Antibodies and Inflammation Against Chlamydia Trachomatis and Ovarian Cancer Risk

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Antibodies and Inflammation against Chlamydia trachomatis and Ovarian Cancer Risk in Two Independent United States Populations

 

Specific Aims

Significance: Ovarian cancer is the most fatal gynecologic malignancy. It ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system with about 22,240 women receiving a diagnosis annually and about 14,070 women will die from ovarian cancer (1). Ovarian cancer has been linked to events and conditions related to inflammation and repair (2-5). Prevention strategies for ovarian cancer has been limited partly due to the lack of understanding of the underlying biology. Pelvic Inflammatory disease (PID) causes inflammation but has received little attention. Most often, PID is caused by infection from two common STIs: gonorrhea and chlamydia. Chlamydia trachomatis (C. trachomatis) being the most common cause of PID in high income countries (6). Infectious agents are of increasing interest as possible precursors or initiators to cancer due to their role in inflammation. To study the role in inflammation as a risk for ovarian cancer the working hypothesis is that levels of antibodies against C.trachomatis (measured using multiplex serology assay) will be higher in those with a confirmed ovarian cancer diagnosis. Innovation: No previous studies in the United States has evaluated the association between chlamydia antibodies and ovarian cancer risk. Investigating this connection between chlamydia infection and ovarian cancer will develop powerful information and potentially inform prevention strategies. Approach: Capitalizing on the two existing population-based case-control studies this will be the first and the largest study evaluating the association between antibodies against C.trachomatis measured by PGP3 antibody levels and ovarian cancer. Pgp3 antibodies are considered the gold standard for detecting current or past chlamydia infections. Potential confounders or effect modifiers such as treatment for chlamydia treatment, age, and other medical conditions will be adjusted for in the analysis of the relationship between serum antibody levels and ovarian cancer. The controls will be individually matched based on age at blood collection, race, and study location. The cases and controls both must not have a history of oophorectomy. The outcome will be analyzed using multivariable adjusted logistic regression. The proposed specific aims are: 1.To evaluate the association between PGP3 serum antibody levels and ovarian cancer. The working hypothesis is that levels of antibodies against C.trachomatis (measured using multiplex serology assay) will be higher in those with a confirmed ovarian cancer diagnosis. Given the Association between C. trachomatis and ovarian cancer is supported by molecular data demonstrating an anti apoptotic effect of prolonged chlamydia facilitating the survival of DNA damaged cells. Milestone: If this pilot studies findings can be validated the outcome will support the development of intervention and ovarian cancer screening programs targeted at those diagnosed with chlamydia in an effort to prevent late stage ovarian cancer diagnosis. 2. To investigate the relationship between all markers of inflammation and lifestyle risk factors to further study the relationship between inflammation and ovarian cancer. 3.To use multi variable analysis to test the association between higher antibodies levels and higher inflammation markers as is related to the outcome of ovarian cancer. Scientific Environment: Capitalizes on the two existing population-based case-control studies, previous studies from non-diverse cohorts show promising results, and strong institutional support for the proposed research. Overall Impact: Using a hypothesis-driven strategy to rationally design the proposed research the outcome will significantly impact the approach to ovarian cancer intervention and prevention. As we can learn more about the underlying risk factors for ovarian cancer individuals can be educated on how to reduce said risk. Also as we can learn more about the underlying risk factors and the role of inflammation in ovarian cancer screening and treatment can be targeted and hopefully lead to reduced mortality due to ovarian cancer.

BACKGROUND:

Ovarian cancer is the most fatal gynecologic malignancy, ranking fifth in cancer deaths among women. Ovarian cancer causes more deaths than any other cancer of the female reproductive system with about 22,240 women receiving a diagnosis annually and about 14,070 women will die from ovarian cancer (1). At present prevention strategies for ovarian cancer has been limited partly due to the lack of understanding of the underlying biology. No firm conclusions have been established as to the etiology of ovarian cancer, with only 5-10% attributed to a genetic predisposition(7).

