins oxidize 5-methylcytosine (mC) to generate 5-hydroxymethyl (hmC), 5-formyl (fC), and 5-carboxylcytosine (caC). The exact function of these oxidative cytosine bases remains elusive. We applied quantitative mass-spectrometry-based proteomics to identify readers for mC and hmC in mouse embryonic stem cells (mESC), neuronal progenitor cells (NPC), and adult mouse brain tissue. Readers for these modifications are only partially overlapping, and some readers, such as Rfx proteins, display strong specificity. Interactions are dynamic during differentiation, as for example evidenced by the mESC-specific binding of Klf4 to mC and the NPC-specific binding of Uhrf2 to hmC, suggesting specific biological roles for mC and hmC. Oxidized derivatives of mC recruit distinct transcription regulators as well as a large number of DNA repair proteins in mouse ES cells, implicating the DNA damage response as a major player in active DNA demethylation.

Published
2013

21. Regulation of DNA methylation patterns by ck2-mediated phosphorylation of dnmt3a

Author

Deplus, R., Blanchon, L., Rajavelu, A., Boukaba, A., Defrance, M., Luciani, J., Rothe, F., Dedeurwaerder, S., Denis, H., Brinkman, A.B., Simmer, F., Muller, F., Bertin, B., Berdasco, M., Putmans, P., Calonne, E., Litchfield, D.W., Launoit, Y. de, Jurkowski, T.P., Stunnenberg, H.G., Bock, C., Sotiriou, C., Fraga, M.F., Esteller, M., Jeltsch, A., Fuks, F., Deplus, R., Blanchon, L., Rajavelu, A., Boukaba, A., Defrance, M., Luciani, J., Rothe, F., Dedeurwaerder, S., Denis, H., Brinkman, A.B., Simmer, F., Muller, F., Bertin, B., Berdasco, M., Putmans, P., Calonne, E., Litchfield, D.W., Launoit, Y. de, Jurkowski, T.P., Stunnenberg, H.G., Bock, C., Sotiriou, C., Fraga, M.F., Esteller, M., Jeltsch, A., and Fuks, F.

Abstract

Contains fulltext : 131557.pdf (publisher's version ) (Open Access)

Published
2014

22. Genome-wide binding of mbd2 reveals strong preference for highly methylated loci

Author

Menafra, R., Brinkman, A.B., Matarese, F., Franci, G., Bartels, S.J., Nguyen, L. Thi Ngoc, Shimbo, T., Wade, P.A., Hubner, N.C., Stunnenberg, H.G., Menafra, R., Brinkman, A.B., Matarese, F., Franci, G., Bartels, S.J., Nguyen, L. Thi Ngoc, Shimbo, T., Wade, P.A., Hubner, N.C., and Stunnenberg, H.G.

Abstract

Contains fulltext : 128075.pdf (publisher's version ) (Open Access)

Published
2014

24. The Lrp family of transcriptional regulators

Author

Brinkman, A.B., Ettema, T.J.G., de Vos, W.M., and van der Oost, J.

Subjects
pap phase variation, dna-binding, Microbiology, bkd operon, sulfolobus-solfataricus, global regulator, Microbiologie, escherichia-coli, lipids (amino acids, peptides, and proteins), activate transcription, protein, VLAG, pseudomonas-putida, self-association
Abstract

Genome analysis has revealed that members of the Lrp family of transcriptional regulators are widely distributed among prokaryotes, both bacteria and archaea. The archetype Leucine-responsive Regulatory Protein from Escherichia coli is a global regulator involved in modulating a variety of metabolic functions, including the catabolism and anabolism of amino acids as well as pili synthesis. Most Lrp homologues, however, appear to act as specific regulators of amino acid metabolism-related genes. Like most prokaryotic transcriptional regulators, Lrp-like regulators consist of a DNA-binding domain and a ligand-binding domain. The crystal structure of the Pyrococcus furiosus LrpA revealed an N-terminal domain with a common helixturnhelix fold, and a C-terminal domain with a typical -sandwich fold. The latter regulatory domain constitutes a novel ligand-binding site and has been designated RAM. Database analysis reveals that the RAM domain is present in many prokaryotic genomes, potentially encoding (1) Lrp-homologues, when fused to a DNA-binding domain (2) enzymes, when fused as a potential regulatory domain to a catalytic domain, and (3) stand-alone RAM modules with unknown function. The architecture of Lrp regulators with two distinct domains that harbour the regulatory (effector-binding) site and the active (DNA-binding) site, and their separation by a flexible hinge region, suggests a general allosteric switch of Lrp-like regulators.

