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1. Copy number architectures define treatment-mediated selection of lethal prostate cancer clones

Author

Hasan, A, Cremaschi, P, Wetterskog, D, Jayaram, A, Wong, S, Williams, S, Pasam, A, Trigos, A, Trujillo, B, Grist, E, Friedrich, S, Vainauskas, O, Parry, M, Ismail, M, Devlies, W, Wingate, A, Linch, M, Naceur-Lombardelli, C, Zaccaria, S, Hessey, S, Shiu, K, Bridgewater, J, Hochhauser, D, Forster, M, Lee, S, Ahmad, T, Papadatos-Pastos, D, Janes, S, Van Loo, P, Enfield, K, Mcgranahan, N, Huebner, A, Quezada, S, Beck, S, Parker, P, Enver, T, Hynds, R, Pearce, D, Falzon, M, Proctor, I, Sinclair, R, Lok, C, Rhodes, Z, Moore, D, Marafioti, T, Mitchison, M, Ellery, P, Sivakumar, M, Brandner, S, Rowan, A, Hiley, C, Veeriah, S, Shaw, H, Toncheva, A, Prymas, P, Watkins, T, Bailey, C, Martinez Ruiz, C, Litchfield, K, Al-Bakir, M, Kanu, N, Ward, S, Lim, E, Reading, J, Chain, B, Akay, M, Flanagan, A, Biswas, D, Pich, O, Dietzen, M, Puttick, C, Colliver, E, Magness, A, Angelova, M, Black, J, Lucas, O, Hill, W, Liu, W, Frankell, A, Magno, N, Athanasopoulou, F, Salgado, R, Lee, C, Grigoriadis, K, Al-Sawaf, O, Karasaki, T, Bunkum, A, Noorani, I, Benafif, S, Barbe, V, Bola, S, Leone, G, Alifrangis, C, Mcgovern, U, Thol, K, Gamble, S, Ung, S, Sahwangarrom, T, Marin, C, Pawlik, P, Lam, J, Richard, C, Vendramin, R, Dijkstra, K, Rane, J, Nicod, J, Dwornik, A, Bowles, K, Zaidi, R, Gishen, F, Stone, P, Stirling, C, Turajlic, S, Larkin, J, Pickering, L, Furness, A, Young, K, Drake, W, Edmonds, K, Hunter, N, Mangwende, M, Pearce, K, Grostate, L, Au, L, Spain, L, Shepherd, S, Yan, H, Shum, B, Tippu, Z, Hanley, B, Spencer, C, Emmerich, M, Gerard, C, Schmitt, A, Del Rosario, L, Carlyle, E, Lewis, C, Holt, L, Lucanas, A, O'Flaherty, M, Hazell, S, Mudhar, H, Messiou, C, Latifoltojar, A, Fendler, A, Byrne, F, Pallikonda, H, Lobon, I, Coulton, A, Cattin, A, Deng, D, Feng, H, Yousaf, N, Popat, S, Curtis, O, Milner-Watts, C, Stamp, G, Nye, E, Murra, A, Korteweg, J, Kelly, D, Terry, L, Biano, J, Peat, K, Kelly, K, Grieco, C, Le, M, D'Arienzo, P, Turay, E, Hill, P, Josephs, D, Irshad, S, Spicer, J, Mahadeva, U, Green, A, Stewart, R, Wright, N, Pulman, G, Mitu, R, Phillips-Boyd, S, Enting, D, Rudman, S, Ghosh, S, Karapanagiotou, E, Pintus, E, Tutt, A, Howlett, S, Brenton, J, Caldas, C, Fitzgerald, R, Jimenez-Linan, M, Provenzano, E, Cluroe, A, Paterson, A, Aitken, S, Allinson, K, Stewart, G, Mcdermott, U, Beddowes, E, Maughan, T, Ansorge, O, Campbell, P, Roxburgh, P, Fraser, S, Blyth, K, Le Quesne, J, Krebs, M, Blackhall, F, Summers, Y, Oliveira, P, Ortega-Franco, A, Dive, C, Gomes, F, Carter, M, Dransfield, J, Thomas, A, Fennell, D, Shaw, J, Wilson, C, Marrone, D, Naidu, B, Baijal, S, Tanchel, B, Langman, G, Robinson, A, Collard, M, Cockcroft, P, Ferris, C, Bancroft, H, Kerr, A, Middleton, G, Webb, J, Kadiri, S, Colloby, P, Olisemeke, B, Wilson, R, Shackleford, H, Osman, A, Tomlinson, I, Jogai, S, Holden, S, Fernandes, T, Mcneish, I, Hampton, B, Mckenzie, M, Hackshaw, A, Sharp, A, Chan, K, Farrelly, L, Bridger, H, Leslie, R, Tookman, A, Swanton, C, Jamal-Hanjani, M, Lise, S, Sandhu, S, Attard, G, Hasan A. M. M., Cremaschi P., Wetterskog D., Jayaram A., Wong S. Q., Williams S., Pasam A., Trigos A., Trujillo B., Grist E., Friedrich S., Vainauskas O., Parry M., Ismail M., Devlies W., Wingate A., Linch M., Naceur-Lombardelli C., Zaccaria S., Hessey S., Shiu K. -K., Bridgewater J., Hochhauser D., Forster M., Lee S. -M., Ahmad T., Papadatos-Pastos D., Janes S., Van Loo P., Enfield K., McGranahan N., Huebner A., Quezada S., Beck S., Parker P., Enver T., Hynds R. E., Pearce D. R., Falzon M., Proctor I., Sinclair R., Lok C. -W., Rhodes Z., Moore D., Marafioti T., Mitchison M., Ellery P., Sivakumar M., Brandner S., Rowan A., Hiley C., Veeriah S., Shaw H., Toncheva A., Prymas P., Watkins T. B. K., Bailey C., Martinez Ruiz C., Litchfield K., Al-Bakir M., Kanu N., Ward S., Lim E., Reading J., Chain B., Watkins T., Akay M., Flanagan A., Biswas D., Pich O., Dietzen M., Puttick C., Colliver E., Magness A., Angelova M., Black J., Lucas O., Hill W., Liu