Integration of copy number aberration and genomic expression data in preinvasive breast cancer

Thesis (Ph.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.DNA aberration is central to cancer initiation and progression. In particular, DNA copy number changes increase in breast ductal carcinoma in situ (DCIS). This study utilized whole genome single-nucleotide polymorphism (SNP) arrays to determine copy number variation (CNV) in primary breast ductal epithelium. A unique combination of methodologies was employed, including laser-capture microdissection (LCM), a focus on early lesions with matched control samples and integration of multiple large-scale array platforms. To discover regions of variation, automated software and manual curation of copy number boundaries was used. For comparison, normal appearing ducts were obtained from both cancer (HN) and reduction mammoplasty (RM) cases. In these control tissues five common CNV sites were found within 3q, 8p, 13q and 17q, two of which are novel. Complex aberrations seen in DCIS were not found in normal ducts. Within the DCIS samples, 37 common copy number aberrations (CNAs) located over 10 chromosomes were identified. Many of the common CNAs identified provided confirmation of previous aberrations seen in DCIS. However, four locations had not previously been reported in DCIS, including losses at two locations on 1 p (1p31.1 and 1p21.3-p13.2) and a gain (19p13.2) and loss (19 p13.3) on 19p. The losses contain potential tumor suppressor genes (PTGER3, NEGR1, and APC2) while the gain contains PIN1, which is associated with tamoxifen resistance in breast cancer. An integrated approach was used to further elucidate these results by analyzing mRNA expression, miRNA expression together with copy number aberrations in DCIS. Overall, the common CNAs correlated to 15% of expression changes and 17% of miRNA expression changes in DCIS cases. Cell-cell adhesion and extracellular matrix genes are often dysregulated in DCIS. Focusing on these genes, downstream genes that might also be deregulated because of copy number aberrations were examined. Several genes downstream of the RET receptor were found to be aberrant, including DOK4, miR-182, RAP1A, TIAM1 and CDC42. The number of aberrations identified in this pathway highlights its potential role in breast cancer progression. DCIS is highly heterogeneous. This study has demonstrated the utility of integrated analyses in assessing the relative importance of the genetic alterations seen in DCIS