We found that a history of any allergies was related to a reduced risk of SCC (OR 0.7, 95% CI 0.6–0.9); the association was principally due to reduced risk of SCC associated with pollen allergies (OR 0.6, 95% CI 0.5–0.8). Although there was a strong log-additive association between the minor allele for rs1800925 (IL13 promoter SNP previously reported to be associated with atopy (30–31)) and pollen allergies among controls (OR 1.7, 95% CI 1.3–2.4, p=0.0007), this SNP was not related to risk of SCC. Interestingly, a rare nonsynonymous coding SNP in CSF2RB, rs16997517, was related to both increased reportage of pollen allergies in controls and decreased risk of SCC. If there is a link between reduced risk of cervical cancer and allergies, there may be an important link that remains to be uncovered between cervical cancer and immune response.
The association between SCC and pollen allergies did not appear to be due to confounding by socioeconomic status (SES) or other characteristics commonly associated with SCC, nor was there appreciable effect modification by these factors. This study had extensive information on demographic characteristics to address this potential source of confounding. We were also able to partially address whether the hyper-immune response related to allergy might lead to increased tumor surveillance. Possibly in support of this hypothesis, the risk of more advanced stage disease (stage 2+, OR 0.3, 95% CI 0.2–0.5) associated with pollen allergies was found to be lower than risk for stage 1a or 1b cervical cancer (microinvasive: OR 0.7, 95% CI 0.5–0.9, stage 1b: OR 0.6, 95% CI 0.4–0.9), even after adjustment for recency of Pap screening. These results should be cautiously interpreted as the stage distribution of our case group is affected by several factors including participants who died prior to recruitment who may have had higher stage disease at diagnosis. It is possible that women with early stage disease may have been more likely to participate than those with later stage disease. The stage distribution may also have been affected by differences in Pap screening that we were not able to capture in our analytic variables.
We also saw that there was variability in the risk of SCC associated with pollen allergies by the type of HPV present in the tumor, with a greater reduced risk of HPV18+ disease than HPV16+ disease. Thus, it is possible that allergies are acting to reduce the exposure to persistent HPV infection in a type-specific manner, supporting a prophylaxis mechanism of reduced cancer risk associated with allergies.
Interpretation of our results is limited by several factors. Our response proportions, though good for epidemiologic studies of cervical cancer, were somewhat low at 64% and 68% for cases and controls, respectively. If the interviewed participants differed on allergy status from those who were not interviewed, our estimates could be hampered by response bias, though this would likely be non-differential based on case-control status, so, the bias would likely be toward the null. Additionally, because our data on allergy history were obtained by self-report, it is possible that reporting bias affected our results. However, differential reporting of allergies seems unlikely, since allergy reporting was unrelated to most of the co-factors that we explored. Also, it is reassuring that the prevalence of allergies in our questionnaire was similar to prevalence estimates found in other studies. The prevalence of allergies was reported from the NHANES III study, which reported a 40% positive skin prick test for “outdoor” allergens, including 26.2% positive for allergy to short ragweed, 18.1% positive for Bermuda grass, and 13.2% positive for white oak.(32
Our genetic analyses are limited to the extent that several SNPs of potential importance failed genotyping, and by the limited number of genes related to allergy. Specifically, not having data for IL5, part of the chromosome 5q31 cluster, limits our ability to examine the impact of genes in that region on allergy and SCC.
Wang and Diegpin (2005), Turner (2006), and Merrill (2007) noted in their reviews that atopy was associated with a reduced risk for cancers at several sites, including pancreatic cancer, leukemia, and brain tumors, and an increased risk of increased risk of lung cancer.8
One published study has explored the relationship between atopy and cervical cancer.11
Montgomery, et al. (2002) reported no association between hay fever in childhood and cervical cancer using two British cohorts (the National Child Development Study and the 1970 British Cohort Study cohorts), OR 1.04 (95% CI 0.50–2.17). The cohorts followed all persons born during April 3–9, 1958 and March 5–11, 1970 to ages 42 and 30 years, respectively, which led to a younger study population relative than that reported on here (average diagnosis age in the current study population was 43 years). The cohorts also collected information on hay fever only at age 16, missing those who developed allergies in adulthood, and captured cervical cancer only by self-report, possibly including women who self-reported cancer but had in situ
disease. A Swedish study reported by Ivansson, et al. (2006), found that women who reported that their sons had allergies were at reduced risk of both in situ
(OR 0.84, 95% CI 0.81–0.86) and invasive (OR 0.80, 95% CI 0.71–0.92) cervical cancer.(33
) Though the latter study suggests that a genetic predisposition to allergies may be associated with reduced risk of cervical disease, it is difficult to draw conclusions based on the association between allergy in sons and cervical disease in mothers.
Previous reports have shown a relationship between the variant allele at IL13
promoter SNP rs1800925 and atopy,(30
) corresponding to the strong increased association between this SNP and allergy history among controls in this study. However, the association between allergy and cervical cancer was not found to be directly mediated by this SNP or any of the other variants in the 5q31 cluster that we studied. We did find an inverse relationship between SCC and rare coding SNP CSF2RB
rs16997517, which was also related to an increased history of allergies (among controls). It is also possible that variation in other genes involved in allergic disease that were not measured in our study could contribute to both an increase in the risk of pollen allergy and decrease in the risk of cervical cancer.
There are two theoretical biologic mechanisms by which allergies could be influencing reduced risk of cervical cancer: prophylaxis against exposure to the primary carcinogen involved in cervical cancer, persistent infection with oncogenic HPV through a hyperimmune response, or the destruction of malignant cells via tumor immunosurveillance shortly after initiation or early in progression.(34
) We hypothesized that if women with allergies had increased tumor immunosurveillance due to generalized hyperimmunity, allergy history would have a stronger inverse relationship to higher stage disease then lower stage cancer because a longer time to tumor development increases the chances for tumors to be detectedat a lower stage. Our data showed a significantly greater reduction in risk of later stage disease (FIGO stage 2+, OR 0.3) than for earlier stage disease (FIGO stage 1a or 1b, ORs 0.7 and 0.6, respectively). An alternative hypothesis based on the data in this study might be that a lower risk of advanced stage at diagnosis could indicate that those with pollen allergies who do develop invasive SCC may have had a less rapid disease progression, perhaps due to hyperstimulation of the immune system. Similarly, if there is conformational homology between HPV epitopes or cervical cancer tumor antigens and pollen fragments recognized by the immune system, there could be efficient elimination of HPV infection before the virus can establish a persistent infection. It is difficult to assess which mechanism may be dominant in the relationship between cervical cancer and pollen allergies, but either or both together could have a role. Given the localized allergic response is specific to mucous membranes, possibly including the cervix, the role of the localized immune response in efficient elimination of HPV either through non-specific humoral response or some correlated Th1 response is possible;(35
) alternatively, even the recruitment of eosinophils may then have a tumoricidal effect.(22
As with many other types of cancer, we found that the risk of cervical cancer is reduced in persons with allergies. This is the first study to report this association, and it needs to be confirmed in other populations. Further genetic characterization of allergy-related phenotypes may uncover shared genetic pathways, and exploration of possible biologic mechanisms mediating this relationship may be warranted.