Published
2003

25. A novel ligand-binding domain involved in allosteric regulation of amino acid metabolism in prokaryotes

Author

Ettema, T.J.G., Brinkman, A.B., Tani, T.H., Rafferty, J.B., and van der Oost, J.

Subjects
Microbiologie, Life Science, Microbiology, VLAG
Abstract

A combination of sequence profile searching and structural protein analysis has revealed a novel type of small molecule binding domain that is involved in the allosteric regulation of prokaryotic amino acid metabolism. This domain, designated RAM, has been found to be fused to the DNA-binding domain of Lrp-like transcription regulators and to the catalytic domain of some metabolic enzymes, and has been found as a stand-alone module. Structural analysis of the RAM domain of Lrp reveals a -fold that is strikingly similar to that of the recently described ACT domain, a ubiquitous allosteric regulatory domain of many metabolic enzymes. However, structural alignment and re-evaluation of previous mutagenesis data suggest that the effector-binding sites of both modules are significantly different. By assuming that the RAM and ACT domains originated from a common ancestor, these observations suggest that their ligand-binding sites have evolved independently. Both domains appear to play analogous roles in controlling key steps in amino acid metabolism at the level of gene expression as well as enzyme activity.

Published
2002

26. Regulation of transcription in hyperthermophilic archaea

Author

Brinkman, A.B., Wageningen University, and W.M. de Vos

Subjects
Microbiologie, thermofiele bacteriën, thermophilic bacteria, transcription factors, transcriptiefactoren, EPS, Microbiology
Abstract

The aim of the research presented here was to insight in the mechanisms by which transcription in hyperthermophilic archaea is regulated. To accomplish this, we have aimed (I) to identify transcriptional regulatory proteins from hyperthermophilic archaea, (II) to characterize these proteins, and (III) to determine how these proteins modulate the process of transcription initiation.Chapter 1 describes the characteristics of the archaeal transcription machinery, and compiles transcription-related data that was obtained in the past two decades. The archaeal transcription machinery appears to be a simplified version of the eukaryal RNA polymerase II system, lacking various general transcription factors that are essential for eukaryal transcription initiation. However, archaeal genomes encode TFE, a homologue eukaryal TFIIEatranscription factor. Its stimulatory role in transcription is described in Chapter 2 .Although the archaeal transcription machinery is eukaryal-like, many genes encoding members of bacterial regulatory protein families can be found within archaeal genomes. Members of the Lrp family are most abundantly present in archaea and Chapter 3 describes the properties of Lrp-like proteins. When this research project was started, fully sequenced archaeal genomes just became available . Only the gene encoding LrpA from P. furiosus had previously been identified in our laboratory and by others , and our initial strategy included the characterization of this protein, which is described in Chapter 4 . LrpA was shown to negatively autoregulate its own transcription in a ligand-independent manner. The efficient production and purification of recombinant LrpA enabled crystallization of the protein and Chapter 5 describes its resolved three-dimensional structure, which is the first structure of a member of the Lrp family. Subsequently, during the participation of our laboratory in the S.solfataricus P2 genome sequencing project, we were able to identify candidate regulatory genes in a more directed, bioinformatics-based approach, resulting in the identification and characterization of LysM and ChoR. LysM is another example of an archaeal Lrp-like protein, and in Chapter 6 we have used the genomic context of LysM in the S.solfataricus genome to experimentally identify its physiological target and ligand. This study indicates for the first time that an Lrp-like protein may activate archaeal transcriptional.Besides bacterial-like regulators, archaeal genomes encode unique archaeal-specific regulators that can be identified on the basis of a present DNA-binding domain. A putative regulator for c opper ho meostasis (ChoR) was identified in the S.solfataricus genome on the basis of a predicted HTH DNA-binding domain and a metal-binding domain. In Chapter 7 it is demonstrated that ChoR is indeed a metal-responsive DNA-binding protein that is most likely involved in the repression of a heavy metal-efflux system.Chapter 8 summarizes the data presented in this thesis, and adds some concluding remarks with respect to the implications of the work.

