High-resolution genomic and expression analyses of copy number alterations in HER2-amplified breast cancer.
BACKGROUND
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.
Staaf
Johan
J
Department of Oncology, Clinical Sciences, Lund University, Barngatan 2B, Lund, Sweden. johan.staaf@med.lu.se
Jönsson
Göran
G
Ringnér
Markus
M
Vallon-Christersson
Johan
J
Grabau
Dorthe
D
Arason
Adalgeir
A
Gunnarsson
Haukur
H
Agnarsson
Bjarni A
BA
Malmström
Per-Olof
PO
Johannsson
Oskar Th
OT
Loman
Niklas
N
Barkardottir
Rosa B
RB
Borg
Ake
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D022202:Chromosomes, Artificial, Bacterial; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015996:Survival Rate
D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases
Breast Cancer Res. 2008;10(3):R53
18559090
J Clin Oncol. 2005 Oct 20;23(30):7483-90
16234514
Science. 1987 Jan 9;235(4785):177-82
3798106
Clin Cancer Res. 2007 Dec 15;13(24):7305-13
18094411
J Clin Oncol. 2008 Oct 20;26(30):4869-74
18794552
Genes Chromosomes Cancer. 2006 Aug;45(8):761-9
16708353
Breast Cancer Res Treat. 2007 Dec;106(2):181-9
17260090
Clin Cancer Res. 2009 Apr 15;15(8):2711-22
19318498
J Natl Cancer Inst. 2009 May 6;101(9):615-8
19401550
J Clin Oncol. 2006 Jun 1;24(16):2428-36
16682728
Genome Biol. 2007;8(8):R157
17683518
Cancer Cell. 2006 Dec;10(6):529-41
17157792
Oncogene. 2005 Jul 7;24(29):4660-71
15897907
Lancet Oncol. 2010 Mar;11(3):266-74
20079691
Genes Chromosomes Cancer. 2006 Nov;45(11):1033-40
16897746
Clin Cancer Res. 2008 Aug 15;14(16):5158-65
18698033
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23
12829800
Genes Chromosomes Cancer. 2004 May;40(1):19-31
15034864
Cancer Res. 2006 Nov 1;66(21):10292-301
17079448
Cancer Res. 2007 Dec 15;67(24):11565-75
18089785
Genome Biol. 2007;8(10):R215
17925008
Carcinogenesis. 2008 Mar;29(3):473-9
17916906
BMC Cancer. 2006 Apr 18;6:96
16620391
Cancer Res. 2003 Dec 15;63(24):8861-8
14695203
Nature. 2000 Aug 17;406(6797):747-52
10963602
J Pathol. 2008 Dec;216(4):399-407
18810758
Lancet. 2007 Jan 6;369(9555):29-36
17208639
Oncogene. 2007 Apr 26;26(19):2799-803
17072344
Breast Cancer Res Treat. 2010 Feb;120(1):1-7
19760503
Am J Pathol. 2003 Nov;163(5):1979-84
14578197
Breast Cancer Res. 2008;10(4):R65
18662380
J Clin Oncol. 2009 Mar 10;27(8):1160-7
19204204
Breast Cancer Res Treat. 1992;24(2):115-26
8443399
J Biol Chem. 1997 Mar 28;272(13):8490-7
9079677
Genes Chromosomes Cancer. 2008 Jun;47(6):530-42
18335499
Annu Rev Biochem. 1996;65:635-92
8811192
Semin Oncol. 1999 Aug;26(4 Suppl 12):78-83
10482197
Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):865s-70s
15701879
N Engl J Med. 2006 Dec 28;355(26):2733-43
17192538
J Clin Oncol. 1990 Jan;8(1):103-12
1967301
Cancer Res. 2009 May 15;69(10):4116-24
19435916
Genes Chromosomes Cancer. 2008 Aug;47(8):697-711
18484635
Mol Cancer Ther. 2006 Oct;5(10):2572-9
17041102
J Clin Oncol. 2007 Jan 1;25(1):118-45
17159189
Genes Chromosomes Cancer. 2007 Jun;46(6):543-58
17334996
Mod Pathol. 2009 Sep;22(9):1169-75
19448591
Breast Cancer Res Treat. 2010 Jun;121(3):575-89
19688261
J Biol Chem. 1999 Aug 20;274(34):24425-30
10446223
Am J Surg Pathol. 2005 Sep;29(9):1221-7
16096413
J Natl Cancer Inst. 2009 May 6;101(9):644-50
19401546
Lab Invest. 2008 May;88(5):491-503
18332872
N Engl J Med. 2005 Oct 20;353(16):1673-84
16236738
Mol Cancer Res. 2009 Apr;7(4):511-22
19372580
Bioinformatics. 2007 Mar 15;23(6):657-63
17234643
J Clin Oncol. 2009 Aug 20;27(24):3881-6
19620488
Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20007-12
18077431
Genes Chromosomes Cancer. 2004 Apr;39(4):288-97
14978790
J Clin Oncol. 2010 Apr 10;28(11):1813-20
20231686
J Pathol. 2009 Sep;219(1):16-24
19670217
BMC Genomics. 2006 Apr 27;7:96
16643655
BMC Genomics. 2007 Oct 22;8:382
17953745
Front Biosci. 2008 May 01;13:3906-12
18508484
Cancer Cell. 2004 Dec;6(6):535-8
15607957
Genome Res. 2006 Dec;16(12):1465-79
17142309
Hum Mutat. 2008 Apr;29(4):555-64
18330910