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A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P < 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.

PDF file - 145K, Supplementary Table 1. Studies in the Ovarian Cancer Association Consortium (OCAC) are listed, as well as the abbreviation, location, type, and number of cases and controls for each study. Supplementary Table 2. The number of cases included in the analysis from each OCAC study site is listed by histologic subtype. Supplementary Table 3. Gene symbols and IDs are listed for NF-κB pathway genes that were tagged in this study, as well as chromosome position, number of SNPs tagged, and bin coverage of each gene using Hapmap or 1000 genomes as a reference. Supplementary Table 4. Reasons and numbers of samples excluded from the analysis following the sample quality control are described. Supplementary Table 5. We evaluated rs17561 and rs6785617 for interactions with known epidemiologic risk factors for risk of clear cell and LMP tumors, respectively, and report interaction p-values in the table below.

Background: Ovarian carcinoma is composed of five major histologic types, which associate with outcome and predict therapeutic response. Our aim was to evaluate histologic type assessments across the centers participating in the Ovarian Tumor Tissue Analysis (OTTA) consortium using an immunohistochemical (IHC) prediction model. Methods: Tissue microarrays (TMA) and clinical data were available for 524 pathologically confirmed ovarian carcinomas. Centralized IHC was conducted for ARID1A, CDKN2A, DKK1, HNF1B, MDM2, PGR, TP53, TFF3, VIM, and WT1, and three histologic type assessments were compared: the original pathologic type, an IHC-based calculated type (termed TB_COSPv2), and a WT1-assisted TMA core review. Results: The concordance between TB_COSPv2 type and original type was 73%. Applying WT1-assisted core review, the remaining 27% discordant cases subdivided into unclassifiable (6%), TB_COSPv2 error (6%), and original type error (15%). The largest discordant subgroup was classified as endometrioid carcinoma by original type and as high-grade serous carcinoma (HGSC) by TB_COSPv2. When TB_COSPv2 classification was used, the difference in overall survival of endometrioid carcinoma compared with HGSC became significant [RR 0.60; 95% confidence interval (CI), 0.37–0.93; P = 0.021], consistent with previous reports. In addition, 71 cases with unclear original type could be histologically classified by TB_COSPv2. Conclusions: Research cohorts, particularly those across different centers within consortia, show significant variability in original histologic type diagnosis. Our IHC-based reclassification produced more homogeneous types with respect to outcome than original type. Impact: Biomarker-based classification of ovarian carcinomas is feasible, improves comparability of results across research studies, and can reclassify cases which lack reliable original pathology. Cancer Epidemiol Biomarkers Prev; 22(10); 1677–86. ©2013 AACR.

Prostate cancer is the most common cancer among men in the United States and is second to lung cancer as a cause of cancer death. The occurrence of prostate cancer is not uniform among different races. It is more prevalent among African Americans than either Caucasians or Asians. This increased risk for prostate cancer among men of African descent is particularly strong in the Caribbean nation of Trinidad and Tobago where the prevalence of screening-detected prostate cancer was 3-fold higher among Tobago men of African descent compared to U.S. Caucasian men. In the present study we test the hypothesis that a polymorphism in the binding domain of gp130 in association with inflammation induced by HHV-8 increases the risk of prostate cancer. As a result, Tobago men with the high-risk gp130 allele whose prostates express HHV-8 proteins have an increased risk of prostate cancer (OR=3.1, 95% C.I. 1.18-8.11). In addition, studies in B cell lines derived from Tobago men with the three different genotypes showed that IL-6 causes a significant increase in cell division based on genotype with a resulting increase in STAT-3 activation via phosphorylation. These results will also aid in defining better a treatment plan for prostatic inflammation that is a result of viral infection and will provide a better understanding of disease progression. Citation Format: Jill D. Henning, Kathrine Kercher, Clareann H. Bunker, Robert E. Ferrel, Alan L. Patrick, Frank J. Jenkins. Analysis of the interaction of human herpes virus 8 and gp130 in prostate cancer risk [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B006.

Objective: to examine the association between breastfeeding patterns and risk of epithelial ovarian cancer. Methods: We examined duration, age, and timing factors related to breastfeeding episodes among parous women in a population-based case-control study conducted in western PA, eastern OH, and southwestern NY from 2003-2008 (the HOPE Study). We compared 689 incident cases of epithelial ovarian cancer (EOC) to 1572 community controls frequency-matched to cases by age and three-digit telephone exchange. Multivariable unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for EOC associated with breastfeeding patterns adjusting for age, race, parity, duration of oral contraceptive use, education, tubal ligation, hysterectomy, talc use, and family history of breast or ovarian cancer. Results: Compared to never breastfeeding, breastfeeding any offspring was associated with a significant 28% reduction in EOC risk (OR=0.72; 95% CI=0.58-0.90). That protection appeared to last more than 30 years (OR=0.70, 95%CI=0.54-0.92), although the magnitude of the protection decreased over time (OR=0.54, 0.74, 0.83 and 0.70 for Conclusions: Breastfeeding is protective against EOC. Although this protection decreases over time, it persists for more than 30 years. Longer total duration and increasing number of offspring nursed increase the protective effect, as does an earlier age at first breastfeeding episode. Impact: Interventions to encourage and support women in breastfeeding can reduce EOC risk. This abstract is also being presented as Poster B18. Citation Format: Danielle Wallack, Clareann H. Bunker, Robert P. Edwards, Joseph L. Kelley, Kunle Odunsi, Kirsten Moysich, Roberta B. Ness, Maria Mori Brooks, Francesmary Modugno. Breastfeeding protects against epithelial ovarian cancer: Results of the HOPE Study. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr PR10.

