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

Charlotte K.Y 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. CottuBritta Weigelt, Anne Vincent-Salomon, Jorge S. Reis-Filho

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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.

Original languageEnglish
Article number107
Number of pages21
JournalGenome Biology
Publication statusPublished - 22 May 2015
Externally publishedYes

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