High-resolution genomic and expression analyses of copy number alterations in HER2-amplified breast cancer
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Agnarsson, Bjarni A
Johannsson, Oskar Th
Barkardottir, Rosa B
MetadataShow full item record
CitationBreast Cancer Res. 2010, 12(3):R25
AbstractINTRODUCTION: HER2 gene amplification and protein overexpression (HER2+) define a clinically challenging subgroup of breast cancer with variable prognosis and response to therapy. Although gene expression profiling has identified an ERBB2 molecular subtype of breast cancer, it is clear that HER2+ tumors reside in all molecular subtypes and represent a genomically and biologically heterogeneous group, needed to be further characterized in large sample sets. METHODS: Genome-wide DNA copy number profiling, using bacterial artificial chromosome (BAC) array comparative genomic hybridization (aCGH), and global gene expression profiling were performed on 200 and 87 HER2+ tumors, respectively. Genomic Identification of Significant Targets in Cancer (GISTIC) was used to identify significant copy number alterations (CNAs) in HER2+ tumors, which were related to a set of 554 non-HER2 amplified (HER2-) breast tumors. High-resolution oligonucleotide aCGH was used to delineate the 17q12-q21 region in high detail. RESULTS: The HER2-amplicon was narrowed to an 85.92 kbp region including the TCAP, PNMT, PERLD1, HER2, C17orf37 and GRB7 genes, and higher HER2 copy numbers indicated worse prognosis. In 31% of HER2+ tumors the amplicon extended to TOP2A, defining a subgroup of HER2+ breast cancer associated with estrogen receptor-positive status and with a trend of better survival than HER2+ breast cancers with deleted (18%) or neutral TOP2A (51%). HER2+ tumors were clearly distinguished from HER2- tumors by the presence of recurrent high-level amplifications and firestorm patterns on chromosome 17q. While there was no significant difference between HER2+ and HER2- tumors regarding the incidence of other recurrent high-level amplifications, differences in the co-amplification pattern were observed, as shown by the almost mutually exclusive occurrence of 8p12, 11q13 and 20q13 amplification in HER2+ tumors. GISTIC analysis identified 117 significant CNAs across all autosomes. Supervised analyses revealed: (1) significant CNAs separating HER2+ tumors stratified by clinical variables, and (2) CNAs separating HER2+ from HER2- tumors. CONCLUSIONS: We have performed a comprehensive survey of CNAs in HER2+ breast tumors, pinpointing significant genomic alterations including both known and potentially novel therapeutic targets. Our analysis sheds further light on the genomically complex and heterogeneous nature of HER2+ tumors in relation to other subgroups of breast cancer.
DescriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links field
- Landscape of somatic allelic imbalances and copy number alterations in HER2-amplified breast cancer.
- Authors: Staaf J, Jönsson G, Ringnér M, Baldetorp B, Borg A
- Issue date: 2011
- Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics.
- Authors: Jönsson G, Staaf J, Vallon-Christersson J, Ringnér M, Holm K, Hegardt C, Gunnarsson H, Fagerholm R, Strand C, Agnarsson BA, Kilpivaara O, Luts L, Heikkilä P, Aittomäki K, Blomqvist C, Loman N, Malmström P, Olsson H, Johannsson OT, Arason A, Nevanlinna H, Barkardottir RB, Borg A
- Issue date: 2010
- Genome profiling of ERBB2-amplified breast cancers.
- Authors: Sircoulomb F, Bekhouche I, Finetti P, Adélaïde J, Ben Hamida A, Bonansea J, Raynaud S, Innocenti C, Charafe-Jauffret E, Tarpin C, Ben Ayed F, Viens P, Jacquemier J, Bertucci F, Birnbaum D, Chaffanet M
- Issue date: 2010 Oct 8
- Clinical array-based karyotyping of breast cancer with equivocal HER2 status resolves gene copy number and reveals chromosome 17 complexity.
- Authors: Gunn S, Yeh IT, Lytvak I, Tirtorahardjo B, Dzidic N, Zadeh S, Kim J, McCaskill C, Lim L, Gorre M, Mohammed M
- Issue date: 2010 Jul 28
- High-resolution genomic analysis of the 11q13 amplicon in breast cancers identifies synergy with 8p12 amplification, involving the mTOR targets S6K2 and 4EBP1.
- Authors: Karlsson E, Waltersson MA, Bostner J, Pérez-Tenorio G, Olsson B, Hallbeck AL, Stål O
- Issue date: 2011 Oct