Radner Familial Ovarian Cancer Registry Research Articles

Frequencies of nonovarian cancers within the Gilda Radner Familial Ovarian Cancer Registry

Frequencies of nonovarian cancers within the Gilda Radner Familial Ovarian Cancer Registry

Abstract LB-87: Association between global DNA hypomethylation in leukocytes and risk of ovarian cancer

Abstract DNA hypomethylation was the first recognized epigenetic defect in human cancer. Most human cancers display global DNA hypomethylation, which is typically manifested by reduced 5-methyl-2′-deoxycytidine (5mdC) levels and/or reduced methylation of repetitive DNA elements, including LINE-1 sequences. DNA hypomethylation may contribute to oncogenesis by promoting genomic instability and oncogene activation. Little is currently known about global DNA methylation status in normal tissues from cancer patients, or in individuals at elevated cancer risk. Recently, we reported that leukocytes from breast cancer patients show a significant reduction in global DNA methylation as compared to controls (p<0.001) (Choi et al., Carcinogenesis, 30, 1889-97). Similar findings have also been reported in colorectal, head and neck, and bladder cancers. Systemic alterations in DNA methylation could provide a novel means for early cancer detection, particularly in asymptomatic cancers such as ovarian cancer. In the current study, we examined global DNA methylation in leukocytes from ovarian cancer patients. Importantly, ovarian cancer patient leukocytes show global DNA hypomethylation, as assessed by quantitative LINE-1 bisulfite pyrosequencing, as compared to controls (p=0.0146). However, 5mdC levels did not show a significant difference between cases and controls (p=0.1178, 95% CI −0.1091 to 0.9056), and hypomethylation of LINE-1 does not appear to correlate with 5mdC levels. We examined the relationship between LINE-1 methylation in leukocytes and LINE-1 methylation in tumor tissues from matched ovarian cancer patients. Notably, there was not an association between these two tissues, using Pearson correlation (p=0.58, 95% CI −0.292-0.4889). We analyzed LINE-1 methylation in different histological subtypes of ovarian cancer and found a difference between clear cell cases as compared to controls (p<0.05). Cases with endometrioid histology showed significant difference in methylation as compared to serous cases (p<0.05) and all cases combined (p<0.05), but not controls. Currently, we are extending our studies to measure methylation of the Alu repetitive DNA element, which lies within a different sequence context from LINE-1. Furthermore, we are assessing whether LINE-1 methylation is altered in leukocytes from patients at high risk for developing ovarian cancer, using samples obtained from the Gilda Radner Familial Ovarian Cancer Registry. In summary, our studies reveal that LINE-1 sequences are hypomethylated in leukocytes from ovarian cancer patients, and that LINE-1 hypomethylation in leukocytes may be linked to particular disease subtypes. This discovery could lead to the development of novel diagnostics for ovarian cancer. 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 LB-87.

Complex Segregation Analysis of Pedigrees from the Gilda Radner Familial Ovarian Cancer Registry Reveals Evidence for Mendelian Dominant Inheritance

BackgroundFamilial component is estimated to account for about 10% of ovarian cancer. However, the mode of inheritance of ovarian cancer remains poorly understood. The goal of this study was to investigate the inheritance model that best fits the observed transmission pattern of ovarian cancer among 7669 members of 1919 pedigrees ascertained through probands from the Gilda Radner Familial Ovarian Cancer Registry at Roswell Park Cancer Institute, Buffalo, New York.Methodology/Principal FindingsUsing the Statistical Analysis for Genetic Epidemiology program, we carried out complex segregation analyses of ovarian cancer affection status by fitting different genetic hypothesis-based regressive multivariate logistic models. We evaluated the likelihood of sporadic, major gene, environmental, general, and six types of Mendelian models. Under each hypothesized model, we also estimated the susceptibility allele frequency, transmission probabilities for the susceptibility allele, baseline susceptibility and estimates of familial association. Comparisons between models were carried out using either maximum likelihood ratio test in the case of hierarchical models, or Akaike information criterion for non-nested models. When assessed against sporadic model without familial association, the model with both parent-offspring and sib-sib residual association could not be rejected. Likewise, the Mendelian dominant model that included familial residual association provided the best-fitting for the inheritance of ovarian cancer. The estimated disease allele frequency in the dominant model was 0.21.Conclusions/SignificanceThis report provides support for a genetic role in susceptibility to ovarian cancer with a major autosomal dominant component. This model does not preclude the possibility of polygenic inheritance of combined effects of multiple low penetrance susceptibility alleles segregating dominantly.

