Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification
AuthorNg, CKY; Martelotto, LG; Gauthier, A; Wen, H-C; Piscuoglio, S; Lim, RS; Cowell, CF; Wilkerson, PM; Wai, P; Rodrigues, DN; ...
Source TitleGenome Biology
University of Melbourne Author/sMartelotto, Luciano
Document TypeJournal Article
CitationsNg, C. K. Y., Martelotto, L. G., Gauthier, A., Wen, H. -C., Piscuoglio, S., Lim, R. S., Cowell, C. F., Wilkerson, P. M., Wai, P., Rodrigues, D. N., Arnould, L., Geyer, F. C., Bromberg, S. E., Lacroix-Triki, M., Penault-Llorca, F., Giard, S., Sastre-Garau, X., Natrajan, R., Norton, L. ,... Reis-Filho, J. S. (2015). Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification. GENOME BIOLOGY, 16 (1), https://doi.org/10.1186/s13059-015-0657-6.
Access StatusOpen Access
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.
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