Title |
Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification
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Published in |
Genome Biology, May 2015
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DOI | 10.1186/s13059-015-0657-6 |
Pubmed ID | |
Authors |
Charlotte KY Ng, Luciano G Martelotto, Arnaud Gauthier, Huei-Chi Wen, Salvatore Piscuoglio, Raymond S Lim, Catherine F Cowell, Paul M Wilkerson, Patty Wai, Daniel N Rodrigues, Laurent Arnould, Felipe C Geyer, Silvio E Bromberg, Magali Lacroix-Triki, Frederique Penault-Llorca, Sylvia Giard, Xavier Sastre-Garau, Rachael Natrajan, Larry Norton, Paul H Cottu, Britta Weigelt, Anne Vincent-Salomon, Jorge 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 DSN1 overexpression/amplification, and the HER2 I767M mutation may be alterations that compensate for the lack of HER2 amplification in the HER2-negative components of HER2 heterogeneous breast cancers. Our results indicate that even driver genetic alterations, such as HER2 gene amplification, can be heterogeneously distributed within a cancer, and that the HER2-negative components are likely driven by genetic alterations not present in the HER2-positive components, including BRF2 and DSN1 amplification and HER2 somatic mutations. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Australia | 1 | 9% |
United States | 1 | 9% |
United Kingdom | 1 | 9% |
Unknown | 8 | 73% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 7 | 64% |
Scientists | 3 | 27% |
Science communicators (journalists, bloggers, editors) | 1 | 9% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Spain | 1 | <1% |
Sweden | 1 | <1% |
Unknown | 146 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 37 | 25% |
Researcher | 24 | 16% |
Student > Master | 14 | 9% |
Student > Bachelor | 13 | 9% |
Professor > Associate Professor | 9 | 6% |
Other | 22 | 15% |
Unknown | 29 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 33 | 22% |
Biochemistry, Genetics and Molecular Biology | 32 | 22% |
Medicine and Dentistry | 23 | 16% |
Pharmacology, Toxicology and Pharmaceutical Science | 5 | 3% |
Engineering | 5 | 3% |
Other | 10 | 7% |
Unknown | 40 | 27% |