The role of hereditary nonpolyposis colorectal cancer in the management of familial ovarian cancer

Purpose: Familial ovarian cancer is most often associated with hereditary breast and ovarian cancer, implicating mutations in the BRCA1 and BRCA2 genes. Hereditary nonpolyposis colorectal cancer, another common syndrome, is also associated with ovarian cancer and is caused by DNA mismatch repair genes. We sought to identify the role of hereditary nonpolyposis colorectal cancer in women with family histories of ovarian cancer.Methods: The likelihood of a genetic syndrome in 226 oophorectomized women in the Gilda Radner Familial Ovarian Cancer Registry was determined by pedigree analysis using clinical criteria and by calculating the probability of a mutation in genes responsible for hereditary breast and ovarian cancer and hereditary nonpolyposis colorectal cancer using available risk models.Results: Some 86% had a BRCA gene mutation likelihood of 7.8% or higher, warranting consideration of hereditary breast and ovarian cancer. Of the 32 women below this threshold, 4 (12.5%) had family histories that met criteria for clinical diagnosis of hereditary nonpolyposis colorectal cancer. In addition, 16 women (7%) with a BRCA mutation likelihood greater than 7.8% met clinical criteria for hereditary nonpolyposis colorectal cancer or warranted its inclusion in the differential diagnosis. Among all study respondents, 9% had family histories warranting consideration of hereditary nonpolyposis colorectal cancer.Conclusion: Hereditary nonpolyposis colorectal cancer should be considered in the differential diagnosis of women with family histories of ovarian cancer.

Role of prophylactic hysterectomy in patients at high risk for hereditary cancers

Background. Current surgical recommendations for ovarian cancer prophylaxis in women at high risk of developing ovarian cancer include bilateral salpingo-oophorectomy (risk-reducing salpingo-oophorectomy (RRSO)). The role of hysterectomy is unclear. We sought to determine outcomes following prophylactic surgery in high-risk women. Methods. We surveyed unaffected members of the Gilda Radner Familial Ovarian Cancer Registry who had undergone oophorectomy from 1981 to 2002. Data were collected and analyzed for statistical significance by the Fisher's Exact Test. Results. Two hundred eighty women were surveyed, and 154 (55%) responded; 97% were Caucasian and 14% reported being Jewish. The median age of the respondents was 51 years (range 29–79); median age at oophorectomy was 41 years (range 15–68). Fifty-eight patients (38%) reported a laparoscopic procedure. One hundred five patients (68%) had a simultaneous hysterectomy, and 4 (3%) had a prior hysterectomy. Forty-four patients (29%) underwent BSO only. Of these 44 patients, 40 (91%) did not require a subsequent hysterectomy. Of the 4 who did, 2 were for leiomyomas, one for menorrhagia and the other was unknown. While not statistically significant, of the 3 patients who developed a subsequent gynecologic malignancy, all had undergone a hysterectomy. There was a statistically significant difference in whether or not the uterus was removed as part of the procedure by time period, whereby women treated prior to 1990 had a higher likelihood of having a hysterectomy ( P = 0.03). Conclusion. The women in our study did not require hysterectomy for prevention of malignancy. We conclude that one should screen for benign gynecological indications for hysterectomy when planning a prophylactic BSO for prevention of ovarian cancer. Other potential risk factors for endometrial cancer, including the role of UPSC in HBOC, remain to be elucidated.

