TY - JOUR
T1 - Subclonal diversification of primary breast cancer revealed by multiregion sequencing
AU - Yates, Lucy R.
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.
N1 - Funding Information:
This work is supported by the Wellcome Trust. P.J.C. is a Wellcome Trust Senior Clinical Fellow (103858/Z/14/Z). L.R.Y., Y.L. and L.B.A. are funded by Wellcome Trust PhD fellowships. S.N.-Z. is funded by a Wellcome Trust Intermediate Clinical Research Fellowship (WT100183MA). P.V.L. is a postdoctoral researcher at the Research Foundation Flanders (FWO). Work within the project is supported by the Belgian Cancer Plan–Ministry of Health, the Breast Cancer Research Foundation, the Brussels Region, the Norwegian Cancer Society, the Norwegian Health Region West and the Bergen Research Foundation. Some samples referenced in this publication will be included in the Breast Cancer Genome Analyses for the International Cancer Genome Consortium (ICGC) Working Group led by the Wellcome Trust Sanger Institute. BASIS is a part of the ICGC working group and is funded by the European Community’s Seventh Framework Programme (FP7/2010-2014) under grant agreement number 242006. This working group also encompasses a triple-negative breast cancer project funded by the Wellcome Trust (grant 077012/Z/05/Z) and a HER2+ breast cancer project funded by Institut National du Cancer (INCa). We thank B. Leirvaag, D. Ekse, N.K. Duong and C. Eriksen for technical assistance. Research performed at Los Alamos National Laboratory was carried out under the auspices of the National Nuclear Security Administration of the US Department of Energy.
Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/7/9
Y1 - 2015/7/9
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84936890500&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84936890500&partnerID=8YFLogxK
U2 - 10.1038/nm.3886
DO - 10.1038/nm.3886
M3 - Article
C2 - 26099045
AN - SCOPUS:84936890500
SN - 1078-8956
VL - 21
SP - 751
EP - 759
JO - Nature Medicine
JF - Nature Medicine
IS - 7
ER -