W. -K., Frankell A., Magno N., Athanasopoulou F., Salgado R., Lee C., Grigoriadis K., Al-Sawaf O., Karasaki T., Bunkum A., Noorani I., Benafif S., Barbe V., Bola S. K., Leone G., Alifrangis C., McGovern U., Thol K., Gamble S., Ung S. K., Sahwangarrom T., Marin C. P., Wong S., Pawlik P., Lam J. M., Richard C., Vendramin R., Dijkstra K., Rane J., Nicod J., Dwornik A., Bowles K., Zaidi R., Gishen F., Stone P., Stirling C., Turajlic S., Larkin J., Pickering L., Furness A., Young K., Drake W., Edmonds K., Hunter N., Mangwende M., Pearce K., Grostate L., Au L., Spain L., Shepherd S., Yan H., Shum B., Tippu Z., Hanley B., Spencer C., Emmerich M., Gerard C., Schmitt A. M., Del Rosario L., Carlyle E., Lewis C., Holt L., Lucanas A., O'Flaherty M., Hazell S., Mudhar H., Messiou C., Latifoltojar A., Fendler A., Byrne F., Pallikonda H., Lobon I., Coulton A., Cattin A. -L., Deng D., Feng H., Yousaf N., Popat S., Curtis O., Milner-Watts C., Stamp G., Nye E., Murra A., Korteweg J., Kelly D., Terry L., Biano J., Peat K., Kelly K., Grieco C., Le M. L., D'Arienzo P. D., Turay E., Hill P., Josephs D., Irshad S., Spicer J., Mahadeva U., Green A., Stewart R., Wright N., Pulman G., Mitu R., Phillips-Boyd S., Enting D., Rudman S., Ghosh S., Karapanagiotou E., Pintus E., Tutt A., Howlett S., Brenton J., Caldas C., Fitzgerald R., Jimenez-Linan M., Provenzano E., Cluroe A., Paterson A., Aitken S., Allinson K., Stewart G., McDermott U., Beddowes E., Maughan T., Ansorge O., Campbell P., Roxburgh P., Fraser S., Blyth K., Le Quesne J., Krebs M., Blackhall F., Summers Y., Oliveira P., Ortega-Franco A., Dive C., Gomes F., Carter M., Dransfield J., Thomas A., Fennell D., Shaw J., Wilson C., Marrone D., Naidu B., Baijal S., Tanchel B., Langman G., Robinson A., Collard M., Cockcroft P., Ferris C., Bancroft H., Kerr A., Middleton G., Webb J., Kadiri S., Colloby P., Olisemeke B., Wilson R., Shackleford H., Osman A., Tomlinson I., Jogai S., Holden S., Fernandes T., McNeish I., Hampton B., McKenzie M., Hackshaw A., Sharp A., Chan K., Farrelly L., Bridger H., Leslie R., Tookman A., Swanton C., Jamal-Hanjani M., Lise S., Sandhu S., Attard G., Hasan, A, Cremaschi, P, Wetterskog, D, Jayaram, A, Wong, S, Williams, S, Pasam, A, Trigos, A, Trujillo, B, Grist, E, Friedrich, S, Vainauskas, O, Parry, M, Ismail, M, Devlies, W, Wingate, A, Linch, M, Naceur-Lombardelli, C, Zaccaria, S, Hessey, S, Shiu, K, Bridgewater, J, Hochhauser, D, Forster, M, Lee, S, Ahmad, T, Papadatos-Pastos, D, Janes, S, Van Loo, P, Enfield, K, Mcgranahan, N, Huebner, A, Quezada, S, Beck, S, Parker, P, Enver, T, Hynds, R, Pearce, D, Falzon, M, Proctor, I, Sinclair, R, Lok, C, Rhodes, Z, Moore, D, Marafioti, T, Mitchison, M, Ellery, P, Sivakumar, M, Brandner, S, Rowan, A, Hiley, C, Veeriah, S, Shaw, H, Toncheva, A, Prymas, P, Watkins, T, Bailey, C, Martinez Ruiz, C, Litchfield, K, Al-Bakir, M, Kanu, N, Ward, S, Lim, E, Reading, J, Chain, B, Akay, M, Flanagan, A, Biswas, D, Pich, O, Dietzen, M, Puttick, C, Colliver, E, Magness, A, Angelova, M, Black, J, Lucas, O, Hill, W, Liu, W, Frankell, A, Magno, N, Athanasopoulou, F, Salgado, R, Lee, C, Grigoriadis, K, Al-Sawaf, O, Karasaki, T, Bunkum, A, Noorani, I, Benafif, S, Barbe, V, Bola, S, Leone, G, Alifrangis, C, Mcgovern, U, Thol, K, Gamble, S, Ung, S, Sahwangarrom, T, Marin, C, Pawlik, P, Lam, J, Richard, C, Vendramin, R, Dijkstra, K, Rane, J, Nicod, J, Dwornik, A, Bowles, K, Zaidi, R, Gishen, F, Stone, P, Stirling, C, Turajlic, S, Larkin, J, Pickering, L, Furness, A, Young, K, Drake, W, Edmonds, K, Hunter, N, Mangwende, M, Pearce, K, Grostate, L, Au, L, Spain, L, Shepherd, S, Yan, H, Shum, B, Tippu, Z, Hanley, B, Spencer, C, Emmerich, M, Gerard, C, Schmitt, A, Del Rosario, L, Carlyle, E, Lewis, C, Holt, L, Lucanas, A, O'Flaherty, M, Hazell, S, Mudhar, H, Messiou, C, Latifoltojar, A, Fendler, A, Byrne, F, Pallikonda, H, Lobon, I, Coulton, A, Cattin, A, Deng, D, Feng, H, Yousaf, N, Popat, S, Curtis, O, Milner-Watts, C, Stamp, G, Nye, E, Murra, A, Korteweg, J, Kelly, D, Terry, L, Biano, J, Peat, K, Kelly, K, Grieco, C, Le, M, D'Arienzo, P, Turay, E, Hill, P, Josephs, D, Irshad, S, Spicer, J, Mahadeva, U, Green, A, Stewart, R, Wright, N, Pulman, G, Mitu, R, Phillips-Boyd, S, Enting, D, Rudman, S, Ghosh, S, Karapanagiotou, E, Pintus, E, Tutt, A, Howlett, S, Brenton, J, Caldas, C, Fitzgerald, R, Jimenez-Linan, M, Provenzano, E, Cluroe, A, Paterson, A, Aitken, S, Allinson, K, Stewart, G, Mcdermott, U, Beddowes, E, Maughan, T, Ansorge, O, Campbell, P, Roxburgh, P, Fraser, S, Blyth, K, Le