Proteomic changes resulting from gene copy number variations in cancer cells.
Along the transformation process, cells accumulate DNA aberrations, including mutations, translocations, amplifications, and deletions. Despite numerous studies, the overall effects of amplifications and deletions on the end point of gene expression--the level of proteins--is generally unknown. Here we use large-scale and high-resolution proteomics combined with gene copy number analysis to investigate in a global manner to what extent these genomic changes have a proteomic output and therefore the ability to affect cellular transformation. We accurately measure expression levels of 6,735 proteins and directly compare them to the gene copy number. We find that the average effect of these alterations on the protein expression is only a few percent. Nevertheless, by using a novel algorithm, we find the combined impact that many of these regional chromosomal aberrations have at the protein level. We show that proteins encoded by amplified oncogenes are often overexpressed, while adjacent amplified genes, which presumably do not promote growth and survival, are attenuated. Furthermore, regulation of biological processes and molecular complexes is independent of general copy number changes. By connecting the primary genome alteration to their proteomic consequences, this approach helps to interpret the data from large-scale cancer genomics efforts.
Geiger
Tamar
T
Department for Proteomics and Signal Transduction, Max-Planck Institute for Biochemistry, Martinsried, Germany.
Cox
Juergen
J
Mann
Matthias
M
D001943:Breast Neoplasms / Q000235:genetics*; D002460:Cell Line; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations / Q000235:genetics*; D030541:Databases, Genetic; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D018628:Gene Dosage / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D020543:Proteome; D012333:RNA, Messenger; D046988:Proteasome Endopeptidase Complex
Anal Chem. 2006 Apr 1;78(7):2113-20
16579588
Nature. 2003 Mar 13;422(6928):198-207
12634793
Biochem Biophys Res Commun. 2009 Dec 25;390(4):1414-8
19896456
Nat Biotechnol. 2008 Dec;26(12):1367-72
19029910
Ann Oncol. 2007 Jun;18(6):977-84
17229773
EMBO J. 1995 Jun 15;14(12):2827-38
7796809
Mol Cell Proteomics. 2002 May;1(5):376-86
12118079
Nucleic Acids Res. 2009 Jan;37(Database issue):D412-6
18940858
Cancer Res. 2003 Sep 15;63(18):5781-4
14522899
J Biol Chem. 2006 Sep 8;281(36):26754-67
16818491
Cancer Res. 2002 Nov 1;62(21):6240-5
12414653
Cancer Res. 2006 Dec 15;66(24):11690-9
17178864
Clin Exp Metastasis. 2009;26(3):215-27
19116762
Nat Rev Cancer. 2004 Mar;4(3):177-83
14993899
Genome Biol. 2007;8(10):R215
17925008
Ann Oncol. 2010 Mar;21(3):466-473
19717535
Nature. 2008 Oct 30;455(7217):1251-4
18820680
Int J Biochem Cell Biol. 1999 May;31(5):533-7
10399313
Cancer Treat Rev. 2010 May;36(3):224-9
20100636
Science. 2008 Oct 31;322(5902):703-9
18974345
Cancer Treat Rev. 2007 Feb;33(1):64-77
17113234
Lung Cancer. 2007 Jan;55(1):1-14
17070615
Int J Cancer. 2010 Jul 15;127(2):355-60
19904758
Cancer Res. 2004 Aug 15;64(16):5527-34
15313885
Breast Cancer Res. 2005;7(6):R1186-98
16457699
Cancer Res. 2005 Feb 15;65(4):1376-83
15735024
Nature. 2010 Feb 18;463(7283):899-905
20164920
Curr Opin Genet Dev. 2007 Apr;17(2):157-62
17324569
Proteomics. 2008 Dec;8(23-24):4862-72
19003865
Mol Cell Proteomics. 2005 Dec;4(12):2010-21
16249172
Cell Signal. 2002 May;14(5):381-95
11882383
Genome Biol. 2002;3(12):RESEARCH0075
12537564
Nature. 2010 Feb 18;463(7283):893-8
20164919
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12963-8
12297621
Nature. 1998 Dec 17;396(6712):643-9
9872311
BMC Genomics. 2005 May 09;6:67
15882461
Mol Pathol. 1998 Feb;51(1):1-7
9624412
Nat Genet. 2006 Dec;38(12):1386-96
17099711
Bioessays. 2003 Feb;25(2):152-62
12539241
Nat Methods. 2009 May;6(5):359-62
19377485
Curr Biol. 2007 May 1;17(9):749-60
17446074
Nat Protoc. 2009;4(5):698-705
19373234
Science. 2007 Aug 17;317(5840):916-24
17702937
Oncogene. 2007 Nov 1;26(50):7163-9
17525746
Trends Genet. 2006 Aug;22(8):447-55
16787682
Mol Cell Proteomics. 2008 Apr;7(4):672-83
18045802
Anal Chem. 2003 Feb 1;75(3):663-70
12585499