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Estrogen Receptor Status in Breast Cancer Is Associated with Remarkably Distinct Gene Expression Patterns
Sofia Gruvberger, Markus Ringnér, Yidong Chen, Sujatha Panavally, Lao H. Saal, Åke Borg, Mårten Fernö, Carsten Peterson and Paul S. Meltzer
Sofia Gruvberger
Markus Ringnér
Yidong Chen
Sujatha Panavally
Lao H. Saal
Åke Borg
Mårten Fernö
Carsten Peterson
Paul S. Meltzer
DOI: Published August 2001
Classification of ER+ and ER− tumors using ANNs and gene expression patterns. A, schematic illustration of the ANN models. Filtering of genes for a minimal level of expression and spot area reduced the number of genes to 3389 (1) . PCA further reduced the dimensionality to 10 PCA components/sample (2) . The samples were randomly partitioned into three groups (3) . Two of these groups were used for training and one for validation (4) using an ANN model with five hidden nodes and the ER status as the output (5) . The training process was repeated so that all three groups were used for validation (6) . The random partition of samples was redone and the training procedure repeated 200 times so that a total of 600 models were trained (7) . By measuring the sensitivity of the classification to a change in the expression level of each gene in the calibrated models, the genes could be ranked (8) . The process (2 3 4 5 6 7) was repeated using fewer genes (9) . The ANN output results from the committee of 600 models, including the SDs, using the top 100 (B) and the top 301–400 (C) discriminator genes. On the X axis, 0 and 1 represent ER− and ER+, respectively, with the decision threshold set at 0.5. The 47 training samples (▪) and the 11 test samples (•) are plotted. Yellow, samples known to be ER− (23 + 6); blue, ER+ samples (24 + 5). Sample numbers (labels) are indicated.
Clustering of gene expression data from ER+ and ER− tumors. Blue, ER+ tumors; yellow, ER−. MDS (A) displays the position of each tumor sample in a three-dimensional Euclidean space, with the distance between the samples reflecting their approximate degree of correlation. Hierarchical clustering (B) presents the clustered samples in columns and the clustered genes in rows. A pseudocolored representation of gene expression ratios is shown, with the scale below. The genes in the cluster, which included the ER gene, are denoted. The 113 genes used for the two clustering methods were generated by WGA.
Top 50 genes extracted from ANNs
Relative expressionb
SAGEc
Clone ID no.
1+0−0 + ESR1 Estrogen receptor 1 NS 725321
2+2−0 + TFF3 Trefoil factor 3 (intestinal) NT 298417
3+1−1 + GATA3 GATA-binding protein 3 NS 214068
4+0−2 + ESTs NS 132140
5+4−0 − S100A8 S100 calcium-binding protein A8 (calgranulin A) NT 562729
6+4−1 − LCN2 Lipocalin 2 (oncogene 24p3) NS 741497
7+3−2 + ESTs NT 155072
8+2−3 − CDH3 Cadherin 3, type 1, P-cadherin (placental) NT 773301
9+2−4 + P28 Dynein, axonemal, light intermediate polypeptide NT 782688
10+3−4 − PFKP Phosphofructokinase, platelet NS 26184
11+5−2 − LAD1 Ladinin 1 NS 121551
12+6−2 − KCNN4 Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4 NS 756708
13+8−3 + SFRS5 Splicing factor, arginine/serine-rich 5 NT 143169
14+8−3 + IGFBP2 Insulin-like growth factor binding protein 2 (36kD) NS 233721