Quesne, J, Krebs, M, Blackhall, F, Summers, Y, Oliveira, P, Ortega-Franco, A, Dive, C, Gomes, F, Carter, M, Dransfield, J, Thomas, A, Fennell, D, Shaw, J, Wilson, C, Marrone, D, Naidu, B, Baijal, S, Tanchel, B, Langman, G, Robinson, A, Collard, M, Cockcroft, P, Ferris, C, Bancroft, H, Kerr, A, Middleton, G, Webb, J, Kadiri, S, Colloby, P, Olisemeke, B, Wilson, R, Shackleford, H, Osman, A, Tomlinson, I, Jogai, S, Holden, S, Fernandes, T, Mcneish, I, Hampton, B, Mckenzie, M, Hackshaw, A, Sharp, A, Chan, K, Farrelly, L, Bridger, H, Leslie, R, Tookman, A, Swanton, C, Jamal-Hanjani, M, Lise, S, Sandhu, S, Attard, G, Hasan A. M. M., Cremaschi P., Wetterskog D., Jayaram A., Wong S. Q., Williams S., Pasam A., Trigos A., Trujillo B., Grist E., Friedrich S., Vainauskas O., Parry M., Ismail M., Devlies W., Wingate A., Linch M., Naceur-Lombardelli C., Zaccaria S., Hessey S., Shiu K. -K., Bridgewater J., Hochhauser D., Forster M., Lee S. -M., Ahmad T., Papadatos-Pastos D., Janes S., Van Loo P., Enfield K., McGranahan N., Huebner A., Quezada S., Beck S., Parker P., Enver T., Hynds R. E., Pearce D. R., Falzon M., Proctor I., Sinclair R., Lok C. -W., Rhodes Z., Moore D., Marafioti T., Mitchison M., Ellery P., Sivakumar M., Brandner S., Rowan A., Hiley C., Veeriah S., Shaw H., Toncheva A., Prymas P., Watkins T. B. K., Bailey C., Martinez Ruiz C., Litchfield K., Al-Bakir M., Kanu N., Ward S., Lim E., Reading J., Chain B., Watkins T., Akay M., Flanagan A., Biswas D., Pich O., Dietzen M., Puttick C., Colliver E., Magness A., Angelova M., Black J., Lucas O., Hill W., Liu W. -K., Frankell A., Magno N., Athanasopoulou F., Salgado R., Lee C., Grigoriadis K., Al-Sawaf O., Karasaki T., Bunkum A., Noorani I., Benafif S., Barbe V., Bola S. K., Leone G., Alifrangis C., McGovern U., Thol K., Gamble S., Ung S. K., Sahwangarrom T., Marin C. P., Wong S., Pawlik P., Lam J. M., Richard C., Vendramin R., Dijkstra K., Rane J., Nicod J., Dwornik A., Bowles K., Zaidi R., Gishen F., Stone P., Stirling C., Turajlic S., Larkin J., Pickering L., Furness A., Young K., Drake W., Edmonds K., Hunter N., Mangwende M., Pearce K., Grostate L., Au L., Spain L., Shepherd S., Yan H., Shum B., Tippu Z., Hanley B., Spencer C., Emmerich M., Gerard C., Schmitt A. M., Del Rosario L., Carlyle E., Lewis C., Holt L., Lucanas A., O'Flaherty M., Hazell S., Mudhar H., Messiou C., Latifoltojar A., Fendler A., Byrne F., Pallikonda H., Lobon I., Coulton A., Cattin A. -L., Deng D., Feng H., Yousaf N., Popat S., Curtis O., Milner-Watts C., Stamp G., Nye E., Murra A., Korteweg J., Kelly D., Terry L., Biano J., Peat K., Kelly K., Grieco C., Le M. L., D'Arienzo P. D., Turay E., Hill P., Josephs D., Irshad S., Spicer J., Mahadeva U., Green A., Stewart R., Wright N., Pulman G., Mitu R., Phillips-Boyd S., Enting D., Rudman S., Ghosh S., Karapanagiotou E., Pintus E., Tutt A., Howlett S., Brenton J., Caldas C., Fitzgerald R., Jimenez-Linan M., Provenzano E., Cluroe A., Paterson A., Aitken S., Allinson K., Stewart G., McDermott U., Beddowes E., Maughan T., Ansorge O., Campbell P., Roxburgh P., Fraser S., Blyth K., Le Quesne J., Krebs M., Blackhall F., Summers Y., Oliveira P., Ortega-Franco A., Dive C., Gomes F., Carter M., Dransfield J., Thomas A., Fennell D., Shaw J., Wilson C., Marrone D., Naidu B., Baijal S., Tanchel B., Langman G., Robinson A., Collard M., Cockcroft P., Ferris C., Bancroft H., Kerr A., Middleton G., Webb J., Kadiri S., Colloby P., Olisemeke B., Wilson R., Shackleford H., Osman A., Tomlinson I., Jogai S., Holden S., Fernandes T., McNeish I., Hampton B., McKenzie M., Hackshaw A., Sharp A., Chan K., Farrelly L., Bridger H., Leslie R., Tookman A., Swanton C., Jamal-Hanjani M., Lise S., Sandhu S., and Attard G.

