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

Overview

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.

publication date

  • August 24, 2015

Research

keywords

  • Breast Neoplasms
  • Genes, erbB-2
  • Genetic Heterogeneity
  • Mutation
  • Phosphatidylinositol 3-Kinases
  • Single-Cell Analysis

Identity

PubMed Central ID

  • PMC4589505

Scopus Document Identifier

  • 84942987073

Digital Object Identifier (DOI)

  • 10.1038/ng.3391

PubMed ID

  • 26301495

Additional Document Info

volume

  • 47

issue

  • 10