Infectious agents such as microorganisms causing chronic inflammatory disease has become a topic of interest to be investigated as possible cancer initiators or promoters and the results have shown Helicobacter pylori linked to gastric cancer, HPV to cervical cancer, and Hepatitis B and C virus to liver cancer. Ovarian cancer has been linked to inflammation and repair (2-5). Recently there has been an increase in the investigation of infectious agents as possible cancer initiators or promoters due to their role in inflammation. This however has not been the case for the association between inflammation via sexually transmitted infections and ovarian cancer.

Chlamydia trachomatis infections have been associated with increased levels of multiple inflammatory markers including CA-125, ESR and CRP(7). There is evidence that on a bacterial level chlamydia bacteria express high levels of cHSP60 suggested to be antiapoptotic and thus facilitate the survival of DNA damaged cells, a known risk for other cancer types (8).  The inflammatory markers increase significantly if the infection is left untreated (9). One marker of inflammation is C-reactive protein (CRP) which has in many studies been shown to serve as an indicator of ovarian cancer risk, CRP is a sensitive and systematic marker of inflammation produced in response to tissue injury and inflammation and released into the blood. Previous studies have demonstrated the association between elevated CRP levels and the risk of epithelial cancers, however data on the association between CRP and ovarian cancer risk has been limited and inconsistent (10). Most often, pelvic inflammatory disease,  is caused by infection from two common STIs: gonorrhea and chlamydia. Chlamydia trachomatis (C. trachomatis) being the most common cause of PID in high income countries (6). In 2017 alone, a total of 1,708,569 cases of Chlamydia trachomatis infection were reported to the Centers for Disease Control and Prevention, making it the most common notifiable condition in the United States (11).

A recent study found that women with Pgp3 antibodies,  highly accurate serological marker for previous or current Chlamydia trachomatis infections, are twice as likely to develop ovarian cancer when other markers of infection were not significant (12). In a blinded cohort study Chlamydia specific Pgp3 antibodies persisted for at least twelve years in 96% of the women and is believed to be a lifelong marker of previous or current chlamydia infection, however studies have not been done at time points greater than twelve years (13).

There are very few prior studies evaluating serologic markers of C. trachomatis or M. genitalium infection and those that exist are limited in sample size, and provided inconsistent results (7, 14, 15). IgG antibodies to chlamydia extracellular elementary. Only one prior study has evaluated the association between chlamydia Pgp3 and ovarian cancer risk and this study was done in high income countries and contained 100% Caucasian women. The results from said study included two independent populations and supported the suggestion that antibodies against C.trachomatis are associated with a risk of ovarian cancer (16).

INNOVATION:

No previous studies in the United States has evaluated the association between chlamydia antibodies and ovarian cancer risk. Investigating this connection between chlamydia infection and ovarian cancer will develop powerful information and potentially inform prevention strategies. The proposed research has several innovative aspects. First, our use of the gold standard for chlamydia detection, PGP3 using multiplex serology assay and the inflammation biomarker CRP together to elucidate the relationship between not only chlamydia and ovarian cancer and inflammation and ovarian cancer, but to solidify the relationship between infection, inflammation, and the outcome of ovarian cancer will be the first study to do so. Second, our long-term objective will evaluate the potential for prevention or intervention to improve early detection, quality of life, and survival of ovarian cancer.

APPROACH:

Overall Study Design:

           The current proposed research will evaluate chlamydia antibody and inflammatory biomarkers in cases of confirmed ovarian cancer reported to the African American Cancer Epidemiology Study (AACES) and the North Carolina Ovarian Cancer Study (NCOCS). The African American Cancer Epidemiology Study (AACES) is an ongoing, population-based case-control study of ovarian cancer in African Americans in 10 geographic locations, aiming to recruit 850 women with confirmed epithelial ovarian cancer and 850 controls age- and geographically-matched to cases. Random-digit-dialing systems were used in this study to get cases and controls. A telephone survey focused on known risk factors. Follow-up surveys, biospecimens and medical records were also obtained at baseline. The North Carolina Ovarian Cancer Study (NCOCS) is a study that concluded in 2008 and involved researchers at the University of North Carolina and Duke University and was originally designed to examine epidemiological risk factors, age at diagnosis, and tumor characteristics. The study identified population based 20-64-year-old case-controls in a 48-county region in North Carolina using random-digit dialing (RDD). Potential controls were recruited over a three-and-a-half-year period that ended in July 2008.

