Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification.
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ICR Authors
Authors
Ng, CKY
Martelotto, LG
Gauthier, A
Wen, H-C
Piscuoglio, S
Lim, RS
Cowell, CF
Wilkerson, PM
Wai, P
Rodrigues, DN
Arnould, L
Geyer, FC
Bromberg, SE
Lacroix-Triki, M
Penault-Llorca, F
Giard, S
Sastre-Garau, X
Natrajan, R
Norton, L
Cottu, PH
Weigelt, B
Vincent-Salomon, A
Reis-Filho, JS
Martelotto, LG
Gauthier, A
Wen, H-C
Piscuoglio, S
Lim, RS
Cowell, CF
Wilkerson, PM
Wai, P
Rodrigues, DN
Arnould, L
Geyer, FC
Bromberg, SE
Lacroix-Triki, M
Penault-Llorca, F
Giard, S
Sastre-Garau, X
Natrajan, R
Norton, L
Cottu, PH
Weigelt, B
Vincent-Salomon, A
Reis-Filho, JS
Document Type
Journal Article
Date
2015-05-22
Date Accepted
2015-04-20
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.
Citation
Genome biology, 2015, 16 pp. 107 - ?
Source Title
Publisher
BMC
ISSN
1474-7596
eISSN
1474-760X
Collections
Research Team
Functional Genomics