Abstract

Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10−8 and 6.4 × 10−4). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.

Published
2023

2. Immune responses following third COVID-19 vaccination are reduced in patients with hematological malignancies compared to patients with solid

Author

Fendler, A, Shepherd, STC, Au, L, Wilkinson, KA, Wu, M, Schmitt, AM, Tippu, Z, Farag, S, Rogiers, A, Harvey, R, Carlyle, E, Edmonds, K, Del Rosario, L, Lingard, K, Mangwende, M, Holt, L, Ahmod, H, Korteweg, J, Foley, T, Barber, T, Emslie-Henry, A, Caulfield-Lynch, N, Byrne, F, Shum, B, Gerard, CL, Deng, D, Kjaer, S, Song, O-R, Queval, C, Kavanagh, C, Wall, EC, Carr, EJ, Namjou, S, Caidan, S, Gavrielides, M, MacRae, JI, Kelly, G, Peat, K, Kelly, D, Murra, A, Kelly, K, O'Flaherty, M, Shea, RL, Gardner, G, Murray, D, Popat, S, Yousaf, N, Jhanji, S, Van As, N, Young, K, Furness, AJS, Pickering, L, Beale, R, Swanton, C, Crick COVID19 consortium, Gandhi, S, Gamblin, S, Bauer, DLV, Kassiotis, G, Howell, M, Nicholson, E, Walker, S, Wilkinson, RJ, Larkin, J, Turajlic, S, CAPTURE consortium, and Wellcome Trust

Subjects
Cancer Research, Crick COVID19 consortium, Oncology, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 1109 Neurosciences, CAPTURE consortium
Abstract

In this report from the CAPTURE study (NCT03226886), we demonstrate that a third dose of COVID-19 vaccine boosts neutralizing antibody (NAb) and cellular responses in patients with cancer, including those that had undetectable NAb titers (NAbT) following two vaccine doses or for whom NAbT waned. We have noted that one key member of the CAPTURE consortium—Sanjay Popat—was inadvertently not included in the author list. We now include him as a co-author. There are no additional changes to the declaration of interests statement, since Dr. Popat declares no competing conflict of interest. This author list change is now reflected in the online version of this letter.

Published
2022
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4. Zakkendragers

Author

Goey, FMM, Korteweg, J., and Department of History

Published
2009

8. Haven van Rotterdam

Author

Goey, FMM, Korteweg, J., and Department of History

Published
2009

9. Maritieme cultuur

Author

Legêne, S., Korteweg, J., History, and CLUE+

Published
2009

11. De Zee als Horizon

Author

Legêne, S., Korteweg, J., History, and CLUE+

Published
2009

12. Holland-Amerka Lijn

Author

Goey, FMM, Korteweg, J., and Department of History

Published
2009

13. High Tech Bio : rijpadensysteem Korteweg

Author

Korteweg, J., Beek, K. Van, Wiel, C. Van Der, Bleeker, P., Vermeulen, B., Hilhorst, M., Steenhuizen, J., Groeneveld, R., Dolfing, J., Rappoldt, C., Korteweg, J., Beek, K. Van, Wiel, C. Van Der, Bleeker, P., Vermeulen, B., Hilhorst, M., Steenhuizen, J., Groeneveld, R., Dolfing, J., and Rappoldt, C.

