The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies

Lindsay Angus; Marcel Smid; Saskia M Wilting; Job van Riet; Arne Van Hoeck; Luan Nguyen; Serena Nik-Zainal; Tessa G Steenbruggen; Vivianne C G Tjan-Heijnen; Mariette Labots; Johanna M G H van Riel; Haiko J Bloemendal; Neeltje Steeghs; Martijn P Lolkema; Emile E Voest; Harmen J G van de Werken; Agnes Jager; Edwin Cuppen; Stefan Sleijfer; John W M Martens

doi:10.1038/s41588-019-0507-7

The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies

Lindsay Angus, Marcel Smid, Saskia M Wilting, Job van Riet, Arne Van Hoeck, Luan Nguyen, Serena Nik-Zainal, Tessa G Steenbruggen, Vivianne C G Tjan-Heijnen, Mariette Labots, Johanna M G H van Riel, Haiko J Bloemendal, Neeltje Steeghs, Martijn P Lolkema, Emile E Voest, Harmen J G van de Werken, Agnes Jager, Edwin Cuppen, Stefan Sleijfer, John W M Martens

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The whole-genome sequencing of prospectively collected tissue biopsies from 442 patients with metastatic breast cancer reveals that, compared to primary breast cancer, tumor mutational burden doubles, the relative contributions of mutational signatures shift and the mutation frequency of six known driver genes increases in metastatic breast cancer. Significant associations with pretreatment are also observed. The contribution of mutational signature 17 is significantly enriched in patients pretreated with fluorouracil, taxanes, platinum and/or eribulin, whereas the de novo mutational signature I identified in this study is significantly associated with pretreatment containing platinum-based chemotherapy. Clinically relevant subgroups of tumors are identified, exhibiting either homologous recombination deficiency (13%), high tumor mutational burden (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This study provides insights into the biology of metastatic breast cancer and identifies clinically useful genomic features for the future improvement of patient management.

Original language	English
Pages (from-to)	1450-1458
Number of pages	9
Journal	Nature Genetics
Volume	51
Issue number	10
Early online date	30 Sep 2019
DOIs	https://doi.org/10.1038/s41588-019-0507-7
Publication status	Published - 1 Oct 2019

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10.1038/s41588-019-0507-7

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Angus, L., Smid, M., Wilting, S. M., van Riet, J., Van Hoeck, A., Nguyen, L., Nik-Zainal, S., Steenbruggen, T. G., Tjan-Heijnen, V. C. G., Labots, M., van Riel, J. M. G. H., Bloemendal, H. J., Steeghs, N., Lolkema, M. P., Voest, E. E., van de Werken, H. J. G., Jager, A., Cuppen, E., Sleijfer, S., & Martens, J. W. M. (2019). The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies. Nature Genetics, 51(10), 1450-1458. https://doi.org/10.1038/s41588-019-0507-7

Angus, Lindsay ; Smid, Marcel ; Wilting, Saskia M ; van Riet, Job ; Van Hoeck, Arne ; Nguyen, Luan ; Nik-Zainal, Serena ; Steenbruggen, Tessa G ; Tjan-Heijnen, Vivianne C G ; Labots, Mariette ; van Riel, Johanna M G H ; Bloemendal, Haiko J ; Steeghs, Neeltje ; Lolkema, Martijn P ; Voest, Emile E ; van de Werken, Harmen J G ; Jager, Agnes ; Cuppen, Edwin ; Sleijfer, Stefan ; Martens, John W M. / The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies. In: Nature Genetics. 2019 ; Vol. 51, No. 10. pp. 1450-1458.

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title = "The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies",

abstract = "The whole-genome sequencing of prospectively collected tissue biopsies from 442 patients with metastatic breast cancer reveals that, compared to primary breast cancer, tumor mutational burden doubles, the relative contributions of mutational signatures shift and the mutation frequency of six known driver genes increases in metastatic breast cancer. Significant associations with pretreatment are also observed. The contribution of mutational signature 17 is significantly enriched in patients pretreated with fluorouracil, taxanes, platinum and/or eribulin, whereas the de novo mutational signature I identified in this study is significantly associated with pretreatment containing platinum-based chemotherapy. Clinically relevant subgroups of tumors are identified, exhibiting either homologous recombination deficiency (13%), high tumor mutational burden (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This study provides insights into the biology of metastatic breast cancer and identifies clinically useful genomic features for the future improvement of patient management.",

author = "Lindsay Angus and Marcel Smid and Wilting, {Saskia M} and {van Riet}, Job and {Van Hoeck}, Arne and Luan Nguyen and Serena Nik-Zainal and Steenbruggen, {Tessa G} and Tjan-Heijnen, {Vivianne C G} and Mariette Labots and {van Riel}, {Johanna M G H} and Bloemendal, {Haiko J} and Neeltje Steeghs and Lolkema, {Martijn P} and Voest, {Emile E} and {van de Werken}, {Harmen J G} and Agnes Jager and Edwin Cuppen and Stefan Sleijfer and Martens, {John W M}",

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Angus, L, Smid, M, Wilting, SM, van Riet, J, Van Hoeck, A, Nguyen, L, Nik-Zainal, S, Steenbruggen, TG, Tjan-Heijnen, VCG, Labots, M, van Riel, JMGH, Bloemendal, HJ, Steeghs, N, Lolkema, MP, Voest, EE, van de Werken, HJG, Jager, A, Cuppen, E, Sleijfer, S & Martens, JWM 2019, 'The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies', Nature Genetics, vol. 51, no. 10, pp. 1450-1458. https://doi.org/10.1038/s41588-019-0507-7

The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies. / Angus, Lindsay; Smid, Marcel; Wilting, Saskia M; van Riet, Job; Van Hoeck, Arne; Nguyen, Luan; Nik-Zainal, Serena; Steenbruggen, Tessa G; Tjan-Heijnen, Vivianne C G; Labots, Mariette; van Riel, Johanna M G H; Bloemendal, Haiko J; Steeghs, Neeltje; Lolkema, Martijn P; Voest, Emile E; van de Werken, Harmen J G; Jager, Agnes; Cuppen, Edwin; Sleijfer, Stefan; Martens, John W M.

In: Nature Genetics, Vol. 51, No. 10, 01.10.2019, p. 1450-1458.

Research output: Contribution to journal › Article › Academic › peer-review

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