Abstract
Breast cancer progression – genomic alterations in a continuum of stages
Jørgen Aarøe1, Vilde D. Haakensen1, Aslaug Muggerud1, Vanessa Dumeaux1,2, Fredrik Wärnberg3, Anne-Lise Børresen-Dale11 Department of Genetics, Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway, 2 Institute of Community Medicine, University of Tromsø, Norway, 3 Department of Surgery, Uppsala University Hospital, Sweden
Aim: To study the progression of genomic alterations in mammary epithelial cells from dense breast tissue to full blown cancers
Materials and methods: In total 127 breast tissue samples from three different series have been analyzed using 244K Agilent Human Genome CGH Microarrays (Santa Clara, CA). The samples comprise: 21 “normal" breast tissue (dense breast tissue, reduction mammoplasties, and normal tissue from mastectomies), 26 ductal carcinoma in situ (DCIS), and 75 breast carcinomas.
Results: Data analysis has been initiated using Nexus software from BioDiscovery (El Segundo, CA). Several of the “normal” samples show signs of alterations in areas known to be commonly altered in breast tumors. Hierarchical clustering revealed heterogeneity within each group of samples, suggesting further stratification. The “normal” samples clustered together with low aberrant tumor- and DCIS samples, while the highly aberrant tumor- and DCIS samples clustered together. Significance Testing for Aberrant Copy number (STAC) was applied to reveal common alterations within each group. Among the “normal” samples 118 genes were found to be in regions having significant frequency p-value (p<0.05) and being present in more than 35% of the samples, whereas the number was 105 for the DCIS and 245 for the tumors. Of these genes, 31 were overlapping between all groups. We identified group-specific events defined as at least 0.25-fold copy number change between two of the groups with a p-value < 0.05 using Fisher exact test. Genomic regions were found significantly altered in DCIS and breast cancer samples compared to the “normal” samples harboring 1341 and 2617 genes, respectively. Fewer genes (N=388) were identified in significantly altered regions when comparing breast cancer to DCIS. Enrichment analysis was performed to identify biological processes of significance.
Conclusion: Preliminary analyses reveal heterogeneity within each group and frequency of aberrations appears proportionally related to disease stage. Some genomic regions were found significantly changed in all groups. Most of these regions correspond to frequently observed copy number variations (CNVs) and might be candidate hotspots for early events of genomic rearrangements towards breast cancer development. More samples will be included and further stratification will be necessary to identify possibly important events that initiate and drive breast cancer carcinogenesis.