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Nat Genet. 2015 Oct;47(10):1212-9. doi: 10.1038/ng.3391. Epub 2015 Aug 24.

In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
3
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
4
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
5
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
6
Belfer Institute of Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
7
Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
8
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
9
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA.
10
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
11
Department of Medicine, Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA.
12
Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
13
Broad Institute, Cambridge, Massachusetts, USA.
14
Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.

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.

PMID:
26301495
PMCID:
PMC4589505
DOI:
10.1038/ng.3391
[Indexed for MEDLINE]
Free PMC Article

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