Subclonal diversification of primary breast cancer revealed by multiregion sequencing

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

doi:10.1038/nm.3886

Title: Subclonal diversification of primary breast cancer revealed by multiregion sequencing

Journal Article · Mon Jun 22 00:00:00 EDT 2015 · Nature Medicine

DOI:https://doi.org/10.1038/nm.3886· OSTI ID:1236604

Yates, Lucy R. ^[1];

^[2]; Knappskog, Stian ^[3]; Desmedt, Christine ^[4]; Gundem, Gunes ^[2]; Van Loo, Peter ^[5]; Aas, Turid ^[6]; Alexandrov, Ludmil B. ^[7]; Larsimont, Denis ^[4]; Davies, Helen ^[2]; Li, Yilong ^[2]; Ju, Young Seok ^[2]; Ramakrishna, Manasa ^[2]; Haugland, Hans Kristian ^[6]; Lilleng, Peer Kaare ^[8]; Nik-Zainal, Serena ^[2]; McLaren, Stuart ^[2]; Butler, Adam ^[2]; Martin, Sancha ^[2]; Glodzik, Dominic ^[2] more »

Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Univ. of Cambridge, Cambridge (United Kingdom)
Wellcome Trust Sanger Institute, Hinxton (United Kingdom)
Univ. of Bergen, Bergen (Norway); Haukeland Univ. Hospital, Bergen (Norway)
Univ. Libre de Bruxelles, Brussels (Belgium)
Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Univ. of Leuven, Leuven (Belgium)
Haukeland Univ. Hospital, Bergen (Norway)
Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Haukeland Univ. Hospital, Bergen (Norway); Univ. of Bergen, Bergen (Norway)
Dana-Farber Cancer Institute, Boston, MA (United States)
Dana-Farber Cancer Institute, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)

Sequencing 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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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1236604

Report Number(s):: LA-UR-14-28200; nm.3886

Journal Information:: Nature Medicine, Vol. 21, Issue 7; ISSN 1078-8956

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 545 works

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