Abstract 3117: Complex genomic regions associated with ERBB2 amplification in breast cancer (2012)

Abstract Repeated DNA segments (Low Copy Repeats, Segmental Duplications) are highly homologous sequences within the human genome. They are typically 10-300 kb in length, and bear &amp;gt;95% sequence identity. In germline, repeated DNA segments mediate recurrent DNA rearrangements and thus cause specific genetic disorders called genomic disorders. Repeated genomic segments could also be prone to rearrangements in somatic cells and thus could mediate recurrent rearrangements in cancer. However, the important role of repeated genomic segments in genome instability in cancer remains elusive, mainly because such regions are less accessible by current genomic technologies due to the difficulty in assembling and interrogating sequences. Gene amplification is a cellular process characterized by the production of multiple copies of a particular gene through DNA rearrangements. ERBB2, an epidermal growth factor receptor gene, is amplified in 15-20% of breast tumors. Due to excessive cell growth signaling, this recurrent amplification is associated with advanced stages and poor prognosis. Despite the clinical importance, the mechanisms giving rises to recurrent ERBB2 amplification remains unclear. We hypothesized that, similar to the recurrent rearrangements for genomic disorders, repeated genomic segments cause DNA rearrangements for ERBB2 amplification. To test the hypothesis and understand the mechanism of ERBB2 amplification, we mapped a common copy-number breakpoint for primary ERBB2-amplified (HER2-positive) breast tumors. Copy number breakpoints were examined at every 300-kilo bases (kb) from the location of ERBB2 to its telomeric region using real-time PCR based assays. The breakpoint that marked a region between normal copy number and low level amplification resided within a 300-kb complex genomic region at the 1.5 mega-bases telomeric side of ERBB2. The region contains many repeated segments from two gene families. Furthermore, the HapMap SNPs, a set of SNPs that tag haploblocks in the human genome, are less well-defined, indicating the difficulty in interrogating the genomic region by current genomic technologies. Normal copy-number variations seem common, as there is several deletion polymorphisms reported in the region. Two sub-regions, each covering 40-kb region, are particularly complex due to a number of direct and inverted repeats. The prevalence of this copy number breakpoint in HER2-positive breast tumors was also shown in a study by Sircoulomb et al.,(BMC Cancer 2010), in which common amplifications and deletions were determined for 54 HER-2 positive breast tumors. Defining (1) the copy-number breakpoint with very high resolution and (2) critical DNA sequences for ERBB2 amplification will lead to better understanding the amplification mechanism underlying this aggressive type of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3117. doi:1538-7445.AM2012-3117