Aberrations of TACC1 and TACC3 are associated with ovarian cancer

BackgroundDysregulation of the human Transforming Acidic Coiled Coil (TACC) genes is thought to be important in the development and progression of multiple myeloma, breast and gastric cancer. Recent, large-scale genomic analysis and Serial Analysis of Gene Expression data suggest that TACC1 and TACC3 may also be involved in the etiology of ovarian tumors from both familial and sporadic cases. Therefore, the aim of this study was to determine the occurrence of alterations of these TACCs in ovarian cancer.MethodsDetection and scoring of TACC1 and TACC3 expression was performed by immunohistochemical analysis of the T-BO-1 tissue/tumor microarray slide from the Cooperative Human Tissue Network, Tissue Array Research Program (TARP) of the National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Tumors were categorized as either positive (greater than 10% of cells staining) or negative. Statistical analysis was performed using Fisher's exact test and p < 0.05 (single comparisons), and p < 0.02 (multiple comparisons) were considered to be significant. Transgenomics WAVE high performance liquid chromatography (dHPLC) was used to pre-screen the TACC3 gene in constitutional DNA from ovarian cancer patients and their unaffected relatives from 76 families from the Gilda Radner Familial Ovarian Cancer Registry. All variant patterns were then sequenced.ResultsThis study demonstrated absence of at least one or both TACC proteins in 78.5% (51/65) of ovarian tumors tested, with TACC3 loss observed in 67.7% of tumors. The distribution pattern of expression of the two TACC proteins was different, with TACC3 loss being more common in serous papillary carcinoma compared with clear cell carcinomas, while TACC1 staining was less frequent in endometroid than in serous papillary tumor cores. In addition, we identified two constitutional mutations in the TACC3 gene in patients with ovarian cancer from the Gilda Radner Familial Ovarian Cancer Registry. These patients had previously tested negative for mutations in known ovarian cancer predisposing genes.ConclusionWhen combined, our data suggest that aberrations of TACC genes, and TACC3 in particular, underlie a significant proportion of ovarian cancers. Thus, TACC3 could be a hitherto unknown endogenous factor that contributes to ovarian tumorigenesis.

Histopathology of familial ovarian tumors in women from families with and without germline BRCA1 mutations

Breast cancers from patients with germline BRCA1 mutations show characteristic histopathologic features. However, similar studies of BRCA1-associated ovarian cancers have reported inconsistent findings. Interobserver differences in histopathologic classification are a significant source of variation, and most studies have obtained histopathologic information from pathology reports rather than from review of histopathology slides. We therefore reviewed the histopathology slides and pathology reports to determine histologic type, grade, and stage for cancers of the ovary or peritoneum in 217 women from 126 families enrolled in the Gilda Radner Familial Ovarian Cancer Registry. Peripheral blood DNA from at least 1 affected member of each family was analyzed for BRCA1 mutations, and tumors from BRCA1 mutation-positive families were compared with those from BRCA1-negative families. Of 66 patients from 36 BRCA1-positive families, 64 had ovarian carcinoma, 1 had an ovarian carcinoma in situ, and 1 had a dysgerminoma. Of 151 patients from 90 BRCA1-negative families, 135 had ovarian carcinoma, 10 had ovarian borderline tumors, 3 had ovarian sex cord/stromal tumors, and 3 had primary peritoneal carcinoma. There were fewer grade 1 (P <.001) and stage I (P =.10) cancers in patients from BRCA1-positive families than in patients from BRCA1-negative families. Neither mucinous nor borderline tumors were found in the BRCA1-positive families. Ovarian cancers arising in women from BRCA1-positive families are more likely to be high grade and nonmucinous than cancers arising in women from BRCA1-negative families. The absence of borderline tumors in patients from BRCA1-positive families adds to accumulating evidence that BRCA1 mutations do not play a role in the development of these tumors. HUM PATHOL 31:1420-1424.

Comparative Study of Ovarian Cancer Histopathology by Registry Pathologists and Referral Pathologists: A Study by the Gilda Radner Familial Ovarian Cancer Registry

Objective. The aim of this study was to evaluate whether there is a significant difference in the pathology diagnoses of women in the Gilda Radner Familial Ovarian Cancer Registry between the two expert Registry pathologists and the referral pathologist. Inaccuracies in verification that ovarian cancer did occur in family members could lead to unnecessary prophylactic surgery or genetic testing.Methods. A retrospective review was performed of (1) site of malignancy; (2) histopathology of malignancy; (3) grade of malignancy; and (4) the presence or absence of malignancy between the Registry and referral pathologists.Results. There was 95.3% complete agreement between the Registry and the referral pathologist on site of origin with a major difference in only 1.0% of the cases. In comparison of histopathology, there was a 61.7% complete agreement, and only 1.0% were considered major differences. There was 68.8% complete agreement in grade of the malignancy, whereas 2.3% were considered major differences.Conclusion. When constructing a family pedigree, it is important to obtain pathology reports to confirm the index case diagnosis of the presence or absence of ovarian cancer. However, because of the small percentage of major differences in diagnosis between the two Registry pathologists and the multiple referral pathologists, we believe genetic counselors and treating physicians can rely, in most instances, on the original histopathology report of verification of ovarian cancer without review of the original histopathology slides when recommending surveillance, genetic testing, and/or prophylactic surgery.

