Supplement 8: Candidate age-related genes and pathways Function Untreated cohort (cohort 1) Treated cohort (cohort 2) Genes Gene sets Effect of age Effect of age FDR of 2 nd Effect of age adjusted Effect of age adjusted adjusted for adjusted for all adjustment for dataset for all covariates dataset covariates Hypoxia-related HIF1A 1.0E-03 0.54 0.66 (1) PGF 0.40 VEGF 1.0E-03 0.3 0.44 CTGF 0.32 0.28 Apoptosisrelated FAS 1.7E-04 6.6E-03 0.03 7.5E-04 3.9E-03 (2) CASP3 2.2E-03 2.2E-02 3.3E-03 2.5E-02 BAD 3.8E-03 3.2E-02 4.0E-03 1.7E-02 BIK 8.3E-03 0.18 0.35 BAX 9.6E-03 0.22 CASP6 0.92 0.40 CASP7 0.81 0.74 0.85 CASP8 0.19 0.13 CASP9 0.80 0.88 CASP10 0.32 0.18 0.35 MAP kinase TGFB1 1.5E-02 3.6E-02 0.12 0.23 related (2) EGFR 2.4E-06 2.1E-03 0.01 1.1E-02 RPS6KA1 0.86 MAPK1 0.79 0.88 FDR of 2 nd adjustment 0.008 0.04 0.03 0.22 0.12
MAP2K1 MAP2K2 MAP3K8 MAPK3 MKNK2 MKNK1 TGFA TGFB3 1.6E-02 0.6 0.09 0.09 8.2E-03 1.4E-02 3.6E-03 0.29 0.49 0.20 0.13 0.94 0.10 0.07 0.64 0.37 MAPK (3) MAPK (4) 1.2E-13 2.3E-02 5.8E-07 0.19 1.6E-08 5.9E-05 0.0002 mtor/pi3k related (5) PDPK1 AKT PI3K PI3KR3 EIF4E PTEN 3.3E-03 0.68 0.99 2.2E-02 2.1E-02 0.94 0.28 2.3E-05 7.6E-04 0.002 PIK3CA-GS (6) PTEN (7) AKT/mTOR (8) 1.4E-12 1.4E-07 6.7E-09 0.25 0.25 0.41 1.7E-11 5.0E-11 P53 (2, 9, 10) P53 2.3E-07 0.41 0.55 P53 (11) Ras (12) RAS (13) 3.2E-04 Myc (5) MYC (13) 1.0E-05 8.1E-03 0.04 0.19 0.51 0.51
b-catenin (5) b-catenin (13) 7.9E-03 0.25 BRCA-related BRCA1 3.3E-04 3.8E-04 0.003 2.4E-02 4.4E-02 (9, 12, 14, 15) BRCA2 0.07 0.63 0.76 BRCA1 mutant (16) 5.4E-09 4.5E-03 0.02 5.6E-06 2.5E-03 0.006 Stem cell-related ALDH1 0.10 (17-19) TOPO2A 8.2E-04 0.51 0.65 ALDH2 0.15 0.66 RANK-ligand 5.8E-08 1.8E-10 1.3E-06 1.6E-06 MaSC (20) 8.1E-11 1.5E-09 3.5E-18 3.2E-15 Embryonic (21) 8.9E-10 5.2E-04 0.004 3.5E-02 0.12 MaSC (22) 0.73 0.85 Luminal c-kit 5.8E-12 3.3E-13 7.9E-08 1.3E-07 progenitor (18) Luminal progenitor 1.7E-09 1.1E-03 0.007 2.4E-05 1.9E-02 0.04 (20) FDR: false discovery rate Legend: List of genes and gene sets that were investigated in a linear regression model to determine their association with age (41 genes, 13 gene sets). For each gene or gene set, adjustments according to data set and covariates are provided along with false discovery rates REFERENCES : 1. Huang ZH, Su GQ, Mao QG, et al. [Expressions of vascular endothelial growth factor and nm23-h1 gene and their relation to the prognosis of breast cancer in young women]. Di Yi Jun Yi Da Xue Xue Bao 2004;24: 1398-401. 2. Eppenberger-Castori S, Moore DH, Jr., Thor AD, et al. Age-associated biomarker profiles of human breast cancer. Int J Biochem Cell Biol 2002;34: 1318-30.
3. Speers C, Tsimelzon A, Sexton K, et al. Identification of novel kinase targets for the treatment of estrogen receptor-negative breast cancer. Clin Cancer Res 2009;15: 6327-40. 4. Creighton CJ, Hilger AM, Murthy S, Rae JM, Chinnaiyan AM, El-Ashry D. Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors. Cancer Res 2006;66: 3903-11. 5. Anders CK, Acharya CR, Hsu DS, et al. Age-specific differences in oncogenic pathway deregulation seen in human breast tumors. PLoS One 2008;3: e1373. 6. Loi S, Haibe-Kains B, Majjaj S, et al. PIK3CA mutations associated with gene signature of low mtorc1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci U S A 2010;107: 10208-13. 7. Trimboli AJ, Cantemir-Stone CZ, Li F, et al. Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 2009;461: 1084-91. 8. Creighton CJ. A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors. Oncogene 2007;26: 4648-55. 9. Klauber-Demore N. A Comprehensive Review of Breast Cancer in Young Women. Breast Dis 2009;23: 1-2. 10. Al-Moundhri M, Nirmala V, Al-Mawaly K, et al. Significance of p53, Bcl-2, and HER-2/neu protein expression in Omani Arab females with breast cancer. Pathol Oncol Res 2003;9: 226-31. 11. Miller LD, Smeds J, George J, et al. An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci U S A 2005;102: 13550-5. 12. Ozer E, Sis B, Ozen E, Sakizli M, Canda T, Sarioglu S. BRCA1, C-erbB-2, and H-ras gene expressions in young women with breast cancer. An immunohistochemical study. Appl Immunohistochem Mol Morphol 2000;8: 12-8. 13. Bild AH, Parker JS, Gustafson AM, et al. An integration of complementary strategies for gene-expression analysis to reveal novel therapeutic opportunities for breast cancer. Breast Cancer Res 2009;11: R55. 14. Zakhartseva LM, Gorovenko NG, Podolskaya SV, et al. Breast cancer immunohistochemical features in young women with BRCA 1/2 mutations. Exp Oncol 2009;31: 174-8. 15. Lee WY. Frequent loss of BRCA1 nuclear expression in young women with breast cancer: an immunohistochemical study from an area of low incidence but early onset. Appl Immunohistochem Mol Morphol 2002;10: 310-5. 16. van't Veer LJ, Dai, H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415: 530-536. 17. Asselin-Labat ML, Vaillant F, Sheridan JM, et al. Control of mammary stem cell function by steroid hormone signalling. Nature 2010;465: 798-802.
18. Siwko SK, Dong J, Lewis MT, Liu H, Hilsenbeck SG, Li Y. Evidence that an early pregnancy causes a persistent decrease in the number of functional mammary epithelial stem cells--implications for pregnancy-induced protection against breast cancer. Stem Cells 2008;26: 3205-9. 19. Heerma van Voss MR, van der Groep P, Bart J, van der Wall E, van Diest PJ. Expression of the stem cell marker ALDH1 in BRCA1 related breast cancer. Cell Oncol (Dordr) 2011;34: 3-10. 20. Lim E, Vaillant F, Wu D, et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 2009;15: 907-13. 21. Ben-Porath I, Thomson MW, Carey VJ, et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 2008;40: 499-507. 22. Creighton CJ, Li X, Landis M, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A 2009;106: 13820-5.