The existing cases and controls were utilized resulting in 3202 potential individuals. This current proposed study will utilize existing biospecimens obtained and multiplex serology assay will be run to test for the levels of antibodies against C.trachomatis as measured primarily by PGP3. Additionally, measures of inflammation, namely C-reactive protein (CRP) and those previously tested in the individual case-control studies will be utilized as well.

Cases and controls will receive a letter of intent and approach that  will describe the studies intention  and invite them to participate. The letter will be followed by telephone contact with an interviewer who will attempt to schedule an in-person interview with the subject if she is consented and willing. All participants will be asked to sign a consent form prior to the scheduled interview. Information collected during the interview will be regarding the period of time before ovarian cancer diagnosis (for cases) or before an assigned, comparable reference date (for controls) and cover the following: demographic and lifestyle characteristics; medical history; family history of cancer; and detailed reproductive/ sexual history, including menstrual, pregnancy, and contraceptive history. Cases and controls will be administered as close to identical questionnaires as possible, except for the addition of questions regarding the circumstances that led to the diagnosis of ovarian cancer.

Flowchart of Ideal Enrollment:

Aim 1: To evaluate the association between PGP3 serum antibody levels and ovarian cancer. The working hypothesis is that levels of antibodies against C.trachomatis (measured using multiplex serology assay) will be higher in those with a confirmed ovarian cancer diagnosis. Given the association between C. trachomatis and ovarian cancer is supported by molecular data demonstrating an anti-apoptotic effect of prolonged chlamydia facilitating the survival of DNA damaged cells. Milestone: If this study’s findings can be validated the outcome will support the development of intervention and ovarian cancer screening programs targeted at those diagnosed with chlamydia in an effort to prevent late stage ovarian cancer diagnosis.

Aim 2: To investigate the relationship between all markers of inflammation and lifestyle risk factors to further study the relationship between inflammation and ovarian cancer. Inflammation will be measured using blood tests for levels of C-reactive protein (CRP). The working hypothesis is that the levels of CRP will be higher in those with a confirmed ovarian cancer diagnosis, given the association between inflammation and ovarian cancer.

Aim 3: To use multi variable analysis to test the association between higher antibodies levels and higher inflammation markers as is related to the outcome of ovarian cancer. If aims one and two hold true the working hypothesis is that both inflammation markers (CRP) and the levels of antibodies against C.trachomatis will be higher in those with a confirmed diagnosis of ovarian cancer.

Investigator Team:

 The proposed analysis will be carried out by an experienced team of investigators including a cancer epidemiologist and a biostatistician in addition to support from the researchers who lead the AACES and NCOCS to be consulted throughout given the cooperation. Molecular biologists will also be consulted in accordance to testing the multiplex serological assay and to test the previously defined cut-off points as specified in Hulstein SH, Matser A, Alberts CJ, et al (submitted for publication in 2018).

Statistical Analysis:

 For Aims 1-3, the distributions of demographics including age, race/ethnicity and other patient characteristics such as BMI, smoking status, and tumor stage was first determined. The test of symmetry will be used to compare the marginal distributions of matched–pairs. Chi-square or Fisher’s exact test will be used to test the association between patient demographics and other characteristics. Alternatively, we will use nonparametric methods (Kruskal-Wallis test for ANOVA, Wilcoxon sign test for paired test) for corresponding analysis of raw data when distributions are significantly skewed Multivariable logistic regression models were used to calculate odds ratios (ORs) and 95 percent confidence intervals (CIs) associated with the measures of inflammation (CRP) and levels of antibodies against C.trachomatis (PGP3), controlling for the matching variables of age, location, and race and other potential confounders including established ovarian cancer risk factors (oral contraceptive use, months of pregnancy, family history of ovarian cancer, menopausal status) and factors related to physical activity (body mass index (BMI) and smoking status).

