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Pan-cancer whole genome analyses of metastatic solid tumors

Peter Priestley, Jonathan Baber, Martijn P. Lolkema, Neeltje Steeghs, Ewart de Bruijn, Korneel Duyvesteyn, Susan Haidari, Arne van Hoeck, Wendy Onstenk, Paul Roepman, Charles Shale, Mircea Voda, Haiko J. Bloemendal, Vivianne C.G. Tjan-Heijnen, Carla M.L. van Herpen, Mariette Labots, Petronella O. Witteveen, Egbert F. Smit, Stefan Sleijfer, Emile E. Voest, Edwin Cuppen
doi: https://doi.org/10.1101/415133
Peter Priestley
1Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
2Hartwig Medical Foundation Australia, Sydney, Australia
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  • For correspondence: p.priestley@hartwigmedicalfoundation.nl e.cuppen@hartwigmedicalfoundation.nl
Jonathan Baber
1Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
2Hartwig Medical Foundation Australia, Sydney, Australia
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Martijn P. Lolkema
3Center for Personalized Cancer Treatment, The Netherlands
4Erasmus MC Cancer Institute, Doctor Molewaterplein 40, Rotterdam, The Netherlands
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Neeltje Steeghs
3Center for Personalized Cancer Treatment, The Netherlands
5Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Plesmanlaan 121, Amsterdam, The Netherlands
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Ewart de Bruijn
1Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
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Korneel Duyvesteyn
1Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
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Susan Haidari
1Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
3Center for Personalized Cancer Treatment, The Netherlands
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Arne van Hoeck
6Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands
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Wendy Onstenk
1Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
3Center for Personalized Cancer Treatment, The Netherlands
4Erasmus MC Cancer Institute, Doctor Molewaterplein 40, Rotterdam, The Netherlands
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Paul Roepman
1Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
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Charles Shale
2Hartwig Medical Foundation Australia, Sydney, Australia
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Mircea Voda
1Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
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Haiko J. Bloemendal
7Meander Medisch Centrum, Maatweg 3, Amersfoort, The Netherlands
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Vivianne C.G. Tjan-Heijnen
8Maastricht University Medical Center, P. Debyelaan 25, Maastricht, The Netherlands
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Carla M.L. van Herpen
9Radboud University Medical Center, Geert Grooteplein Zuid 10, Nijmegen, The Netherlands
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Mariette Labots
10VU Medical Center, De Boelelaan 1117, Amsterdam, The Netherlands
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Petronella O. Witteveen
11Cancer Center, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands
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Egbert F. Smit
3Center for Personalized Cancer Treatment, The Netherlands
5Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Plesmanlaan 121, Amsterdam, The Netherlands
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Stefan Sleijfer
3Center for Personalized Cancer Treatment, The Netherlands
4Erasmus MC Cancer Institute, Doctor Molewaterplein 40, Rotterdam, The Netherlands
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Emile E. Voest
3Center for Personalized Cancer Treatment, The Netherlands
5Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Plesmanlaan 121, Amsterdam, The Netherlands
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Edwin Cuppen
1Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
3Center for Personalized Cancer Treatment, The Netherlands
6Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands
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  • For correspondence: p.priestley@hartwigmedicalfoundation.nl e.cuppen@hartwigmedicalfoundation.nl
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Abstract

Metastatic cancer is one of the major causes of death and is associated with poor treatment efficiency. A better understanding of the characteristics of late stage cancer is required to help tailor personalised treatment, reduce overtreatment and improve outcomes. Here we describe the largest pan-cancer study of metastatic solid tumor genomes, including 2,520 whole genome-sequenced tumor-normal pairs, analyzed at a median depth of 106x and 38x respectively, and surveying over 70 million somatic variants. Metastatic lesions were found to be very diverse, with mutation characteristics reflecting those of the primary tumor types, although with high rates of whole genome duplication events (56%). Metastatic lesions are relatively homogeneous with the vast majority (96%) of driver mutations being clonal and up to 80% of tumor suppressor genes bi-allelically inactivated through different mutational mechanisms. For 62% of all patients, genetic variants that may be associated with outcome of approved or experimental therapies were detected. These actionable events were distributed over the various mutation types (single and multiple nucleotide variants, insertions and deletions, copy number alterations and structural variants) underlining the importance of comprehensive genomic tumor profiling for cancer precision medicine for advanced cancer treatment.

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Posted January 16, 2019.
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Pan-cancer whole genome analyses of metastatic solid tumors
Peter Priestley, Jonathan Baber, Martijn P. Lolkema, Neeltje Steeghs, Ewart de Bruijn, Korneel Duyvesteyn, Susan Haidari, Arne van Hoeck, Wendy Onstenk, Paul Roepman, Charles Shale, Mircea Voda, Haiko J. Bloemendal, Vivianne C.G. Tjan-Heijnen, Carla M.L. van Herpen, Mariette Labots, Petronella O. Witteveen, Egbert F. Smit, Stefan Sleijfer, Emile E. Voest, Edwin Cuppen
bioRxiv 415133; doi: https://doi.org/10.1101/415133
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Pan-cancer whole genome analyses of metastatic solid tumors
Peter Priestley, Jonathan Baber, Martijn P. Lolkema, Neeltje Steeghs, Ewart de Bruijn, Korneel Duyvesteyn, Susan Haidari, Arne van Hoeck, Wendy Onstenk, Paul Roepman, Charles Shale, Mircea Voda, Haiko J. Bloemendal, Vivianne C.G. Tjan-Heijnen, Carla M.L. van Herpen, Mariette Labots, Petronella O. Witteveen, Egbert F. Smit, Stefan Sleijfer, Emile E. Voest, Edwin Cuppen
bioRxiv 415133; doi: https://doi.org/10.1101/415133

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