Published
2002

27. DNA methylation code : in search of novel DNA methylation readers

Author

Stunnenberg, H.G., Brinkman, A.B., Bartels, S.J.J., Stunnenberg, H.G., Brinkman, A.B., and Bartels, S.J.J.

Abstract

Radboud Universiteit Nijmegen, 24 januari 2013, Promotor : Stunnenberg, H.G. Co-promotor : Brinkman, A.B., Contains fulltext : 100596.pdf (publisher's version ) (Open Access)

Published
2013

28. Dynamic binding of RBPJ is determined by Notch signaling status

Author

Castel, D., Mourikis, P., Bartels, S.J.J., Brinkman, A.B., Tajbakhsh, S., Stunnenberg, H.G., Castel, D., Mourikis, P., Bartels, S.J.J., Brinkman, A.B., Tajbakhsh, S., and Stunnenberg, H.G.

Abstract

Item does not contain fulltext

Published
2013

29. Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells

Author

Habibi, E., Brinkman, A.B., Arand, J., Kroeze, L., Kerstens, H.H., Matarese, F., Lepikhov, K., Gut, M., Brun-Heath, I., Hubner, N.C., Benedetti, R., Altucci, L., Jansen, J.H., Walter, J., Gut, I.G., Marks, H., Stunnenberg, H.G., Habibi, E., Brinkman, A.B., Arand, J., Kroeze, L., Kerstens, H.H., Matarese, F., Lepikhov, K., Gut, M., Brun-Heath, I., Hubner, N.C., Benedetti, R., Altucci, L., Jansen, J.H., Walter, J., Gut, I.G., Marks, H., and Stunnenberg, H.G.

Abstract

Contains fulltext : 128583.pdf (Publisher’s version ) (Closed access), The use of two kinase inhibitors (2i) enables derivation of mouse embryonic stem cells (ESCs) in the pluripotent ground state. Using whole-genome bisulfite sequencing (WGBS), we show that male 2i ESCs are globally hypomethylated compared to conventional ESCs maintained in serum. In serum, female ESCs are hypomethyated similarly to male ESCs in 2i, and DNA methylation is further reduced in 2i. Regions with elevated DNA methylation in 2i strongly correlate with the presence of H3K9me3 on endogenous retroviruses (ERVs) and imprinted loci. The methylome of male ESCs in serum parallels postimplantation blastocyst cells, while 2i stalls ESCs in a hypomethylated, ICM-like state. WGBS analysis during adaptation of 2i ESCs to serum suggests that deposition of DNA methylation is largely random, while loss of DNA methylation during reversion to 2i occurs passively, initiating at TET1 binding sites. Together, our analysis provides insight into DNA methylation dynamics in cultured ESCs paralleling early developmental processes.

Published
2013

30. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives

Author

Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub NMR Spectroscopy, Spruijt, C.G., Gnerlich, F., Smits, A.H., Pfaffeneder, T., Jansen, P.W.T.C., Bauer, C., Munzel, M., Wagner, M., Müller, M., Khan, F., Eberl, H.C., Mensinga, A., Brinkman, A.B., Lephikov, K., Muller, U., Walter, J., Boelens, R., van Ingen, H., Leonhardt, H., Carell, T., Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub NMR Spectroscopy, Spruijt, C.G., Gnerlich, F., Smits, A.H., Pfaffeneder, T., Jansen, P.W.T.C., Bauer, C., Munzel, M., Wagner, M., Müller, M., Khan, F., Eberl, H.C., Mensinga, A., Brinkman, A.B., Lephikov, K., Muller, U., Walter, J., Boelens, R., van Ingen, H., Leonhardt, H., and Carell, T.

Published
2013

31. Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk

Author

Brinkman, A.B., Gu, H., Bartels, S.J.J., Zhang, Y., Matarese, F., Simmer, F., Marks, H., Bock, C., Gnirke, A., Meissner, A., Stunnenberg, H.G., Brinkman, A.B., Gu, H., Bartels, S.J.J., Zhang, Y., Matarese, F., Simmer, F., Marks, H., Bock, C., Gnirke, A., Meissner, A., and Stunnenberg, H.G.

