Genomic distance entrained clustering and regression modelling highlights interacting genomic regions contributing to proliferation in breast cancer.
BACKGROUND
Genomic copy number changes and regional alterations in epigenetic states have been linked to grade in breast cancer. However, the relative contribution of specific alterations to the pathology of different breast cancer subtypes remains unclear. The heterogeneity and interplay of genomic and epigenetic variations means that large datasets and statistical data mining methods are required to uncover recurrent patterns that are likely to be important in cancer progression.


RESULTS
We employed ridge regression to model the relationship between regional changes in gene expression and proliferation. Regional features were extracted from tumour gene expression data using a novel clustering method, called genomic distance entrained agglomerative (GDEC) clustering. Using gene expression data in this way provides a simple means of integrating the phenotypic effects of both copy number aberrations and alterations in chromatin state. We show that regional metagenes derived from GDEC clustering are representative of recurrent regions of epigenetic regulation or copy number aberrations in breast cancer. Furthermore, detected patterns of genomic alterations are conserved across independent oestrogen receptor positive breast cancer datasets. Sequential competitive metagene selection was used to reveal the relative importance of genomic regions in predicting proliferation rate. The predictive model suggested additive interactions between the most informative regions such as 8p22-12 and 8q13-22.


CONCLUSIONS
Data-mining of large-scale microarray gene expression datasets can reveal regional clusters of co-ordinate gene expression, independent of cause. By correlating these clusters with tumour proliferation we have identified a number of genomic regions that act together to promote proliferation in ER+ breast cancer. Identification of such regions should enable prioritisation of genomic regions for combinatorial functional studies to pinpoint the key genes and interactions contributing to tumourigenicity.
Dexter
Tim J
TJ
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK. tim.dexter@icr.ac.uk
Sims
David
D
Mitsopoulos
Costas
C
Mackay
Alan
A
Grigoriadis
Anita
A
Ahmad
Amar S
AS
Zvelebil
Marketa
M
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D023281:Genomics / Q000379:methods*; D008954:Models, Biological; D011960:Receptors, Estrogen / Q000378:metabolism; D012044:Regression Analysis; D015203:Reproducibility of Results
D011960:Receptors, Estrogen
Br J Cancer. 2004 Apr 5;90(7):1422-8
15054466
Nature. 2000 Jun 22;405(6789):974-8
10879542
Mol Cell Biol. 2002 Jun;22(12):4309-18
12024041
Lancet. 2005 Feb 19-25;365(9460):671-9
15721472
Breast Cancer Res Treat. 2010 Nov;124(2):567-72
20563840
Mol Biol Cell. 2002 Jun;13(6):1977-2000
12058064
J Clin Oncol. 2007 Apr 1;25(10):1239-46
17401012
Nat Rev Cancer. 2006 Feb;6(2):99-106
16491069
Bioinformatics. 2003 Jan 22;19(2):185-93
12538238
J Natl Cancer Inst. 2006 Feb 15;98(4):262-72
16478745
Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13550-5
16141321
Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4164-9
15016911
J Clin Oncol. 2007 Feb 20;25(6):662-8
17308270
Genes Chromosomes Cancer. 2006 Nov;45(11):1033-40
16897746
Nucleic Acids Res. 2002 Jan 1;30(1):207-10
11752295
Mol Cell Biol. 2004 Jan;24(2):924-35
14701762
Pathobiology. 2008;75(2):104-11
18544965
Mol Cell. 2009 May 15;34(3):271-84
19450526
Breast Cancer Res. 2005;7(6):R953-64
16280042
Clin Cancer Res. 2007 Jun 1;13(11):3207-14
17545524
Biostatistics. 2004 Oct;5(4):557-72
15475419
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12963-8
12297621
Nat Genet. 2003 Jun;34(2):226-30
12754511
Cancer Res. 2008 Oct 15;68(20):8616-25
18922938
J Pathol. 2005 Jan;205(2):248-54
15641021
Cancer Cell. 2006 Dec;10(6):529-41
17157792
Cancer Res. 2005 May 15;65(10):4059-66
15899795
Cancer Res. 2006 Nov 15;66(22):10664-70
17090521
Genome Res. 2006 Dec;16(12):1465-79
17142309