@article{bda0e3679ef04b94bfcf20c80c1a5b02,
title = "In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer",
abstract = "Detection of minor, genetically distinct subpopulations within tumors is a key challenge in cancer genomics. Here we report STAR-FISH (specific-to-allele PCR-FISH), a novel method for the combined detection of single-nucleotide and copy number alterations in single cells in intact archived tissues. Using this method, we assessed the clinical impact of changes in the frequency and topology of PIK3CA mutation and HER2 (ERBB2) amplification within HER2-positive breast cancer during neoadjuvant therapy. We found that these two genetic events are not always present in the same cells. Chemotherapy selects for PIK3CA-mutant cells, a minor subpopulation in nearly all treatment-naive samples, and modulates genetic diversity within tumors. Treatment-associated changes in the spatial distribution of cellular genetic diversity correlated with poor long-term outcome following adjuvant therapy with trastuzumab. Our findings support the use of in situ single cell-based methods in cancer genomics and imply that chemotherapy before HER2-targeted therapy may promote treatment resistance.",
author = "Michalina Janiszewska and Lin Liu and Vanessa Almendro and Yanan Kuang and Cloud Paweletz and Sakr, {Rita A.} and Britta Weigelt and Hanker, {Ariella B.} and Sarat Chandarlapaty and King, {Tari A.} and Reis-Filho, {Jorge S.} and Arteaga, {Carlos L.} and Park, {So Yeon} and Franziska Michor and Kornelia Polyak",
note = "Funding Information: We thank E. Winer, I. Krop, B. Vogelstein and members of the Polyak and Michor laboratories for their critical reading of the manuscript and useful discussions. We thank A. Marusyk and D. Tabassum for their help with the xenograft assays, R. Witwicki for help with data processing, L. Cameron in the Dana-Farber Cancer Institute Confocal Microscopy center for her technical support, A. Richardson (Dana-Farber Cancer Institute) for providing slides from a human breast tumor with known status for the PIK3CA mutation encoding p.His1047Arg, and H. Russness and I. Rye (Oslo University Hospital) for providing the BAC probe for HER2. This work was supported by the Dana-Farber Cancer Institute Physical Sciences–Oncology Center (U54CA143798 to F.M.), the European Molecular Biology Organization (EMBO; M.J.), the Swiss National Science Foundation (M.J.), the American Cancer Society (CRP-07-234-06-COUN to C.L.A.) and the Breast Cancer Research Foundation (K.P.). Publisher Copyright: {\textcopyright} 2015 Nature America, Inc.",
year = "2015",
month = sep,
day = "29",
doi = "10.1038/ng.3391",
language = "English (US)",
volume = "47",
pages = "1212--1219",
journal = "Nature genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "10",
}