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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-12

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

BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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. More... »

PAGES

107

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s13059-015-0657-6

    DOI

    http://dx.doi.org/10.1186/s13059-015-0657-6

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1048024169

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25994018


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