Circulating antibodies against infectious agents and self-reported history of syphilis and gonorrhea represent an individual's cumulative lifetime exposure or past infections and thus are particularly suited for risk evaluation of cancer with a long latent disease process. Our analysis is among the first to examine the effects of many STIs simultaneously in a large prospective study of prostate cancer risk. We found no strong association between prior evidence of specific STIs and prostate cancer, but having had any STI was associated with a modestly increased risk among whites. In the smaller number of black men studied, we found an increased risk associated with IgA antibody to C. trachomatis, and a non-significant elevation with 2 or more prior STIs.
Race-specific seroprevalence estimates for some STIs were available from nationally representative populations, although further specification by gender and age were often not provided. Seroprevalences for whites in this study were similar to NHANES for CMV (78.2%) (48
), HPV-16 (8.0%) (49
) and HSV-2 (13.7%) (50
), while the black controls had higher seroprevalences for the latter two agents (90.2% (48
), 9.6% (49
), and 40.3% (50
), respectively, in the NHANES). Seroprevalence reports for HHV-8 were highly variable (51
); our measure of HHV-8 K8.1 was higher for both blacks and whites than our laboratory had previously reported from NHANES (2.1% and 1.5%, respectively) (52
), although it was similar to their alternative NHANES estimate (7.1%, both races) based on a less-specific cutoff (52
), as used in this study. For C. trachomatis
IgG and HPV-18, our results were similar to findings from large population-based case-control studies of whites (11% (8
) and 3.8% (9
), respectively); national survey data were unavailable for black men.
Compared with other STIs, characterization of syphilis and gonorrhea is relatively achievable through self-reported survey because these conditions are typically symptomatic in men and routinely investigated in clinical settings. The frequencies of self- reported history of syphilis and gonorrhea among our control subjects were similar to self-reports in two large U.S. studies (0.1% (53
) and 0.2% (10
) in whites; 2% in blacks (53
)) and the seroprevalence of syphilis (0.6%, mixed races) in the 2001-2002 National Health and Nutrition Examination Survey (NHANES) (http://cdc.confex.com/cdc/std2006/techprogram/P10818.HTM
While both serologic measures and questionnaire-based self-reports may have error, such errors should be non-differential between cases and controls, as materials and data were prospectively collected and laboratory personnel were blinded to case-control status. To the extent that nondifferential misclassification occurred, our results may be biased toward the null.
) showed overall modest associations of prostate cancer with self-reported syphilis (OR = 1.4-2.3), gonorrhea (OR = 1.3-1.4), and history of any STIs (OR = 1.4-1.5). These analyses were based predominantly on case-control data for Caucasians; studies of African Americans, serological measures, and prospective data have been lacking. A large population-based case-control study of prostate cancer in U.S. blacks (479 cases) and whites (502 cases) found a 1.6-fold risk associated with self-reported history of gonorrhea or syphilis and, in a subgroup with available serum (125 black cases, 146 white cases), a 1.8-fold risk association with antibodies to syphilis (53
); patterns of risk were similar for whites and blacks (53
). The prospective Health Professionals Follow-up Study (10
), not included in either of these meta-analyses, investigated white men with a low prevalence of self-reported history of syphilis and gonorrhea and found no association of either with prostate cancer risk.
is the most common bacterial STI (54
) and may cause chronic persistent infections. In sexually active men, it is the main cause of nongonococcal urethritis and has been suspected as a probable cause of prostatitis (12
). C. trachomatis
IgG antibodies were not associated with prostate cancer in our study nor in another prospective study in US whites (7
), and an inverse association was reported in a Scandanavian study (8
). However, our findings of a significant association of C. trachomatis
IgA seropositivity with prostate cancer risk among blacks is suggestive. Further investigation is warranted to illuminate whether the observed racial disparity was due to differences in seroprevalence, susceptibility to infection or cancer, other differences between the racial groups, or occurred by chance.
HPV and the herpesviruses HSV-2, CMV, and HHV-8 are all sexually transmissible, although non-sexual routes have also been established for CMV and suggested for HHV-8 (52
). Sero-epidemiologic associations with prostate cancer have been mixed. A meta-analysis of 8 retrospective and 2 prospective studies found a significant 1.4-fold increased risk of prostate cancer with HPV seropositivity (5
), but two additional reports not included in the meta-analysis found no association with antibodies to HPV types 16, 18 or 33 (7
). HSV-2 seropositivity was not associated with prostate cancer in a sub-sample of the Nordic nested case-control study (165 cases) (59
). Using small convenience samples, findings have been mixed for associations of CMV infection and prostate cancer risk (16
). Findings also were mixed for HHV-8 seropositivity (46
), with the largest reported study (691 cases) showing a modest inverse association with antibodies to HHV-8 lytic antigens (7
Other infections also were linked with prostate cancer risk. Seropositivity for Trichomonas vaginalis
, a relatively prevalent but under-recognized STI, increased prostate cancer risk in the Health Professionals Follow-up Study (6
). A novel retrovirus named XMRV was discovered in prostate cancer tissues from men carrying genetic variants of RNASEL
). Four or more years use of tetracycline, an antibiotic used to treat severe acne, was found to be associated with increased prostate cancer risk (64
A potential explanation for these disparate associations is that the host response of infection, specifically inflammation, represents a final common pathway for prostate cancer risk. Prostate cancer tissues frequently contain activated inflammatory cells, including the proliferative inflammatory atrophy lesions thought to be precursors of early cancer development, and may have somatic alterations in inflammation-related markers (65
). Genetic and circulating markers of inflammation and host response to infection have been variably shown to increase prostate cancer risk, whereas intake of NSAIDs and antioxidants has been protective (67
). These considerations implicate chronic inflammation as a potential mechanism of prostate carcinogenesis. Alternatively, the diffuse associations with the various infections may be due to correlation with a true causal factor not directly measured.
Our study has several notable features that overcome important limitations of previous investigations. Cases and controls were identified from the same source population which was screened for prostate cancer by a standardized procedure. Data and specimens were collected prospectively prior to diagnosis, and were used to assess a large number of STIs simultaneously. However, prevalences of the individual infections were relatively low in our white participants and we had few black participants which limited our statistical power. We attempted to address this deficiency by including black cases diagnosed within one year of blood draw. Potentially these cases may be more slowly progressing or less clinically aggressive than cases arising at least one year after the initial screen; nevertheless, risk patterns did not grossly differed between these two groups of black cases. White participants with at least one past infection had modestly increased prostate cancer risk; this pattern was not replicated among our black participants, but very few had no past infections.
In summary, this large prospective study found no consistent association between history of individual STIs and prostate cancer risk. Our novel finding of an increased risk with C. trachomatis IgA antibodies was restricted to blacks and requires confirmation. By studying many STIs simultaneously, we found a modest risk associated with any prior STI among whites. The modest associations and lack of specificity parallel the variable findings from previous reports and may suggest involvement of a correlated factor or shared underlying response (e.g. inflammation) not directly measured. Further studies in high risk populations would help advance our understanding of the role of STIs in the etiology of prostate cancer.