Vierkant, Robert A.

Abstract Background: While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). Methods: The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E−6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E−6; Pcorrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. Impact: This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446–54. ©2016 AACR.

AbstractBackground: Hormonal and reproductive history has been associated with risk of some hematologic malignancies, but their role in myeloproliferative neoplasms (MPN) is largely unknown.Methods: Using a population-based cohort study, we evaluated the association of these factors with risk of MPN overall, and for essential thrombocythemia (ET) and polycythemia vera (PV) specifically. Incident MPN cases from 1993 to 2004 were identified via linkage to Medicare. RR and 95% confidence intervals (CI) were estimated utilizing Cox proportional hazard regression.Results: After >250,000 person-years of follow-up, 257 cases of MPN were identified (172 ET, 64 PV). Ever use of hormone therapy (HT) was associated with an increased risk of ET (RR = 1.63; 95% CI, 1.19–2.23) but a decreased risk of PV (RR = 0.58; 95% CI, 0.34–0.98). There were no statistically significant associations of oral contraceptives or reproductive factors with MPN risk overall, or by MPN subtype. Bilateral oophorectomy was associated with increased risk of ET (RR = 1.58; 95% CI, 1.11–2.25) and decreased risk of PV (RR = 0.32; 95% CI, 0.12–0.88). There was no association of ovulatory years with ET risk; however, there was increased risk of PV (RR = 1.68 for >36.8 compared with ≤27.6 years; P trend = 0.045). Adjustment for potential confounding factors did not alter these associations.Conclusions: HT use and bilateral oophorectomy had opposite associations for ET and PV. Except for ovulatory years and PV risk, reproductive history did not appear to play a role in the etiology of MPN.Impact: This study suggests different mechanistic impacts of estrogen, and perhaps distinct etiologies, for the two major MPN subtypes. Cancer Epidemiol Biomarkers Prev; 25(1); 151–7. ©2015 AACR.

BACKGROUNDWomen with benign breast disease (BBD) have an increased risk of developing breast cancer (BC). Nearly 30% of all BCs develop in women with prior BBD. Information regarding features of the expected number of BCs after BBD would enhance individualized surveillance and prevention strategies for these women. In the current study, the authors sought to characterize BCs developing in a large cohort of women with BBD.METHODSThe current study cohort included 13,485 women who underwent breast biopsy for mammographic or palpable concerns between 1967 and 2001. Biopsy slides were reviewed and classified as nonproliferative disease, proliferative disease without atypia, or atypical hyperplasia. BCs were identified by follow‐up questionnaires, medical records, and Tumor Registry data. BC tissues were obtained and reviewed.RESULTSWith median follow‐up of 15.8 years, 1273 women developed BC. The majority of BCs were invasive (81%), of which 61% were ductal, 13% were mixed ductal/lobular, and 14% were lobular. Approximately two‐thirds of the BC cases were intermediate or high grade, and 29% were lymph node positive. Cancer characteristics were similar across the 3 histologic categories of BBD, with a similar frequency of ductal carcinoma in situ, invasive disease, tumor size, time to invasive BC, histologic type of BC, lymph node positivity, and human epidermal growth factor receptor 2 positivity. Women with atypical hyperplasia were found to have a higher frequency of estrogen receptor‐positive BC (91%) compared with women with proliferative disease without atypia (80%) or nonproliferative disease (85%) (P = .02).CONCLUSIONSA substantial percentage of all BCs develop in women with prior BBD. The majority of BCs after BBD are invasive tumors of ductal type, with a substantial number demonstrating lymph node positivity. Of all the BCs in the current study, 84% were estrogen receptor positive. Prevention therapy should be strongly encouraged in higher‐risk women with BBD. Cancer 2016;122:378–385. © 2015 American Cancer Society.