15+7−4 + HSPC195 ESTs NS 139354
16+6−5 + COX6C Cytochrome c oxidase subunit VIc NS 838568
17+7−5 − PFKP Phosphofructokinase, platelet NS 950682
18+7−6 + FBP1 Fructose-1,6-bisphosphatase 1 NS 433253
19+7−6 − EGFR Epidermal growth factor receptor (avian erythroblastic leukemia viral (v-erb-b) oncogene homolog) NS 324861
20+6−7 + CRIP1 Cysteine-rich protein 1 (intestinal) NS 1323448
21+6−8 + STC2 Stanniocalcin 2 + 130057
22+5−8 − SCYD1 Small inducible cytokine subfamily D (Cys-X3-Cys), member 1 (fractalkine, neurotactin) NT 140574
23+6−6 − GALNT3 UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-T3) NT 148225
24+5−7 − KRT7 Keratin 7 NS 843321
25+5−7 − LMO4 LIM domain only 4 NS 162533
26+7−7 + TIMP3 Tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory) NS 768370
27+6−6 + CCND1 Cyclin D1 (PRAD1: parathyroid adenomatosis 1) + 841641
28+13−5 − ATDC Ataxia-telangiectasia group D-associated protein NT 377275
29+12−6 − ABP/ZF Alu-binding protein with zinc finger domain NT 417424
30+14−5 + IGF2 Insulin-like growth factor 2 (somatomedin A) NT 207274
31+13−5 + IGHG3 Immunoglobulin heavy constant γ 3 (Gm marker) NT 855745
32+12−6 + PIB5PA Phosphatidylinositol (4,5) bisphosphate 5-phosphatase, A NT 1359579
33+13−7 + ARHH Ras homolog gene family, member H NS 302591
34+15−6 − MSE55 Serum constituent protein NS 214982
35+14−7 + SLC9A3R1 Solute carrier family 9 (sodium/hydrogen exchanger), isoform 3 regulatory factor 1 NS 773286
36+13−8 + EIF3S4 Eukaryotic translation initiation factor 3, subunit 4 (δ, 44kD) NS 857319
37+12−9 − SOD3 Superoxide dismutase 3, extracellular NT 795309
38+11−10 − SLC7A5 Solute carrier family 7 (cationic amino acid transporter, y+ system), member 5 − 755578
39+10−11 − NDRG1 N-myc downstream regulated NT 842863
40+13−12 − S100P S100 calcium-binding protein P NS 135221
41+14−13 + THBS1 Thrombospondin 1 NT 810512
42+14−12 − IMPA2 Inositol(myo)-1(or 4)-monophosphatase 2 NS 32299
43+13−13 − CHI3L1 Chitinase 3-like 1 (cartilage glycoprotein-39) NT 770212
44+13−14 + SERPINI1 Serine (or cysteine) proteinase inhibitor, clade I (neuroserpin), member 1 NT 564621
45+14−12 − HMGIY High-mobility group (nonhistone chromosomal) protein isoforms I and Y NS 782811
46+14−13 + APOD Apolipoprotein D NS 838611
47+16−13 + PVALB Parvalbumin NT 430318
48+16−14 + A2M α-2-macroglobulin NT 878182
49+16−15 + SELENBP1 Selenium binding protein 1 NS 80338
50+27−10 − FABP7 Fatty acid binding protein 7, brain NS 345626
a The genes are ranked according to the sensitivity analysis (see "Materials and Methods"). The sensitivity is calculated averaged over all 600 ANN models. The errors for a rank are calculated from the SD of the sensitivities for the 600 ANN models.
b +, higher expression in ER+; −, higher expression in ER−. Defined as the sign of the ANN sensitivity.
c NT, no tag; NS, not significant; +, up-regulated by E2; −, down-regulated by E2.
Prediction of ER status
Correcta
ROC area
Correctb
Top–100 47 100.00% 11 100.00%
51–150 43 97.80% 9 100.00%
101–200 45 99.30% 11 100.00%
151–250 44 97.50% 9 100.00%
251–350 39 95.30% 9 93.30%
Random 38.8 ± 0.2 91.8 ± 0.2% 5.5 ± 0.2 53.0 ± 2.6%
a Number of correct classifications of 47 samples.
b Number of correct classifications of 11 samples.
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