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Purpose: High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers. Experimental Design: We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS). Results: LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOH and was further divided into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other high-grade breast cancers. Our analysis revealed an LOH cluster with lower treatment resistance and a significant correlation between LOH burden and PFS. Conclusions: Separating HGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors. Clin Cancer Res; 18(20); 5806–15. ©2012 AACR.

To determine whether urinary matrix metalloproteinases (MMPs) predict the presence of ovarian cancer in patients with CA125 levels below the normal threshold of 35U/mL, a critical group of patients for whom no ovarian cancer biomarker is currently available. To determine whether these noninvasive biomarkers provide clinically useful information in the general ovarian cancer patient population as well.ELISA analyses and substrate gel electrophoresis detected the levels and activity of urinary MMP-2, MMP-9, MMP-9/neutrophil gelatinase-associated lipocalin (NGAL) complex, and MMP-9 dimer in all ovarian cancer patients (n=97), those with CA12535U/mL (n=26) and controls (n=81).In patients with CA12535U/mL, receiver-operating characteristic (ROC) area under curve (AUC) analysis demonstrated that either urinary MMP-2 or MMP-9 or NGAL significantly discriminated between controls and ovarian cancer patients with normal CA125. Multivariate logistic regression revealed that the combination of urinary MMP-2 and MMP-9 provided the best diagnostic accuracy when multiplexed. When further multiplexed with age, the diagnostic accuracy of these biomarkers increased to a significant AUC of 0.820. These findings were consistent among the general ovarian cancer population studied as well, where the combination of urinary MMP-2 and MMP-9 multiplexed with age resulted in a highly significant AUC of 0.881. Pearson chi-square analysis revealed that higher urinary levels of either MMP-2 or MMP-9 were strongly associated with the increasing percentage of women with ovarian cancer independent of CA125 levels.This study demonstrates the potential utility of urinary MMP-2 and MMP-9 to differentiate between ovarian cancer patients with normal CA125 levels and controls and suggests that urinary MMP-2 and MMP-9 may be a clinically useful aid in the diagnosis of advanced or recurrent ovarian cancer.

The majority of women with ovarian cancer are diagnosed with advanced disease (FIGO stage III and IV) and have a five year survival rate of approximately 20%. In contrast, the survival rate of women diagnosed with stage I ovarian cancer is greater than 90%, highlighting an unmet and dire need for accurate and reliable diagnostic tests for the early detection of ovarian cancer. We have previously demonstrated that urinary matrix metalloproteinases (MMPs) are independent predictors of disease status and stage in a variety of human cancers as well as predictors of breast cancer risk. We have also reported that neutrophil gelatinase-associated lipocalin (NGAL) is present in the urine of women with metastatic breast cancer and that the levels of urinary NGAL are significantly higher in these patients compared to normal controls. In the current study, we asked whether urinary MMPs and NGAL, alone or in combination, could provide useful clinical information with respect to the presence of ovarian cancer. Urine samples were obtained from a total of 166 women: 96 women with known FIGO stage III and IV ovarian cancer (newly diagnosed and recurrent) and 70 normal controls. All urine samples were analyzed for NGAL levels by ELISA and for urinary MMP levels by quantitative gelatin zymography. We found that urinary NGAL, MMP9-dimer, MMP9/NGAL complex, MMP9, and MMP2 were each significantly elevated in the urine of women with ovarian cancer compared to normal controls (p55 years of age with significant measurable levels of urinary MMP9-dimer and MMP2 had a 95% probability of ovarian cancer (95% CI= 85-98% probability), AUC = 0.860 (95% CI = 0.802 – 0.915 (p (Supported by NIH P01 CA045548, the Weitzman Family Foundation and Ovations for the Cure) 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 2719.

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.