Determination of Molecular Markers for BRCA1 and BRCA2 Heterozygosity Using Gene Expression Profiling

Determination of Molecular Markers for BRCA1 and BRCA2 Heterozygosity Using Gene Expression Profiling

1. Asher Y. Salmon4,
2. Mali Salmon-Divon5,
3. Tamar Zahavi1,
4. Yulia Barash1,
5. Rachel S. Levy-Drummer3,
6. Jasmine Jacob-Hirsch2, and
7. Tamar Peretz1

+ Author Affiliations

1. Authors' Affiliations: ¹Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Ein-Kerem, Jerusalem; ²Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer; ³The Everard & Mina Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel; ⁴Barzilai Medical Center, Ashkelon, Israel; and ⁵Department of Molecular Biology, Ariel University Center, Ariel, Israel

1. Corresponding Author:
   Asher Y. Salmon, Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Ein-Kerem, Jerusalem 92000, Israel. Phone: 97-2508573595; Fax: 97-226777765; E-mail: asalmon@hadassah.org.il

Abstract

Approximately 5% of all breast cancers can be attributed to an inherited mutation in one of two cancer susceptibility genes, BRCA1 and BRCA2. We searched for genes that have the potential to distinguish healthy BRCA1 and BRCA2 mutation carriers from noncarriers based on differences in expression profiling. Using expression microarrays, we compared gene expression of irradiated lymphocytes from BRCA1 and BRCA2 mutation carriers versus control noncarriers. We identified 137 probe sets in BRCA1 carriers and 1,345 in BRCA2 carriers with differential gene expression. Gene Ontology analysis revealed that most of these genes relate to regulation pathways of DNA repair processes, cell-cycle regulation, and apoptosis. Real-time PCR was conducted on the 36 genes, which were most prominently differentially expressed in the microarray assay; 21 genes were shown to be significantly differentially expressed in BRCA1 and/or BRCA2 mutation carriers as compared with controls (P < 0.05). On the basis of a validation study with 40 mutation carriers and 17 noncarriers, a multiplex model that included six or more coincidental genes of 18 selected genes was constructed to predict the risk of carrying a mutation. The results using this model showed sensitivity 95% and specificity 88%. In summary, our study provides insight into the biologic effect of heterozygous mutations in BRCA1 and BRCA2 genes in response to ionizing irradiation-induced DNA damage. We also suggest a set of 18 genes that can serve as a prediction and screening tool for BRCA1 or BRCA2 mutational carriers by using easily obtained lymphocytes. Cancer Prev Res; 6(2); 1–9. ©2013 AACR.

Footnotes

• Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).

• Received May 21, 2012.
• Revision received November 21, 2012.
• Accepted November 26, 2012.

• ©2013 American Association for Cancer Research.