Abstract

Contains fulltext : 94090.pdf (preprint version ) (Open Access)

Published
2012

32. Comparative genome-wide DNA methylation analysis of colorectal tumor and matched normal tissues

Author

Simmer, F., Brinkman, A.B., Assenov, Y., Matarese, F., Kaan, A., Sabatino, L., Villanueva, A., Huertas, D., Esteller, M., Lengauer, T., Bock, C., Colantuoni, V., Altucci, L., Stunnenberg, H.G., Simmer, F., Brinkman, A.B., Assenov, Y., Matarese, F., Kaan, A., Sabatino, L., Villanueva, A., Huertas, D., Esteller, M., Lengauer, T., Bock, C., Colantuoni, V., Altucci, L., and Stunnenberg, H.G.

Abstract

Contains fulltext : 103245.pdf (publisher's version ) (Closed access)

Published
2012

33. The transcriptional regulator LrpA from the hyperthermophilic archaeon Pyrococcus furiosus is negatively autoregulated

Author

Brinkman, A.B., Dahlke, I., Tuininga, J.E., Lammers, T., Dumay, V., de Heus, E., Lebbink, J.H.G., Thomm, M., de Vos, W.M., and van der Oost, J.

Subjects
Microbiologie, Life Science, Microbiology, VLAG
Abstract

The archaeal transcriptional initiation machinery closely resembles core elements of the eukaryal polymerase II system. However, apart from the established basal archaeal transcription system, little is known about the modulation of gene expression in archaea. At present, no obvious eukaryal-like transcriptional regulators have been identified in archaea. Instead, we have previously isolated an archaeal gene, the Pyrococcus furiosus lrpA, that potentially encodes a bacterial-like transcriptional regulator. In the present study, we have for the first time addressed the actual involvement of an archaeal Lrp homologue in transcription modulation. For that purpose, we have produced LrpA in Escherichia coli. In a cell-free P. furiosus transcription system we used wild-type and mutated lrpA promoter fragments to demonstrate that the purified LrpA negatively regulates its own transcription. In addition, gel retardation analyses revealed a single protein-DNA complex, in which LrpA appeared to be present in (at least) a tetrameric conformation. The location of the LrpA binding site was further identified by DNaseI and hydroxyl radical footprinting, indicating that LrpA binds to a 46-base pair sequence that overlaps the transcriptional start site of its own promoter. The molecular basis of the transcription inhibition by LrpA is discussed.

Published
2000

35. Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis

Author

Bogdanovic, O., Long, S.W., Heeringen, S.J. van, Brinkman, A.B., Gomez-Skarmeta, J.L., Stunnenberg, H.G., Jones, P.L., Veenstra, G.J.C., Bogdanovic, O., Long, S.W., Heeringen, S.J. van, Brinkman, A.B., Gomez-Skarmeta, J.L., Stunnenberg, H.G., Jones, P.L., and Veenstra, G.J.C.

Abstract

Contains fulltext : 92410.pdf (publisher's version ) (Open Access)

Published
2011

36. Cdk2ap1/doc-1 is a bona fide subunit of the mi-2/nurd complex

Author

Spruijt, C.G., Bartels, S.J.J., Brinkman, A.B., Tjeertes, J.V., Poser, I., Stunnenberg, H.G., Vermeulen, M., Spruijt, C.G., Bartels, S.J.J., Brinkman, A.B., Tjeertes, J.V., Poser, I., Stunnenberg, H.G., and Vermeulen, M.

Abstract

Item does not contain fulltext

Published
2010

37. Quantitative comparison of genome-wide DNA methylation mapping technologies

Author

Bock, C., Tomazou, E.M., Brinkman, A.B., Muller, F., Simmer, F., Gu, H.C., Jager, N., Gnirke, A., Stunnenberg, H.G., Meissner, A., Bock, C., Tomazou, E.M., Brinkman, A.B., Muller, F., Simmer, F., Gu, H.C., Jager, N., Gnirke, A., Stunnenberg, H.G., and Meissner, A.

