Abstract 2189: Genomic dynamics in breast cancer progression analyzed by miFISH analysis
Authors: Irianna Marie Torres, Leanora Hernandez, Jausheng Tzeng, Russell Schwartz, Alejandro Schaffer, Edward Michael Gertz, Daniela Hirsch, Steven Brower, Miguel Sanchez, Gert Auer, Kerstin Heselmeyer-Haddad, Thomas Ried
Journal: Cancer Research (2018)

Abstract Our previous studies of synchronous Ductal Carcinomas in Situ (DCIS) and Invasive Ductal Carcinomas (IDC) often showed a high degree of chromosomal instability already in DCIS, and frequently a direct clonal evolution from DCIS to IDC. We now asked the question whether this degree of instability is also present in DCIS that did not progress to IDC. In collaboration with Englewood Hospital and Medical Center, we are therefore conducting a retrospective study analyzing FFPE material from 20 DCIS patients with low-grade or high-grade DCIS who did not present with invasive breast carcinoma during their follow-up (5-10 years) and compared the findings to 10 DCIS patients who presented with synchronous IDC. Using our novel multiplex interphase FISH (miFISH) assay, we are able to determine copy number changes of five oncogenes (COX2, MYC, CCND1, HER2, ZNF217) and three tumor suppressor genes (DBC2, CDH1, TP53) and assessed intratumor heterogeneity (ITH) and clonal evolution during disease progression. The miFISH analysis showed that low-grade DCIS displayed mostly stable patterns of gene copy numbers in a diploid genome, while high-grade DCIS frequently had increased nuclear DNA content (ploidy) associated with a higher degree of ITH. However, some low-grade DCIS exhibited complex and unstable patterns with higher ploidy. Also, a few high-grade DCIS were defined by few copy number changes, e.g., the gain of a whole chromosome 8 (DBC and MYC), resulting in a clonal population with a low instability index. DCIS and their synchronous IDC often displayed very similar miFISH patterns indicating direct expansion of dominant clones. Of note, the DCIS cells of one case were defined by the well described 1q gain/16q loss pattern and acquired subsequently a chromosome 8 gain in the IDC, confirming our previous observation that the gain of MYC is a pivotal step in breast cancer progression. Our data also show that DCIS with or without synchronous IDC exhibited similar patterns. This could indicate that DCIS in general, regardless of grading, should be treated as lesions with progressive potential. Phylogenetic tree modeling with our custom FISHtrees software will further elucidate the dynamics of DCIS lesions. In summary, miFISH analysis and phylogenetic tree modeling allow an in-depth characterization of precursor lesions and their evolutionary trajectory. We anticipate that this approach will ultimately help to stratify progression risk in patients with DCIS. Citation Format: Irianna Marie Torres, Leanora Hernandez, Jausheng Tzeng, Russell Schwartz, Alejandro Schaffer, Edward Michael Gertz, Daniela Hirsch, Steven Brower, Miguel Sanchez, Gert Auer, Kerstin Heselmeyer-Haddad, Thomas Ried. Genomic dynamics in breast cancer progression analyzed by miFISH analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2189.