Abstract Purpose: Low breast cancer screening participation and adherence to guidelines is problematic. Our prior work found that on average 18% of women from four tribes adhered to Indian Health Service (IHS) mammographic screening guidelines over five years (study funded by Native American Research Centers for Health (NARCH IV). We sought to identify how adherent (persistent) and non-adherent (sporadic) screeners may differ by demographic and theoretical mediators that have successfully guided interventions in other health disparities populations. As part of planning interventions to increase AI/AN women's persistent screening, we characterized differences in persistent and sporadic screeners' responses to Social Norms and Health Beliefs in the context of social networks. Methods: From 2013-2014, we interviewed 55 recruited women (41 sporadic screeners and 14 persistent screeners) who had been randomly assigned unique identifiers. Data from interviews included demographic characteristics, assessments of health literacy, and social relationships from theoretical perspectives of: Theory of Planned Behavior, Social Support, Social Norms, Health Beliefs, and Social Networks. In this study, we examined areas that distinguished persistent from sporadic screeners—social norms and health beliefs--and we conceptualized the make-up of screeners' social networks to consider members by their generational status relative to the screener. We coded and categorized data; Fisher's Exact Test and Kruskal-Wallis Test were applied as appropriate. Results: We identified three mediators with four significant differences. 1. Social Norms: (A) Persistent screeners were significantly more likely to believe reservation women favored getting an annual mammogram while sporadic screeners were more likely to believe women were against getting annual mammograms (P = 0.03). Responses are consistent with Social Norms theory, but screeners' beliefs about friends' screening participation appear less consistent with the theory. (B) Persistent screeners by a large proportion believed friends obtained fewer mammograms than themselves while sporadic screeners had no prevailing view (P = 0.02). 2. Health Beliefs (susceptibility to breast cancer): (C) While sporadic screeners expressed considerable uncertainty about their susceptibility, persistent screeners expressed no uncertainty (P = 0.02). 3. Social Networks: (D) Examination of the generational membership of screeners' Social Networks showed that sporadic screeners' networks had significantly more members from generations younger than themselves compared to persistent screeners' networks ( P = 0.01). Conclusions: Screeners with younger social networks may in part be influenced to be sporadic screeners because they do not benefit from exposure to more mature and experienced individuals in their social networks. The excess of younger generation members in sporadic screeners' networks may expose them generally to people who do not screen (or have limited screening experience) due to age. This exposure would confirm for them that reservation women generally do not favor screening and would explain their mixed view of friends' screening behavior. The younger membership of sporadic screeners' networks also may explain why this group would express substantial uncertainty about their own susceptibility to breast cancer relative to other women. If the network is not of an age where breast cancer and screening are pertinent topics, screeners may not have a knowledgebase (accurate or not) from which to build their views. We anticipate further testing to ascertain the role of social networks in the views and behaviors of sporadic and persistent screeners before considering any interventions. Citation Format: Corinna Sabaque, Ann M. Nicometo, Robert Vierkant, Wesley O. Petersen. Do generational cohort differences in social networks influence persistent and sporadic screeners' perceptions of breast cancer screening? [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B73.

ABSTRACTEpithelial‐mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single‐nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome‐wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT‐related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive‐cancer patients and 23,447 controls. A P‐value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07–1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69–0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.

Abstract Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P &lt; 0.05 and FDR &lt; 0.05). These results were replicated (P &lt; 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

Abstract Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.

Abstract Purpose: The ultimate purpose of these studies and the proposed study is to use community-based interventions to increase overall use of mammographic services and to increase adherence with tribes' screening guidelines. Our immediate purposes by study: For Study 1, the purpose was to understand the risk and screening adherence profiles of women from four Bemidji Area tribes; for Study 2, the purpose was to ascertain whether non-adherent screeners and adherent screeners could be differentiated on any of six theoretical mediators of health behavior; in the proposed Study 3, the purpose is to use theoretical mediators that distinguish adherent and non-adherent screeners to design and test interventions to increase screening participation and adherence with tribes' screening guidelines. Experimental Procedures: All studies were designed to reflect principles of community-based participatory research. Study 1 was a chart review study that involved four tribes. Each tribe desired different levels of involvement that ranged from close control of all elements of the chart review to assigning the investigators to do the retrieval, review, and replacement of the medical records, and all elements of the analysis. All tribes managed the unique identifiers book which was a list of all women who were 40 years and older who had no prior history of breast cancer. Investigators retained only the unique identifiers and each individual's associated screening history and risk factors. Tribes received aggregated results from the study, but did not receive information on individual women's screening adherence or risk factors. Study 2, is guided by a community advisory committee that meets quarterly and involves one tribe. The study employs one tribal member and one tribal subcontractor, and has supported one student participant. The study team interviewed 55 women and used the results to develop a survey that is being administered to approximately 1400 women who are age 40 and older. Both the interviews and the survey are designed to examine the influence of six theoretical mediators (social norms, social networks, social support, health literacy, health beliefs, and theory of planned behavior) and demographic features on the behaviors of adherent and non-adherent mammographic screeners. Study 3 will involve four tribes and is designed to use the findings from Study 2 to develop and test interventions based on influential screening mediators. Each tribe has identified members who will serve on tribal research and advising units that will determine the specific interventions and receive training and mentoring to design and administer the interventions. The proposed interventions will be based on a case-control intervention design. Unpublished Data to Date: STUDY 1 showed that there were few significant differences (p = 0.05) based between adherent and non-adherent screeners based on risk factors. STUDY 2 interview results have shown some significant differences (p= 0.05) between adherent and non-adherent screeners related to self-efficacy (health beliefs model), perceived community support for annual mammograms (social norms), presence of 3rd degree relatives in social networks. There were no significant differences associated with health literacy, social support, and the theory of planned behavior. Conclusions: Findings in Study 2 show that potential differences between adherent and non-adherent screeners justify continuation to the survey phase. Should results of the survey demonstrate significant differences in the influential mediators of adherent compared to non-adherent screeners, follow-up with the intervention study (Study 3) will be an important next step. Citation Format: Wesley Petersen, Ann Nicometo, Robert Vierkant. Advancing toward interventions: Summary of two projects and a proposed intervention to improve mammography participation in Bemidji area native women. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B91. doi:10.1158/1538-7755.DISP13-B91