Abstract

Item does not contain fulltext

Published
2010

38. Pml-rar alpha/rxr alters the epigenetic landscape in acute promyelocytic leukemia

Author

Martens, J.H.A., Brinkman, A.B., Simmer, F., Francoijs, K.J., Nebbioso, A., Ferrara, F., Altucci, L., Stunnenberg, H.G., Martens, J.H.A., Brinkman, A.B., Simmer, F., Francoijs, K.J., Nebbioso, A., Ferrara, F., Altucci, L., and Stunnenberg, H.G.

Abstract

Contains fulltext : 84175.pdf (publisher's version ) (Closed access)

Published
2010

39. Whole-genome DNA methylation profiling using methylcap-seq

Author

Brinkman, A.B., Simmer, F., Ma, K., Kaan, A., Zhu, J., Stunnenberg, H.G., Brinkman, A.B., Simmer, F., Ma, K., Kaan, A., Zhu, J., and Stunnenberg, H.G.

Abstract

Contains fulltext : 83650.pdf (Publisher’s version ) (Closed access)

Published
2010

41. BD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties.

Author

Guezennec, X.S. le, Vermeulen, M., Brinkman, A.B., Hoeijmakers, W.A.M., Cohen, A., Lasonder, E., Stunnenberg, H.G., Guezennec, X.S. le, Vermeulen, M., Brinkman, A.B., Hoeijmakers, W.A.M., Cohen, A., Lasonder, E., and Stunnenberg, H.G.

Abstract

Contains fulltext : 35684.pdf (publisher's version ) (Closed access), The human genome contains a number of methyl CpG binding proteins that translate DNA methylation into a physiological response. To gain insight into the function of MBD2 and MBD3, we first applied protein tagging and mass spectrometry. We show that MBD2 and MBD3 assemble into mutually exclusive distinct Mi-2/NuRD-like complexes, called MBD2/NuRD and MBD3/NuRD. We identified DOC-1, a putative tumor suppressor, as a novel core subunit of MBD2/NuRD as well as MBD3/NuRD. PRMT5 and its cofactor MEP50 were identified as specific MBD2/NuRD interactors. PRMT5 stably and specifically associates with and methylates the RG-rich N terminus of MBD2. Chromatin immunoprecipitation experiments revealed that PRMT5 and MBD2 are recruited to CpG islands in a methylation-dependent manner in vivo and that H4R3, a substrate of PRMT, is methylated at these loci. Our data show that MBD2/NuRD and MBD3/NuRD are distinct protein complexes with different biochemical and functional properties.

Published
2006

42. Molecular characterization of a conserved archaeal copper resistance (cop) gene cluster and its copper-responsive regulator in Sulfolobus solfataricus P2

Author

Ettema, T.J.G., Brinkman, A.B., Lamers, P.P., Kornet, N.G., Vos, W.M. de, van der Oost, J., Ettema, T.J.G., Brinkman, A.B., Lamers, P.P., Kornet, N.G., Vos, W.M. de, and van der Oost, J.

Abstract

Contains fulltext : 164892.pdf (Publisher’s version ) (Closed access), Using a comparative genomics approach, a copper resistance gene cluster has been identified in multiple archaeal genomes. The cop cluster is predicted to encode a metallochaperone (CopM), a P-type copper-exporting ATPase (CopA) and a novel, archaea-specific transcriptional regulator (CopT) which might control the expression of the cop genes. Sequence analysis revealed that CopT has an N-terminal DNA-binding helix-turn-helix domain and a C-terminal TRASH domain; TRASH is a novel domain which has recently been proposed to be uniquely involved in metal-binding in sensors, transporters and trafficking proteins in prokaryotes. The present study describes the molecular characterization of the cop gene cluster in the thermoacidophilic crenarchaeon Sulfolobus solfataricus. The polycistronic copMA transcript was found to accumulate in response to growth-inhibiting copper concentrations, whereas copT transcript abundance appeared to be constitutive. DNA-binding assays revealed that CopT binds to the copMA promoter at multiple sites, both upstream and downstream of the predicted TATA-BRE site. Copper was found to specifically modulate the affinity of DNA binding by CopT. This study describes a copper-responsive operon in archaea, a new family of archaeal DNA-binding proteins, and supports the idea that this domain plays a prominent role in the archaeal copper response. A model is proposed for copper-responsive transcriptional regulation of the copMA gene cluster.

