Subclonal diversification of primary breast cancer revealed by multiregion sequencing

Lucy R. Yates; Moritz Gerstung; Stian Knappskog; Christine Desmedt; Gunes Gundem; Peter Van Loo; Turid Aas; Ludmil B. Alexandrov; Denis Larsimont; Helen Davies; Yilong Li; Young Seok Ju; Manasa Ramakrishna; Hans Kristian Haugland; Peer Kaare Lilleng; Serena Nik-Zainal; Stuart McLaren; Adam Butler; Sancha Martin; Dominic Glodzik; Andrew Menzies; Keiran Raine; Jonathan Hinton; David Jones; Laura J. Mudie; Bing Jiang; Delphine Vincent; April Greene-Colozzi; Pierre Yves Adnet; Aquila Fatima; Marion Maetens; Michail Ignatiadis; Michael R. Stratton; Christos Sotiriou; Andrea L. Richardson; Per Eystein Lønning; David C. Wedge; Peter J. Campbell

doi:10.1038/nm.3886

Subclonal diversification of primary breast cancer revealed by multiregion sequencing

Lucy R. Yates, Moritz Gerstung, Stian Knappskog, Christine Desmedt, Gunes Gundem, Peter Van Loo, Turid Aas, Ludmil B. Alexandrov, Denis Larsimont, Helen Davies, Yilong Li, Young Seok Ju, Manasa Ramakrishna, Hans Kristian Haugland, Peer Kaare Lilleng, Serena Nik-Zainal, Stuart McLaren, Adam Butler, Sancha Martin, Dominic GlodzikAndrew Menzies, Keiran Raine, Jonathan Hinton, David Jones, Laura J. Mudie, Bing Jiang, Delphine Vincent, April Greene-Colozzi, Pierre Yves Adnet, Aquila Fatima, Marion Maetens, Michail Ignatiadis, Michael R. Stratton, Christos Sotiriou, Andrea L. Richardson, Per Eystein Lønning, David C. Wedge, Peter J. Campbell

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

444 Scopus citations

Abstract

The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.

Original language	English (US)
Pages (from-to)	751-759
Number of pages	9
Journal	Nature medicine
Volume	21
Issue number	7
DOIs	https://doi.org/10.1038/nm.3886
State	Published - Jul 9 2015
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Yates, L. R., Gerstung, M., Knappskog, S., Desmedt, C., Gundem, G., Van Loo, P., Aas, T., Alexandrov, L. B., Larsimont, D., Davies, H., Li, Y., Ju, Y. S., Ramakrishna, M., Haugland, H. K., Lilleng, P. K., Nik-Zainal, S., McLaren, S., Butler, A., Martin, S., ... Campbell, P. J. (2015). Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nature medicine, 21(7), 751-759. https://doi.org/10.1038/nm.3886

Yates, LR, Gerstung, M, Knappskog, S, Desmedt, C, Gundem, G, Van Loo, P, Aas, T, Alexandrov, LB, Larsimont, D, Davies, H, Li, Y, Ju, YS, Ramakrishna, M, Haugland, HK, Lilleng, PK, Nik-Zainal, S, McLaren, S, Butler, A, Martin, S, Glodzik, D, Menzies, A, Raine, K, Hinton, J, Jones, D, Mudie, LJ, Jiang, B, Vincent, D, Greene-Colozzi, A, Adnet, PY, Fatima, A, Maetens, M, Ignatiadis, M, Stratton, MR, Sotiriou, C, Richardson, AL, Lønning, PE, Wedge, DC & Campbell, PJ 2015, 'Subclonal diversification of primary breast cancer revealed by multiregion sequencing', Nature medicine, vol. 21, no. 7, pp. 751-759. https://doi.org/10.1038/nm.3886

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title = "Subclonal diversification of primary breast cancer revealed by multiregion sequencing",

abstract = "The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.",

author = "Yates, {Lucy R.} and Moritz Gerstung and Stian Knappskog and Christine Desmedt and Gunes Gundem and {Van Loo}, Peter and Turid Aas and Alexandrov, {Ludmil B.} and Denis Larsimont and Helen Davies and Yilong Li and Ju, {Young Seok} and Manasa Ramakrishna and Haugland, {Hans Kristian} and Lilleng, {Peer Kaare} and Serena Nik-Zainal and Stuart McLaren and Adam Butler and Sancha Martin and Dominic Glodzik and Andrew Menzies and Keiran Raine and Jonathan Hinton and David Jones and Mudie, {Laura J.} and Bing Jiang and Delphine Vincent and April Greene-Colozzi and Adnet, {Pierre Yves} and Aquila Fatima and Marion Maetens and Michail Ignatiadis and Stratton, {Michael R.} and Christos Sotiriou and Richardson, {Andrea L.} and L{\o}nning, {Per Eystein} and Wedge, {David C.} and Campbell, {Peter J.}",

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doi = "10.1038/nm.3886",

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AU - Gerstung, Moritz

AU - Knappskog, Stian

AU - Desmedt, Christine

AU - Gundem, Gunes

AU - Van Loo, Peter

AU - Aas, Turid

AU - Alexandrov, Ludmil B.

AU - Larsimont, Denis

AU - Davies, Helen

AU - Li, Yilong

AU - Ju, Young Seok

AU - Ramakrishna, Manasa

AU - Haugland, Hans Kristian

AU - Lilleng, Peer Kaare

AU - Nik-Zainal, Serena

AU - McLaren, Stuart

AU - Butler, Adam

AU - Martin, Sancha

AU - Glodzik, Dominic

AU - Menzies, Andrew

AU - Raine, Keiran

AU - Hinton, Jonathan

AU - Jones, David

AU - Mudie, Laura J.

AU - Jiang, Bing

AU - Vincent, Delphine

AU - Greene-Colozzi, April

AU - Adnet, Pierre Yves

AU - Fatima, Aquila

AU - Maetens, Marion

AU - Ignatiadis, Michail

AU - Stratton, Michael R.

AU - Sotiriou, Christos

AU - Richardson, Andrea L.

AU - Lønning, Per Eystein

AU - Wedge, David C.

AU - Campbell, Peter J.

PY - 2015/7/9

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N2 - The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.

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Subclonal diversification of primary breast cancer revealed by multiregion sequencing

Abstract

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