Prophylactic Oophorectomy: Reducing the U.S. Death Rate from Epithelial Ovarian Cancer. A Continuing Debate

The Oncologist 1996;1:326-330 Correspondence: M. Steven Piver, M.D., Department of Gynecologic Oncology, Gilda Radner Familial Ovarian Cancer Registry, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Telephone: 716-845-3110; Fax: 716-845-7608. Received August 1, 1996; accepted for publication August 27, 1996. ©AlphaMed Press 1083-7159/96/$5.00/0 If instead of the title “Prophylactic Oophorectomy: Reducing the U.S. Death Rate from Epithelial Ovarian Cancer,” the title were “Drug X Reducing the U.S. Death Rate from Epithelial Ovarian Cancer,” there would be great media and medical attention worldwide to such a report. Correctly so. Regrettably, there probably is no new Drug X in the foreseeable future that will significantly reduce the death rate from ovarian cancer, be it Taxol®, taxotere, topotecan, gemcitabine, or liposomal doxorubicin—although each may result in significant responses and some prolongation of median survival. Epithelial ovarian cancer is a much more complex disease than anyone envisioned, when it was believed that extensive debulking surgery and the newest cytotoxic chemotherapy would radically reduce the death rate from ovarian cancer in the United States. Over 20 years after the first patient was treated with cisplatin for epithelial ovarian cancer, the annual death rate from ovarian cancer continued to increase. Just in the past decade, the number of women in the United States dying from ovarian cancer has increased 18% (Fig. 1) [1]. Although ovarian cancer is estimated to account for 26,700 cases and 14,800 deaths in 1996, it is a low-prevalence disease in comparison with breast cancer, which in 1996 is estimated to account for 185,700 cases and 44,560 deaths. Inexplicably, similar to breast cancer, the lifetime risk for ovarian cancer in the United States continues to increase. The most recent Surveillance, Epidemiology and End Results (SEER) calculations of lifetime risk for ovarian cancer are that 1 in 55 women will develop ovarian cancer over their lifetime, or 1.8%, up from the 1970 figures of 1 in 70, or 1.4% [2]. The 1.8% baseline lifetime risk for the general population is used to estimate the lifetime risk of known ovarian cancer risk factors (Table 1). Even utilizing what are now believed to be two of the most effective cytotoxic drugs against stage III and IV epithelial ovarian cancer, Taxol® and cisplatin, researchers reported that this resulted in an increase in the median disease-free survival of only five months, as compared with those women allocated to receive cisplatin and cyclophosphamide (median diseasefree survival of 18 and 12.9 months, respectively), felt then to be the standard therapy [3]. Patients treated with Taxol® and cisplatin survived a median of 14 months longer than those

Risks of cancer among members of families in the Gilda Radner Familial Ovarian Cancer Registry.

Increasing scientific and public interest in hereditary cancer syndromes has created a need for estimates of lifetime cancer risks among members of families with such syndromes. Data from the Gilda Radner Familial Ovarian Cancer Registry were used to evaluate risk for cancers of the breast, cervix, uterus, colorectum, and prostate in members of 143 families containing three or more reported cases of ovarian cancer among first- or second-degree relatives. These risks were compared with those that were expected based on general population rates obtained from the Connecticut Tumor Registry. Overall, family members' risk of cancer at any nonovarian site was 1.5 times that of the general population (P < 0.001). Among female members, risk for cancer of the breast was 2.5 times that of the general population. Risk for cancer of the uterus was 5 times that of the general population and increased with increasing number of first-degree relatives with ovarian cancer. Among male family members having three or more first-degree relatives with ovarian cancer, prostate cancer risk was 4.5 times that of the general population. No excess risks were observed for cancer of the colorectum. These data support previous reports of coaggregation of cancer of the breast, uterus and ovary, and suggest coaggregation between cancer of the ovary and prostate. Differences in cancer risk profiles observed in these families with multiple ovarian cancer and in carriers of the gene BRCA1 suggest that hereditary ovarian cancer is genetically heterogeneous.