Published
2006

43. Histone modification patterns associated with the human X chromosome

Author

Brinkman, A.B., Roelofsen, T., Pennings, S.W., Martens, J.H.A., Jenuwein, T., Stunnenberg, H.G., Brinkman, A.B., Roelofsen, T., Pennings, S.W., Martens, J.H.A., Jenuwein, T., and Stunnenberg, H.G.

Abstract

Item does not contain fulltext, X inactivation is associated with chromosome-wide establishment of inactive chromatin. Although this is classically regarded as facultative heterochromatin that is uniform in nature, the exact distribution of associated epigenetic marks is not well defined. Here we have analysed histone modifications in human somatic cells within two selected regions of the X chromosome. Intergenic, coding and promoter regions are segregated into differentially marked chromatin. H3K27me3 is most prominent in intergenic and silenced coding regions, but is associated with some active coding regions as well. Histone H3/H4 acetylation and H3K4me3 are locally enriched at promoter regions but do not necessarily mark continuing transcription. Remarkably, H3K9me3 is predominant in coding regions of active genes, a phenomenon that is not restricted to the X chromosome. These results argue against the exclusiveness of individual marks to heterochromatin or euchromatin, but rather suggest that composite patterns of interdependent or mutually exclusive modifications together signal the gene expression status.

Published
2006

44. Structural insight into gene transcriptional regulation and effector binding by the Lrp/AsnC family

Author

Thaw, P., Sedelnikova, S.E., Muranova, T., Wiese, S., Ayora, S., Alonso, J.C., Brinkman, A.B., Akerboom, A.P., van der Oost, J., Rafferty, J.B., Thaw, P., Sedelnikova, S.E., Muranova, T., Wiese, S., Ayora, S., Alonso, J.C., Brinkman, A.B., Akerboom, A.P., van der Oost, J., and Rafferty, J.B.

Abstract

The Lrp/AsnC family of transcriptional regulatory proteins is found in both archaea and bacteria. Members of the family influence cellular metabolism in both a global (Lrp) and specific (AsnC) manner, often in response to exogenous amino acid effectors. In the present study we have determined both the first bacterial and the highest resolution structures for members of the family. Escherichia coli AsnC is a specific gene regulator whose activity is triggered by asparagine binding. Bacillus subtilis LrpC is a global regulator involved in chromosome condensation. Our AsnC-asparagine structure is the first for a regulator¿effector complex and is revealed as an octameric disc. Key ligand recognition residues are identified together with a route for ligand access. The LrpC structure reveals a stable octamer supportive of a topological role in dynamic DNA packaging. The structures yield significant clues to the functionality of Lrp/AsnC-type regulators with respect to ligand binding and oligomerization states as well as to their role in specific and global DNA regulation.

Published
2006

45. Targeted discovery tools: proteomics and chromatin immunoprecipitation-on-chip

Author

Guezennec, X.S. le, Brinkman, A.B., Vermeulen, M., Denissov, S., Gazziola, C., Lohrum, M.A.E., Stunnenberg, H.G., Guezennec, X.S. le, Brinkman, A.B., Vermeulen, M., Denissov, S., Gazziola, C., Lohrum, M.A.E., and Stunnenberg, H.G.

Abstract

Item does not contain fulltext, Despite the availability of several completely sequenced genomes, we are still, for the most part, ignorant about how genes interact and regulate each other within a given cell type to specify identity, function and cellular memory. A realistic model of cellular regulation based on current knowledge indicates that many interacting networks operate at the epigenetic, transcriptional, translational and post-translational levels, with feedback between the various levels. Protein-protein and protein-DNA interactions help to define which genes may be activated in a particular cell, and determine whether external cues cause activation or repression. New technologies, e.g. proteomics using mass spectrometry, high-density DNA or oligonucleotide microarrays (chips), and chromatin immunoprecipitation (ChIP), provide new and exciting tools for deciphering the pathways and proteins controlling gene expression. Analysis of these pathways offers new insight that aids targeted drug development.

Published
2005

46. Application of a newly developed ELISA for BCAR1 protein for prediction of clinical benefit of tamoxifen therapy in patients with advanced breast cancer.