Abstract

Powerpointpresentatie over grondbewerking in het voorjaar met het High Tech Bio rijpadensysteem

Published
2008

14. Onderzoek preciese rijpadenteelt voor de biologische landbouw

Author

Vermeulen, B., Korteweg, J., Vermeulen, B., and Korteweg, J.

Abstract

Onderzoekspresentatie met resultaten uit een vier-jarig vergelijkingsonderzoek naar de voordelen voor gewas, milieu en bedrijfsrendement bij het geruik van vaste rijpaden

Published
2008

18. II. Meloplasty

Author

Korteweg, J. A.

Subjects
Original Memoirs
Published
1891

19. Onderzoek preciese rijpadenteelt voor de biologische landbouw

Author

Vermeulen, B., Korteweg, J., Vermeulen, B., and Korteweg, J.

Abstract

Onderzoekspresentatie met resultaten uit een vier-jarig vergelijkingsonderzoek naar de voordelen voor gewas, milieu en bedrijfsrendement bij het geruik van vaste rijpaden

20. High Tech Bio : rijpadensysteem Korteweg

Author

Korteweg, J., Beek, K. van, Wiel, C. van der, Bleeker, P., Vermeulen, B., Hilhorst, M., Steenhuizen, J., Groeneveld, R., Dolfing, J., Rappoldt, C., Korteweg, J., Beek, K. van, Wiel, C. van der, Bleeker, P., Vermeulen, B., Hilhorst, M., Steenhuizen, J., Groeneveld, R., Dolfing, J., and Rappoldt, C.

Abstract

Powerpointpresentatie over grondbewerking in het voorjaar met het High Tech Bio rijpadensysteem

23. Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways.

Author

Spain L, Coulton A, Lobon I, Rowan A, Schnidrig D, Shepherd STC, Shum B, Byrne F, Goicoechea M, Piperni E, Au L, Edmonds K, Carlyle E, Hunter N, Renn A, Messiou C, Hughes P, Nobbs J, Foijer F, van den Bos H, Wardenaar R, Spierings DCJ, Spencer C, Schmitt AM, Tippu Z, Lingard K, Grostate L, Peat K, Kelly K, Sarker S, Vaughan S, Mangwende M, Terry L, Kelly D, Biano J, Murra A, Korteweg J, Lewis C, O'Flaherty M, Cattin AL, Emmerich M, Gerard CL, Pallikonda HA, Lynch J, Mason R, Rogiers A, Xu H, Huebner A, McGranahan N, Al Bakir M, Murai J, Naceur-Lombardelli C, Borg E, Mitchison M, Moore DA, Falzon M, Proctor I, Stamp GWH, Nye EL, Young K, Furness AJS, Pickering L, Stewart R, Mahadeva U, Green A, Larkin J, Litchfield K, Swanton C, Jamal-Hanjani M, and Turajlic S

Subjects
Humans, Mutation, Evolution, Molecular, DNA, Melanoma pathology, Brain Neoplasms
Abstract

Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma., Significance: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275., (©2023 The Authors; Published by the American Association for Cancer Research.)

Published
2023
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24. Sotrovimab restores neutralization against current Omicron subvariants in patients with blood cancer.

Author

Wu MY, Shepherd STC, Fendler A, Carr EJ, Au L, Harvey R, Dowgier G, Hobbs A, Herman LS, Ragno M, Adams L, Schmitt AM, Tippu Z, Shum B, Farag S, Rogiers A, O'Reilly N, Bawumia P, Smith C, Carlyle E, Edmonds K, Del Rosario L, Lingard K, Mangwende M, Holt L, Ahmod H, Korteweg J, Foley T, Barber T, Hepworth S, Emslie-Henry A, Caulfield-Lynch N, Byrne F, Deng D, Williams B, Brown M, Caidan S, Gavrielides M, MacRae JI, Kelly G, Peat K, Kelly D, Murra A, Kelly K, O'Flaherty M, Popat S, Yousaf N, Jhanji S, Tatham K, Cunningham D, Van As N, Young K, Furness AJS, Pickering L, Beale R, Swanton C, Gandhi S, Gamblin S, Bauer DLV, Kassiotis G, Howell M, Walker S, Nicholson E, Larkin J, Wall EC, and Turajlic S

Subjects
Humans, SARS-CoV-2, COVID-19, Hematologic Neoplasms drug therapy, Neoplasms
Abstract

Wu et al. report that patients with hematologic malignancies have reduced immunity against SARS-CoV-2 Omicron subvariants and Sotrovimab retains neutralizing capacity against all tested Omicron subvariants., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Published
2023
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25. Functional immune responses against SARS-CoV-2 variants of concern after fourth COVID-19 vaccine dose or infection in patients with blood cancer.

