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Gene expression signature of hereditary breast cancer
Breast Cancer Research volume 7, Article number: P4.30 (2005)
Some clinical features of hereditary breast cancer, which develops in the presence of germline mutations in BRCA genes, are different from those of sporadic cases. Within recent years, better understanding of cancer biology and successful classification of tumors into distinct, clinically relevant subgroups were made possible by the methods of global gene expression analysis. Thus, we decided to compare gene expression profiles of hereditary versus sporadic breast cancer and possibly find the molecular basis underlying clinical observations.
Microarray analysis was performed with HG U133 Plus 2.0 (Affymetrix, Santa Clara, CA, USA) oligonucleotide microarrays, allowing detection of 47,500 transcripts. We have so far performed gene expression profiling in 25 tumor samples obtained from 24 patients: 14 patients with hereditary breast cancer (with and without proven BRCA1 mutation) and 10 patients with sporadic breast carcinoma. We also analyzed, as the reference, six normal breast tissues collected from patients with breast cancer.
We compared the expression profile in hereditary breast cancer and the normal breast tissue and found 2983 differentially expressed genes (Welch t test, Benjamini-Hochberg False Discovery Rate below 0.01). By identical criteria we found 648 genes that are significantly changed between sporadic breast cancer and normal tissue. The merged list contained 3138 genes showing changed expression between cancer and normal breast tissue, with 493 genes that were common in both comparisons. We further verified which of the 3138 genes exhibit differences between hereditary and sporadic tumors. We found that 42 probe sets show statistically significant differences between these groups (non-parametric Mann–Whitney test, False Discovery Rate < 0.05). However, only one of these genes (PARK7) remained significantly changed (both by parametric and non-parametric approach) between hereditary and sporadic cases, when taking into account all probe sets present on the array. This gene has been shown to be associated with poor prognosis in ER-negative breast cancer by Nagahata and colleagues . Next, we analyzed hereditary and sporadic cancer tissues in subgroups of ER-positive and ER-negative tumors. Interestingly, in the ER-negative group, top genes differentiating between hereditary and sporadic cancers were still functionally related to the estrogen metabolism and signaling. Finally, we verified the signature of hereditary breast cancer published by Hedenfalk and colleagues [2, 3] – two lists of genes, characteristic for BRCA1/BRCA2-linked breast cancer and for BRCAx-linked hereditary breast cancer, that in total correspond to 204 probe sets on the U133 2.0 Plus array (ESTs not included). In our dataset the most significant of these genes (TOB1, transducer of ERBB2) exhibited a False Discovery Rate equal to 0.13, thus not passing the criteria of statistical significance.
We have specified a signature of 42 genes that differentiate between normal breast tissue and breast cancer and simultaneously allow classification of hereditary and sporadic tumors. However, the range of difference between these classes is rather mild and is strongly influenced by the ER status. Taking this into account, together with the fact that in our study group the signature proposed by Hedenfalk and colleagues does not allow for differentiation between sporadic and hereditary cancers, it is clear that further studies on the larger group of cases are necessary.
Nagahata T, Onda M, Emi M, Nagai H, Tsumagari K, Fujimoto T, Hirano A, Sato T, Nishikawa K, Akiyama F, et al: Expression profiling to predict postoperative prognosis for estrogen receptor-negative breast cancers by analysis of 25 344 genes on cDNA microarray. Cancer Sci. 2004, 95: 218-225.
Hedenfalk I, Duggan D, Chen Y, Radmasher M, Bittner M, Simon R, Meltzer P, Gusterson B, Esteller M, Kallioniemi OP, et al: Gene-expression profiles in hereditary breast cancer. N Engl J Med. 2001, 344: 539-548. 10.1056/NEJM200102223440801.
Hedenfalk I, Ringner M, Ben-Dor A, Yakhini Z, Chen Y, Chebil G, Ach R, Loman N, Olsson H, Meltzer P, et al: Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc Natl Acad Sci USA. 2003, 100: 2532-2537. 10.1073/pnas.0533805100.
The study was supported by the Ministry of Science and Information Society Technologies (grant number PBZ-KBN-040/P04/2001). VD is a fellow of a Fellowship Program totally supported by the National Cancer Institute – Office for International Affairs, NIH, Bethesda, MD, USA.
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Dudaladava, V., Jarzab, M., Pamula, J. et al. Gene expression signature of hereditary breast cancer. Breast Cancer Res 7, P4.30 (2005) doi:10.1186/bcr1160
- Breast Cancer
- False Discovery Rate
- BRCA1 Mutation
- Normal Breast Tissue
- Hereditary Breast Cancer