Author

Dorssers, L.C., Grebenchtchikov, N.J., Brinkman, A.B., Look, M.P., Klijn, J.G.M., Geurts-Moespot, A., Span, P.N., Foekens, J.A., Sweep, C.G.J., Dorssers, L.C., Grebenchtchikov, N.J., Brinkman, A.B., Look, M.P., Klijn, J.G.M., Geurts-Moespot, A., Span, P.N., Foekens, J.A., and Sweep, C.G.J.

Abstract

Contains fulltext : 58218.pdf (publisher's version ) (Closed access)

Published
2004

47. Development of an ELISA for measurement of BCAR1 protein in human breast cancer tissue.

Author

Grebenchtchikov, N.J., Brinkman, A.B., Broekhoven, S.P. van, Jong, D. de, Geurts-Moespot, A., Span, P.N., Peters, H.A., Portengen, H., Foekens, J.A., Sweep, C.G.J., Dorssers, L.C., Grebenchtchikov, N.J., Brinkman, A.B., Broekhoven, S.P. van, Jong, D. de, Geurts-Moespot, A., Span, P.N., Peters, H.A., Portengen, H., Foekens, J.A., Sweep, C.G.J., and Dorssers, L.C.

Abstract

Contains fulltext : 58220.pdf (publisher's version ) (Closed access), BACKGROUND: High concentrations of breast cancer anti-estrogen resistance 1 (BCAR1) protein measured by Western blotting in primary breast tumor cytosols are associated with early disease progression and failure of tamoxifen therapy. The aim of the present study was to develop an ELISA to measure BCAR1 quantitatively in extracts of human breast cancer tissue. METHODS: A recombinant fragment of BCAR1 (the human homolog of murine p130Cas) was produced in bacterial M15 cells, purified, and injected into chickens and rabbits. The generated antibodies were affinity-purified and used for the construction of an ELISA. After validation, the results obtained with the ELISA were compared with Western blot findings on primary breast tumors. RESULTS: The detection limit the BCAR1 ELISA was 0.0031 microg/L, and the within-run imprecision (CV) was <20% at concentrations down to 0.004 microg/L. The within-run imprecision (CV) was 1.0-7.2%, and the between-run CV was 3.6-5.4%. There was no cross-reactivity with family member HEF1. The assay exhibited parallelism of results between serial dilutions and a mean recovery (range) of 96 (79-118)%. CONCLUSIONS: The ELISA measures BCAR1 in human breast cancer cytosols with high sensitivity and specificity. The assay can be used to confirm and to quantitatively extend previous semiquantitative Western blot data on the prognostic and predictive value of BCAR1 in human breast cancer; it can also be applied for other diseases.

Published
2004

48. The prognostic value of BCAR1 in patients with primary breast cancer.

Author

Dorssers, L.C., Grebenchtchikov, N.J., Brinkman, A.B., Look, M.P., Broekhoven, S.P. van, Jong, D. de, Peters, H.A., Portengen, H., Meijer-van Gelder, M.E., Klijn, J.G.M., Tienoven, T.H. van, Geurts-Moespot, A., Span, P.N., Foekens, J.A., Sweep, C.G.J., Dorssers, L.C., Grebenchtchikov, N.J., Brinkman, A.B., Look, M.P., Broekhoven, S.P. van, Jong, D. de, Peters, H.A., Portengen, H., Meijer-van Gelder, M.E., Klijn, J.G.M., Tienoven, T.H. van, Geurts-Moespot, A., Span, P.N., Foekens, J.A., and Sweep, C.G.J.