Author

Fendler A, Shepherd STC, Au L, Wu M, Harvey R, Wilkinson KA, Schmitt AM, Tippu Z, Shum B, Farag S, Rogiers A, Carlyle E, Edmonds K, Del Rosario L, Lingard K, Mangwende M, Holt L, Ahmod H, Korteweg J, Foley T, Barber T, Emslie-Henry A, Caulfield-Lynch N, Byrne F, Deng D, Kjaer S, Song OR, Queval CJ, Kavanagh C, Wall EC, Carr EJ, Caidan S, Gavrielides M, MacRae JI, Kelly G, Peat K, Kelly D, Murra A, Kelly K, O'Flaherty M, Shea RL, Gardner G, Murray D, Popat S, Yousaf N, Jhanji S, Tatham K, Cunningham D, Van As N, Young K, Furness AJS, Pickering L, Beale R, Swanton C, Gandhi S, Gamblin S, Bauer DLV, Kassiotis G, Howell M, Nicholson E, Walker S, Wilkinson RJ, Larkin J, and Turajlic S

Subjects
Humans, Antibodies, Neutralizing, Antibodies, Viral, BNT162 Vaccine, Clinical Studies as Topic, Immunity, SARS-CoV-2, COVID-19 prevention & control, COVID-19 Vaccines immunology, Neoplasms
Abstract

Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2022
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26. Omicron neutralising antibodies after third COVID-19 vaccine dose in patients with cancer.

Author

Fendler A, Shepherd STC, Au L, Wu M, Harvey R, Schmitt AM, Tippu Z, Shum B, Farag S, Rogiers A, Carlyle E, Edmonds K, Del Rosario L, Lingard K, Mangwende M, Holt L, Ahmod H, Korteweg J, Foley T, Barber T, Emslie-Henry A, Caulfield-Lynch N, Byrne F, Deng D, Kjaer S, Song OR, Queval C, Kavanagh C, Wall EC, Carr EJ, Caidan S, Gavrielides M, MacRae JI, Kelly G, Peat K, Kelly D, Murra A, Kelly K, O'Flaherty M, Shea RL, Gardner G, Murray D, Yousaf N, Jhanji S, Tatham K, Cunningham D, Van As N, Young K, Furness AJS, Pickering L, Beale R, Swanton C, Gandhi S, Gamblin S, Bauer DLV, Kassiotis G, Howell M, Nicholson E, Walker S, Larkin J, and Turajlic S

Subjects
Antibodies, Neutralizing immunology, Antibodies, Viral immunology, COVID-19 Vaccines, Humans, SARS-CoV-2, COVID-19 prevention & control, Neoplasms
Abstract

Competing Interests: DC has received institutional grant funding from MedImmune/AstraZeneca, Clovis, Eli Lilly, 4SC, Bayer, Celgene, Leap, Roche. DLVB has received grant funding from AstraZeneca. CS is funded by CRUK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence (C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, the Novo Nordisk Foundation (ID16584), a Royal Society Professorship Enhancement award (RP/EA/180007), the National Institute of Health Research (NIHR) Biomedical Research Centre at University College London Hospitals, the CRUK University College London Centre, the Experimental Cancer Medicine Centre and the Breast Cancer Research Foundation (BCRF 20-157). This work was supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational research grant (SU2C-AACR-DT23-17 to SMD and AES). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. CS received an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union's Horizon 2020 research and innovation programme (835297). CS is a Royal Society Napier Research Professor (RP150154). ST is funded by Cancer Research UK (A29911); the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC10988), the UK Medical Research Council (FC10988), and the Wellcome Trust (FC10988); the NIHR Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research (grant reference number A109), the Royal Marsden Cancer Charity, The Rosetrees Trust (A2204), Ventana Medical Systems (grant reference numbers 10467 and 10530), the National Institute of Health (U01 CA247439) and Melanoma Research Alliance (686061). ST has received speaking fees from Roche, Astra Zeneca, Novartis, and Ipsen. ST has the following patents filed: Indel mutations as a therapeutic target and predictive biomarker PCTGB2018/051892 PCTGB2018/051893 and Clear Cell Renal Cell Carcinoma Biomarkers P113326GB. All other authors declare no competing interests. AF, STCS, LA, MW, and RH contributed equally.

Published
2022
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27. Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study.

Author

Fendler A, Shepherd STC, Au L, Wilkinson KA, Wu M, Byrne F, Cerrone M, Schmitt AM, Joharatnam-Hogan N, Shum B, Tippu Z, Rzeniewicz K, Boos LA, Harvey R, Carlyle E, Edmonds K, Del Rosario L, Sarker S, Lingard K, Mangwende M, Holt L, Ahmod H, Korteweg J, Foley T, Bazin J, Gordon W, Barber T, Emslie-Henry A, Xie W, Gerard CL, Deng D, Wall EC, Agua-Doce A, Namjou S, Caidan S, Gavrielides M, MacRae JI, Kelly G, Peat K, Kelly D, Murra A, Kelly K, O'Flaherty M, Dowdie L, Ash N, Gronthoud F, Shea RL, Gardner G, Murray D, Kinnaird F, Cui W, Pascual J, Rodney S, Mencel J, Curtis O, Stephenson C, Robinson A, Oza B, Farag S, Leslie I, Rogiers A, Iyengar S, Ethell M, Messiou C, Cunningham D, Chau I, Starling N, Turner N, Welsh L, van As N, Jones RL, Droney J, Banerjee S, Tatham KC, O'Brien M, Harrington K, Bhide S, Okines A, Reid A, Young K, Furness AJS, Pickering L, Swanton C, Gandhi S, Gamblin S, Bauer DLV, Kassiotis G, Kumar S, Yousaf N, Jhanji S, Nicholson E, Howell M, Walker S, Wilkinson RJ, Larkin J, and Turajlic S