For Aim 1 and 2 Models were conditioned on matching factors and adjusted for the following a priori–defined ovarian cancer risk factors. Associations of ovarian cancer with seropositivity were based on laboratory cut-points that were defined independently of the current studies.

Potential risks for subjects:

Data to be analyzed are coming from data files that do not contain personal identifiers such as names or addresses. All data are deidentified and known by study identification number only, therefore expected risks such as a breach of confidentiality,  to study participants are extremely low.

Procedures for protecting against or minimizing potential risks:

Existing data that will be used in this analysis project are identified only by study ID numbers as the data was deidentified prior to ascertainment. No preliminary or results will be released or published with identifying information.

Expected Results and Impact:

To our knowledge, this will be the first comprehensive analysis that will assess whether differences exist between levels of inflammation and levels of antibodies and ovarian cancer. It is expected that higher levels of PGP3 and CRP will be found independently associated with ovarian cancer as well as higher levels of both with the outcome of ovarian cancer.

References:

  1. Key Statistics for Ovarian Cancer [Internet]. Available from: https://www.cancer.org/cancer/ovarian-cancer/about/key-statistics.html.
  2. Hagemann T, Balkwill F, Lawrence T. Inflammation and cancer: a double-edged sword. Cancer Cell. 2007;12(4):300-1.
  3. Munn LL. Cancer and inflammation. Wiley Interdiscip Rev Syst Biol Med. 2017;9(2).
  4. Ness RB, Cottreau C. Possible role of ovarian epithelial inflammation in ovarian cancer. J Natl Cancer Inst. 1999;91(17):1459-67.
  5. Philip M, Rowley DA, Schreiber H. Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol. 2004;14(6):433-9.
  6. Bautista CT, Hollingsworth BP, Sanchez JL. Repeat Chlamydia Diagnoses Increase the Hazard of Pelvic Inflammatory Disease among US Army Women: A Retrospective Cohort Analysis. Sex Transm Dis. 2018;45(11):770-3.
  7. Idahl A, Lundin E, Jurstrand M, Kumlin U, Elgh F, Ohlson N, et al. Chlamydia trachomatis and Mycoplasma genitalium plasma antibodies in relation to epithelial ovarian tumors. Infect Dis Obstet Gynecol. 2011;2011:824627.
  8. Dean D, Powers VC. Persistent Chlamydia trachomatis infections resist apoptotic stimuli. Infect Immun. 2001;69(4):2442-7.
  9. Park ST, Lee SW, Kim MJ, Kang YM, Moon HM, Rhim CC. Clinical characteristics of genital chlamydia infection in pelvic inflammatory disease. BMC Womens Health. 2017;17(1):5.
  10. Li J, Jiao X, Yuan Z, Qiu H, Guo R. C-reactive protein and risk of ovarian cancer: A systematic review and meta-analysis. Medicine (Baltimore). 2017;96(34):e7822.
  11. Center for Disease Control and Prevention: STD Surveillance 2017 National Profile. 2017.
  12. Das M. Chlamydia infection and ovarian cancer risk. Lancet Oncol. 2018;19(7):e338.
  13. Horner PJ, Wills GS, Righarts A, Vieira S, Kounali D, Samuel D, et al. Chlamydia trachomatis Pgp3 Antibody Persists and Correlates with Self-Reported Infection and Behavioural Risks in a Blinded Cohort Study. PLoS One. 2016;11(3):e0151497.
  14. Ness RB, Goodman MT, Shen C, Brunham RC. Serologic evidence of past infection with Chlamydia trachomatis, in relation to ovarian cancer. J Infect Dis. 2003;187(7):1147-52.
  15. Ness RB, Shen C, Bass D, Jackson C, Moysich K, Edwards R, et al. Chlamydia trachomatis serology in women with and without ovarian cancer. Infect Dis Obstet Gynecol. 2008;2008:219672.
  16. Trabert B, Waterboer T, Idahl A, Brenner N, Brinton LA, Butt J, et al. Antibodies Against Chlamydia trachomatis and Ovarian Cancer Risk in Two Independent Populations. J Natl Cancer Inst. 2018.
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