Abstract

Contains fulltext : 57138.pdf (publisher's version ) (Closed access), PURPOSE: BCAR1, the human homologue of the rat p130Cas protein, was identified in a functional screen for human breast cancer cell proliferation resistant to antiestrogen drugs. Here, we study the prognostic value of quantitative BCAR1 levels in a large series of breast cancer specimens. EXPERIMENTAL DESIGN: A specific ELISA was developed to measure BCAR1 protein levels in 2593 primary breast tumor cytosols. Tumor levels of BCAR1 were correlated with relapse-free survival (RFS) and overall survival (OS) and compared with collected data on urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1). RESULTS: In tumor cytosols, BCAR1 protein levels varied between 0.02 and 23 ng/mg protein. BCAR1 levels exhibited a positive correlation with steroid hormone receptor levels, age and menopausal status, and uPA and PAI-1 levels. The level of BCAR1 (continuous or categorized as low, intermediate, or high) was inversely related with RFS and OS time. Multivariate analysis showed that BCAR1 levels contributed independently to a base model containing the traditional prognostic factors for both RFS and OS (both P < 0.0001). When added together with uPA and PAI-1 in the multivariate model, BCAR1 contributed independently of PAI-1 and was favored over uPA. Interaction tests allowed for additional analyses of BCAR1 protein levels in clinically relevant subgroups stratified by nodal and menopausal status. CONCLUSIONS: The quantitative BCAR1 protein level represents a prognostic factor for RFS and OS in primary breast cancer, independent of the traditional prognostic factors and the other novel marker PAI-1.

Published
2004

49. Transcription of the Rod-Shaped Viruses SIRV1 and SIRV2 of the Hyperthermophilic Archaeon Sulfolobus

Author

Kessler, A., Brinkman, A.B., van der Oost, J., Prangishvili, D., Kessler, A., Brinkman, A.B., van der Oost, J., and Prangishvili, D.

Abstract

The double-stranded DNA genomes of the crenarchaeal rudiviruses SIRV1 (32 kb) and SIRV2 (35 kb) were previously sequenced. Here we present results of the analysis of gene expression of these viruses at different time points after infection of the host cell, Sulfolobus islandicus, and of the mapping of transcriptional start sites. Transcription of both genomes starts simultaneously at multiple sites spread over the total length of the genome and from both strands. The earliest time point when viral transcripts could be detected in cells was 30 min after infection. At this time point all the viral genes, except one, were transcribed. Many genes were clustered and appeared to be transcribed as polycistronic messengers. Although the coat protein-encoding gene was initially also transcribed as a polycistronic messenger, an abundant monocistronic transcript of this gene was detected 2 to 3 h after infection, just before assembly of viral particles. The expression of a single gene, adjacent to the coat protein gene, was upregulated at the late phase of infection, suggesting that it might be involved in specific processing and activation of the coat protein messenger. Start sites of 13 transcripts from the SIRV1 genome have been mapped by primer extension, and promoter sequences have been identified. Similar to host promoters, these viral promoters all contain potential binding sites for the archaeal transcription factors TATA binding protein and transcription factor B. In addition, most of them contain a virus-specific consensus element, suggesting the involvement of alternative transcription factors.

Published
2004

50. Regulation of transcription in hyperthermophilic archaea

Author

de Vos, W.M., Brinkman, A.B., de Vos, W.M., and Brinkman, A.B.

Abstract

The aim of the research presented here was to insight in the mechanisms by which transcription in hyperthermophilic archaea is regulated. To accomplish this, we have aimed (I) to identify transcriptional regulatory proteins from hyperthermophilic archaea, (II) to characterize these proteins, and (III) to determine how these proteins modulate the process of transcription initiation.Chapter 1 describes the characteristics of the archaeal transcription machinery, and compiles transcription-related data that was obtained in the past two decades. The archaeal transcription machinery appears to be a simplified version of the eukaryal RNA polymerase II system, lacking various general transcription factors that are essential for eukaryal transcription initiation. However, archaeal genomes encode TFE, a homologue eukaryal TFIIEatranscription factor. Its stimulatory role in transcription is described in Chapter 2 .Although the archaeal transcription machinery is eukaryal-like, many genes encoding members of bacterial regulatory protein families can be found within archaeal genomes. Members of the Lrp family are most abundantly present in archaea and Chapter 3 describes the properties of Lrp-like proteins. When this research project was started, fully sequenced archaeal genomes just became available . Only the gene encoding LrpA from P. furiosus had previously been identified in our laboratory and by others , and our initial strategy included the characterization of this protein, which is described in Chapter 4 . LrpA was shown to negatively autoregulate its own transcription in a ligand-independent manner. The efficient production and purification of recombinant LrpA enabled crystallization of the protein and Chapter 5 describes its resolved three-dimensional structure, which is the first structure of a member of the Lrp family. Subsequently, during the participation of our laboratory in the S.solfataricus P2 genome sequencing project, we were able to identify candidate regul

Published
2002

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