Subjects
Aged, Antibodies, Neutralizing blood, Antibodies, Neutralizing immunology, Antibodies, Viral blood, Antibodies, Viral immunology, BNT162 Vaccine administration & dosage, COVID-19 blood, COVID-19 immunology, ChAdOx1 nCoV-19 administration & dosage, Female, Humans, Immunity, Cellular, Immunogenicity, Vaccine, Male, Middle Aged, Neoplasms blood, Neoplasms complications, Prospective Studies, T-Lymphocytes immunology, BNT162 Vaccine immunology, COVID-19 prevention & control, ChAdOx1 nCoV-19 immunology, Neoplasms immunology, SARS-CoV-2 immunology
Abstract

Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) ( NCT03226886 ) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic., (© 2021. The Author(s).)

Published
2021
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28. Population screening for variant Creutzfeldt-Jakob disease using a novel blood test: diagnostic accuracy and feasibility study.

Author

Jackson GS, Burk-Rafel J, Edgeworth JA, Sicilia A, Abdilahi S, Korteweg J, Mackey J, Thomas C, Wang G, Schott JM, Mummery C, Chinnery PF, Mead S, and Collinge J

Subjects
Animals, Cattle, Cohort Studies, Creutzfeldt-Jakob Syndrome epidemiology, Cross-Sectional Studies, Feasibility Studies, Hematologic Tests trends, Humans, Prion Diseases blood, Prion Diseases diagnosis, Prion Diseases epidemiology, Retrospective Studies, United Kingdom epidemiology, United States epidemiology, Creutzfeldt-Jakob Syndrome blood, Creutzfeldt-Jakob Syndrome diagnosis, Hematologic Tests methods, Population Surveillance methods
Abstract

Importance: Our study indicates a prototype blood-based variant Creutzfeldt-Jakob disease (vCJD) assay has sufficient sensitivity and specificity to justify a large study comparing vCJD prevalence in the United Kingdom with a bovine spongiform encephalopathy-unexposed population. In a clinical diagnostic capacity, the assay's likelihood ratios dramatically change an individual's pretest disease odds to posttest probabilities and can confirm vCJD infection., Objectives: To determine the diagnostic accuracy of a prototype blood test for vCJD and hence its suitability for clinical use and for screening prion-exposed populations., Design, Setting, and Participants: Retrospective, cross-sectional diagnostic study of blood samples from national blood collection and prion disease centers in the United States and United Kingdom. Anonymized samples were representative of the US blood donor population (n = 5000), healthy UK donors (n = 200), patients with nonprion neurodegenerative diseases (n = 352), patients in whom a prion disease diagnosis was likely (n = 105), and patients with confirmed vCJD (n = 10)., Main Outcome and Measure: Presence of vCJD infection determined by a prototype test (now in clinical diagnostic use) that captures, enriches, and detects disease-associated prion protein from whole blood using stainless steel powder., Results: The assay's specificity among the presumed negative American donor samples was 100% (95% CI, 99.93%-100%) and was confirmed in a healthy UK cohort (100% specificity; 95% CI, 98.2%-100%). Of potentially cross-reactive blood samples from patients with nonprion neurodegenerative diseases, no samples tested positive (100% specificity; 95% CI, 98.9%-100%). Among National Prion Clinic referrals in whom a prion disease diagnosis was likely, 2 patients with sporadic CJD tested positive (98.1% specificity; 95% CI, 93.3%-99.8%). Finally, we reconfirmed but could not refine our previous sensitivity estimate in a small blind panel of samples from unaffected individuals and patients with vCJD (70% sensitivity; 95% CI, 34.8%-93.3%)., Conclusions and Relevance: In conjunction with the assay's established high sensitivity (71.4%; 95% CI, 47.8%-88.7%), the extremely high specificity supports using the assay to screen for vCJD infection in prion-exposed populations. Additionally, the lack of cross-reactivity and false positives in a range of nonprion neurodegenerative diseases supports the use of the assay in patient diagnosis.

Published
2014
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29. A highly specific blood test for vCJD.

Author

Jackson GS, Burk-Rafel J, Edgeworth JA, Sicilia A, Abdilahi S, Korteweg J, Mackey J, Thomas C, Wang G, Mead S, and Collinge J

Subjects
False Positive Reactions, Hematologic Tests methods, Humans, Predictive Value of Tests, Prevalence, Prions blood, Sensitivity and Specificity, Creutzfeldt-Jakob Syndrome blood, Creutzfeldt-Jakob Syndrome diagnosis, Hematologic Tests standards
Published
2014
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30. Down modulation of human TLR3 function by a monoclonal antibody.

