Pepłońska, Beata

Abstract Background: Prior infection with Chlamydia trachomatis, indicated by the presence of circulating antibodies against plasmid encoded glycoprotein 3 (Pgp3), is associated with an increased risk of ovarian cancer. The aberrant expression of p53 can be found in up to 95% of ovarian cancers and is an especially frequent feature among high-grade serous cancers. Prior studies have described mechanisms by which Chlamydia reprogram DNA damage response pathways, including those involving p53. However, tumor level expression of p53 among women with and without prior exposure to chlamydia is poorly described. We evaluated whether the association between prior chlamydial infection (Pgp3 seropositivity) and ovarian cancer varied by tumor p53 expression and whether Pgp3 seropositivity was associated with ovarian tumor expression of p53. Methods: Available serologic data for Pgp3 in tubo-ovarian cancer cases (n=155) and matched controls (n=556) from the Polish Ovarian Cancer Study were evaluated and stratified by p53 mutation status of cases inferred from immunohistochemical staining. Expression of p53 was assessed in tissue microarrays (2+ cores per case) and classified as aberrant (i.e., no expression or overexpression: ≥60% positive cells) or wild- type. Multinomial logistic regression with controls as the reference was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of Pgp3 seropositivity with ovarian cancer with stratification by p53 expression among the cases. Logistic regression among cases was only used to evaluate the association between Pgp3 and aberrant p53 expression. Results: Aberrant p53 expression was found in 70% of cases. Pgp3 seropositivity was associated with increased ovarian cancer risk (OR [95% CI]: 1.86 [1.28-2.68]). Pgp3 seropositivity was associated with risk for both p53 aberrant (1.79 [1.16-2.75]) or p53 wild-type ovarian cancers (2.06 [1.11-3.80], p for heterogeneity=0.80). When restricted to high-grade serous cancers, the association with Pgp3 was also not differential by p53 status (p for heterogeneity=0.16; 83% of high-grade serous cases had aberrant p53 expression). Among women with cancer, Pgp3 seropositivity was not associated with aberrant p53 expression (versus wild-type, OR [95% CI]: 0.90 [0.45-1.81], spearman correlation: -0.05, p-value=0.55). Conclusion/Discussion: Our study provides support that previous C. trachomatis infection is associated with ovarian cancer, irrespective of aberrant p53 tumor expression. There are many possible mechanisms by which Chlamydia may influence ovarian cancer. While the current results do not rule out interactions with p53-related pathways, it is likely that C. trachomatis increases ovarian cancer risk via multiple mechanisms (e.g., infection related sequelae like chronic inflammation). Citation Format: Sarina Pollat, Nicolas Wentzensen, Tim Waterboer, Manila Hada, Jolanta Lissowska, Beata Peplonska, Mark E. Sherman, Kara A. Michels, Britton Trabert. Prior chlamydial infection and ovarian cancer risk by tumor p53 expression [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A051.

Abstract Background: Pelvic inflammatory disease (PID) has been associated with ovarian cancer and Chlamydia trachomatis (chlamydia) is the leading cause of PID in the developed world. Primary infection with chlamydia is often asymptomatic and may persist for several months/years, thus ascertainment of PID in epidemiologic studies is challenging due to pervasive misclassification and under-reporting. To improve our understanding of the role of chlamydia and other infectious agents in developing ovarian cancer, we evaluated serologic markers of infection with incident ovarian cancer using a staged approach in two independent populations. Methods: Studies included: 1) a case-control study conducted in Poland of 278 ovarian cancer cases diagnosed from 2000 to 2003 and age- and study site-matched controls (n=556) and 2) a nested case-control study from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial including 160 women who eventually developed ovarian cancer and 159 matched controls. We calculated odds ratios (OR) and 95% confidence intervals (CI) for the association between serologic marker titers and ovarian cancer risk using logistic regression adjusted for matching factors and potential confounders. We evaluated laboratory cutpoints indicative of prior chlamydia infection and tested more stringent marker thresholds, identified in Poland and applied in PLCO, that could be relevant for a PID-like infection. Results: In the Polish study, positivity for the chlamydia plasmid-encoded Pgp3 protein was associated with increased ovarian cancer risk [OR (95% CI): 1.63 (1.20-2.22)]; when a positive result was redefined at a higher titer, ovarian cancer risk increased [cutpoint 2: 2.00 (1.38-2.89); cutpoint 3 (max OR): 2.19 (1.29-3.73)]. All other chlamydia markers measured were associated with increased risk at the more stringent positivity threshold in Poland. In the prospective PLCO study, Pgp3 was associated with elevated risk at the laboratory cutpoint [1.43 (0.78-2.63)]; using higher thresholds, Pgp3 was associated with increased ovarian cancer risk [cutpoint 2: 2.25 (1.07-4.71); cutpoint 3: 2.53 (0.63-10.08)]. In both studies, markers of other infections (i.e., Mycoplasma genitalium, herpes simplex virus-2, human papillomavirus, herpes simplex virus-1, polyomavirus, hepatitis B, hepatitis C, Epstein Barr virus, cytomegalovirus) measured were not associated with risk. Conclusions: In two independent populations, the gold standard serologic marker of prior/current chlamydia infection (Pgp3) was associated with a doubling in ovarian cancer risk, whereas markers of other infectious agents were unrelated. Although these findings need to be replicated, they suggest potential ovarian cancer risk reduction through targeted treatment of chlamydia infections. Citation Format: Britton Trabert, Tim Waterboer, Sally B. Coburn, Louise A. Brinton, Mark E. Sherman, Jolanta Lissowska, Beata Peplonska, Patricia Hartge, Michael Pawlita, Nicolas Wentzensen. Serologic markers of infectious agents and ovarian cancer: Markers of prior Chlamydia trachomatis infection associated with increased ovarian cancer risk in two independent populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4942.

Abstract Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.

Abstract Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1610–6)

Abstract The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r2 = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07–1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01–1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region. [Cancer Res 2009;69(6):2349–57]

Abstract High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)–tagging approach to evaluate common variants in 13 genes involved in cell cycle control—CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D—and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark (∼1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States (∼2,000 cases and ∼3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85–0.98) for rs3731257; and OR, 0.93 (0.87–0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies. [Cancer Res 2007;67(7):3027–35]