Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification

Genome Biology
Charlotte K Y NgJorge S Reis-Filho

Abstract

HER2 is overexpressed and amplified in approximately 15% of invasive breast cancers, and is the molecular target and predictive marker of response to anti-HER2 agents. In a subset of these cases, heterogeneous distribution of HER2 gene amplification can be found, which creates clinically challenging scenarios. Currently, breast cancers with HER2 amplification/overexpression in just over 10% of cancer cells are considered HER2-positive for clinical purposes; however, it is unclear as to whether the HER2-negative components of such tumors would be driven by distinct genetic alterations. Here we sought to characterize the pathologic and genetic features of the HER2-positive and HER2-negative components of breast cancers with heterogeneous HER2 gene amplification and to define the repertoire of potential driver genetic alterations in the HER2-negative components of these cases. We separately analyzed the HER2-negative and HER2-positive components of 12 HER2 heterogeneous breast cancers using gene copy number profiling and massively parallel sequencing, and identified potential driver genetic alterations restricted to the HER2-negative cells in each case. In vitro experiments provided functional evidence to suggest that BRF2 and DSN...Continue Reading

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Datasets Mentioned

BETA
GSE67908
SRP049005

Methods Mentioned

BETA
exome sequencing
amplicon sequencing
exome
Assay
biopsy
biopsies
transfection
Antibody
immunoprecipitation

Clinical Trials Mentioned

NCT01670877

Software Mentioned

Image Studio
MetaMorph Image Analysis
Image J
R
GitHub
ABSOLUTE
GraphPad
aCGH
GraphPad Prism

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