Author

Duffy KE, Lamb RJ, San Mateo LR, Jordan JL, Canziani G, Brigham-Burke M, Korteweg J, Cunningham M, Beck HS, Carton J, Giles-Komar J, Duchala C, Sarisky RT, and Mbow ML

Subjects
Animals, Antibodies, Blocking metabolism, Binding Sites, Antibody, Cell Line, Cell Line, Transformed, Female, Humans, Mice, Mice, Inbred BALB C, Pilot Projects, Toll-Like Receptor 3 metabolism, Antibodies, Monoclonal metabolism, Toll-Like Receptor 3 antagonists & inhibitors, Toll-Like Receptor 3 immunology
Abstract

Toll-like receptors are a family of pattern-recognition receptors that contribute to the innate immune response. Toll-like receptor 3 (TLR3) signals in response to foreign, endogenous and synthetic ligands including viral dsRNA, bacterial RNA, mitochondrial RNA, endogenous necrotic cell mRNA and the synthetic dsRNA analog, poly(I:C). We have generated a monoclonal antibody (mAb CNTO2424) that recognizes the extracellular domain (ECD) of human TLR3 in a conformation-dependent manner. CNTO2424 down-regulates poly(I:C)-induced production of IL-6, IL-8, MCP-1, RANTES, and IP-10 in human lung epithelial cells. In addition, mAb CNTO2424 was able to interfere with the known TLR3-dependent signaling pathways, namely NF-kappaB, IRF-3/ISRE, and p38 MAPK. The generation of this neutralizing anti-TLR3 mAb provides a unique tool to better understand TLR3 signaling and potential cross-talk between TLR3 and other molecules.

Published
2007
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31. Comparison of platelet membrane markers for the detection of platelet activation in vitro and during platelet storage and cardiopulmonary bypass surgery.

Author

Metzelaar MJ, Korteweg J, Sixma JJ, and Nieuwenhuis HK

Subjects
Antibodies, Monoclonal, Antigens, Differentiation, Myelomonocytic blood, Blood Platelets immunology, Flow Cytometry, Humans, In Vitro Techniques, Platelet Endothelial Cell Adhesion Molecule-1, Platelet Membrane Glycoproteins metabolism, Reference Values, Thrombin pharmacology, Blood Platelets metabolism, Blood Preservation, Cardiopulmonary Bypass, Platelet Activation physiology
Abstract

Changes in the platelet plasma membrane during activation were investigated by flow cytometry in a comparative study of in vitro platelet activation during platelet storage and cardiopulmonary bypass surgery. We studied changes in the expression of the plasma membrane glycoproteins lb and llla and CD31 antigen (PECAM-1), the alpha-granule membrane proteins GMP-140 (PADGEM, CD62 antigen) and GMP-33, and lysosomal integral membrane protein-CD63. A simultaneous change in the expression of the various glycoproteins induced by platelet activation was seen after thrombin stimulation in vitro and during platelet storage. Platelet activation in vivo in patients showed a more complex change in the expression of membrane glycoproteins. During cardiopulmonary bypass the mean fluorescence values for glycoprotein llla, GMP-33, and the percentage of GMP-140 and lysosome integral membrane protein-CD63 expressing platelets increased significantly. CD31 antigen expression was significantly decreased, whereas glycoprotein lb expression did not change. We conclude that flow cytometry is useful for the detection of changes in the expression of membrane glycoproteins induced by platelet activation in vitro and during platelet storage. Application of flow cytometry as clinical tool for screening platelet activation in patients or for identification of a prethrombotic state requires evaluation of a panel of platelet membrane glycoproteins because the changes in membrane expression may be different in various clinical situations.

Published
1993

32. Biochemical characterization of PECAM-1 (CD31 antigen) on human platelets.

Author

Metzelaar MJ, Korteweg J, Sixma JJ, and Nieuwenhuis HK

Subjects
Antibodies, Monoclonal, Blotting, Western, Cells, Cultured, Electrophoresis, Gel, Two-Dimensional, Endothelium, Vascular immunology, Fluorescent Antibody Technique, Humans, Isoelectric Focusing, Microscopy, Immunoelectron, Platelet Adhesiveness immunology, Platelet Aggregation immunology, Platelet Endothelial Cell Adhesion Molecule-1, Precipitin Tests, Antigens, Differentiation, Myelomonocytic blood, Blood Platelets immunology, Cell Adhesion Molecules blood
Abstract

The platelet plasma membrane expresses several membrane glycoproteins with a high molecular weight. In this study we have investigated the properties of the CD31 antigen on platelets and endothelial cells using the monoclonal antibody (MoAb) RUU-PL 7E8. Comparative studies revealed that the CD31 antigen, PECAM-1 and endoCAM are the same protein. The CD31 antigen was immunoprecipitated with a molecular mass of 125 kDa nonreduced and 135 kDa reduced from Nonidet-P40 lysates of surface labeled human platelets. The relative position in two-dimensional nonreduced/reduced SDS-PAGE and IEF-PAGE, compared to other glycoproteins of similar molecular weight, was elucidated. The position of the CD31 antigen was clearly distinct from the position of the platelet membrane glycoproteins Ia, Ib, IIa, IIb, IIIa and the granule membrane protein GMP-140. Native resting platelets bound 7,760 +/- 1,670 molecules/platelet, whereas thrombin-stimulated platelets bound 14,500 +/- 3,790 molecules/platelet. Immunoelectron microscopy revealed the presence of the CD31 antigen on the membrane of both resting and thrombin-activated platelets. Immunofluorescence studies showed the presence of the CD31 antigen in the membrane of endothelial cells on sites of cell-cell contact, suggesting that the CD31 antigen might be involved in cell-cell interaction. In functional studies, MoAb RUU-PL 7E8 did not inhibit platelet aggregation, platelet adherence to the extracellular matrix of endothelial cells and purified collagen fibrils under flow conditions, nor was any influence found on endothelial cell detachment and growth.

Published
1991

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