Abstract 2135: Genetic relationships between ovarian and breast cancers

Abstract

Abstract Background: Ovarian cancer is the most fatal gynecological cancer, and breast cancer is the most common malignant disease in women. The existence of a common etiology to these diseases is suggested by the fact that BRCA1 or BRCA2 germline mutation-associated tumors are primarily restricted to the breast and the ovary. While in the ovary, BRCA mutations are associated with high-grade serous carcinomas (HGSC), and in the breast, BRCA1 mutation carriers can develop tumors that are phenotypic copies of sporadic basal-like breast cancer (BLBC). Hypothesis/objective: We hypothesize that HGSC and BLBC's are similar with respect to genetic instability and chromosomal aberrations and that these similarities may reflect their common pathogenesis. The objective of our proposed project is to identify the common patterns of loss of heterozygosity (LOH) and regions of gain or amplification shared by the two diseases. Materials and Methods: Fifty two HGSC were collected and tumor cells enriched by needle microdissection from frozen tissue sections if available to remove stroma before DNA isolation. DNA was subjected to Affymetrix 250K SNP array analysis. SNP array data from a DFCI-BWH cohort of breast cancers were analyzed for comparison. dChip software was used for LOH and copy number analysis. Results: LOH pattern-based hierarchical clustering defined two subgroups in HGSC, the major subgroup (∼60% of the cases) with high-level LOH [mean fraction of LOH/genome (FLOH) 36.6%] and the minor subgroup (∼40% of the cases) with lower levels of LOH (mean FLOH 13%). These data suggest the differences in chromosomal instability in the two subgroups. The major group of ovarian tumors shared similar high levels of LOH with BRCA1-associated or sporadic BLBCs. In contrast, the lower frequency of LOH in the minor subgroup of serous tumors is similar to that in HER2 positive or estrogen receptor positive luminal breast tumors. LOH on chromosome 17 is the most common alteration in ∼78% of the cases. However, frequent LOH on chromosomes 4, 5, 9, 13, 22, and X is characteristic of the major ovarian cancer subgroup defined by this analysis. These features are also found in BLBC, but not in non-basal-like breast tumors. Chromosomal copy gain/amplification is most common on chromosome 8q (>40%), and frequent on 3q, 19q12, 19q13, and 20q (>15%) in two subgroups of serous ovarian cancer. These changes on 8q and 20q are shared by a proportion of breast cancers. Conclusion: A major subset of serous ovarian cancer, like breast BLBCs, reveals a high degree of chromosomal instability with high levels of LOH. This suggests a defect(s) in maintenance of genome stability. Another subset of serous cancer, like non-basal-like breast tumors, has a lower degree of genome instability with low levels of LOH. We propose that these features may reflect a different pathogenesis of the two subgroups of serous ovarian tumors, and possibly are associated with differences in response to chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2135.