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

   

Authors:	Ng, 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.; Cottu, P. H.; Weigelt, B.; Vincent-Salomon, A.; Reis-Filho, J. S.
Article Title:	Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification
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. © 2015 Ng et al.; licensee BioMed Central.
Keywords:	clinical article; controlled study; sequence analysis; somatic mutation; clinical feature; gene; gene overexpression; breast cancer; gene expression profiling; in vitro study; mutational analysis; gene dosage; genetic heterogeneity; oncogene neu; copy number variation; human; article; brf2 gene; dsn1 gene
Journal Title:	Genome Biology
Volume:	16
Issue:	1
ISSN:	1465-6906
Publisher:	Biomed Central Ltd
Date Published:	2015-05-22
Start Page:	107
Language:	English
DOI:	10.1186/s13059-015-0657-6
PROVIDER:	scopus
PMCID:	PMC4440518
PUBMED:	25994018
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84939165961&partnerID=40&md5=145bd6390b358faa826875864c711965
Notes:	Export Date: 2 September 2015 -- Source: Scopus

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