Background: Survival estimates are traditionally reported from the time of diagnosis or remission. Although these estimates provide important information, they are not necessarily still applicable to patients who have already survived a period of time after their initial diagnosis and treatment. Conditional disease-free survival accounts for elapsed time since achieving remission and may offer more relevant prognostic information to patients and their clinicians. More accurate information about risk of recurrence will not only allow patients and clinicians to make better informed decisions regarding follow-up care after cancer treatment but may also improve quality of life by ameliorating patients’ fear of recurrence. This study aimed to estimate conditional disease-free survival among ovarian cancer patients and to identify factors that impact disease-free survival. To our knowledge, no prior studies have assessed conditional disease-free survival among ovarian cancer patients. Patients and Methods: We used data collected as part of the Hormones and Ovarian Cancer Prediction (HOPE) case-control study; in total, 404 cases, all of whom had achieved remission after a diagnosis of ovarian cancer, were included in the current analyses. The majority of patients were Caucasian, median age at diagnosis was 58.6 years, and 5.5% had a family history of ovarian-only or breast and ovarian cancer. Demographic and lifestyle information was collected at enrollment; disease and clinical characteristics, including follow-up data, were abstracted from medical records. Disease-free survival was calculated using the Kaplan-Meier method. Conditional disease-free survival estimates were computed using cumulative disease-free survival estimates. Results: Median disease-free survival was 2.54 years (range: 0.03-9.96 years) and 3-year disease-free survival was 48.2%. The probability of surviving an additional 3 years without recurrence, conditioned on having already survived 1, 2, 3, 4, and 5 years after remission, was 63.8%, 80.5%, 90.4%, 97.0% and 97.7%, respectively. Initial differences in disease-free survival at time of remission between age, stage, histology and grade groups diminished over time. Conclusion: Disease-free survival estimates for ovarian cancer patients improved dramatically over time, in particular among those with poorer initial prognoses. Our results demonstrate that conditional disease-free survival is a more relevant measure of prognosis for ovarian cancer patients who have already achieved a period of remission and that time elapsed since remission should be taken into account when making follow-up care decisions. Citation Format: Michelle Kurta, Robert Edwards, Kirsten Moysich, Kathleen McDonough, Marnie Bertolet, Joel Weissfeld, Janet Catov, Francesmary Modugno, Clareann Bunker, Roberta Ness, Brenda Diergaarde. Prognosis and conditional disease-free survival among ovarian cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-273. doi:10.1158/1538-7445.AM2014-LB-273

Background: Prostate cancer is more prevalent among African Americans than Caucasians and this increased risk among men of African descent is not limited to the United States, suggesting a role for genetic or shared lifestyle factors. In our previous population-based study on the Caribbean island of Tobago, the prevalence of screening-detected prostate cancer was 3-fold higher compared to similarly screened US Caucasian men. The island of Tobago is 95% of African descent and represents a homogeneous population for studying genetic factors associated with disease. Inflammation has also been suggested as a co-factor for increased prostate cancer risk, and studies have demonstrated positive correlations with prostatitis and sexually transmitted diseases. We have previously reported an increased seroprevalence to human herpesvirus 8 (HHV-8) among Tobago men with prostate cancer (n=138) compared to Tobago age-matched controls (n=140; OR 2.24, 95% C.I. 1.29-3.90). In the current study we have expanded our earlier findings demonstrating an association between HHV-8 infection, inflammation and a polymorphism in the IL-6 signaling receptor gp130 in prostate cancer risk among men of African descent. Methods: Biopsies (n=19) and prostectomies (n=20) of Tobago men with histologically confirmed prostate cancer were analyzed by immunohistochemistry for expression of the HHV-8 proteins LANA-1, K8.1 or vIL-6 and the presence of B cells and macrophages. SNP analysis for the G148R polymorphism was performed on Tobago (n=1,217) and U.S. (n=149) men. Lymphoblastoid cell lines (LCLs) were constructed from Tobago men representing the three possible genotypes of the gp130 polymorphism (G148R; G/G, G/R and R/R). Growth curve analyses were performed on the LCLs grown in the absence or presence of 25ng/ml IL-6. Results: HHV-8 proteins were expressed in 75% of the prostate biopsies and 100% of the prostectomies of seropositive men. Viral protein expression was more prevalent in sections containing cancer compared to cancer free sections (p=0.001). Seropositive men who were homozygous for the R/R gp130 allele were significantly more likely to have prostate cancer than seronegative men who were homozygous for the G/G allele (n=400; OR 3.1, 95% C.I. 1.18-8.11). Increased inflammation (macrophage infiltration) in non-cancerous sections was associated with gp130 status (p=0.023). LCLs homozygous for the high risk gp130 allele demonstrated a 250% increase in growth compared to the homozygous low risk. Summary: Taken together, our results support the hypothesis that HHV-8 establishes a chronic infection producing chronic inflammation which, in association with a polymorphism in the IL-6 signaling receptor, results in increased prostate cancer risk among men of African descent in Tobago. 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 5726.