In this study, we found that sera from individuals during (or just after) symptomatic mumps parotitis have a significantly higher level of anti-MUC1 antibodies than sera from controls without active parotitis. Showing the relevance of this observation to ovarian cancer clearly requires background data that would link mumps, ovarian cancer, and anti-MUC1 antibodies. Concerning the mumps and ovarian cancer association, we performed a meta-analysis of all published original reports to obtain an overall estimate of the effect. In eight observational studies addressing the association, the summary odds ratio was 0.81 with 95% confidence limits of 0.68–0.96 (p
= 0.01), suggesting a 19% decrease in risk of ovarian cancer associated with history of mumps parotitis. One of the studies not finding an odds ratio<1 also did not find an association with parity [2
], and the second study in which the association was null [9
] was the most recent of the studies and would have included many more subjects who had been vaccinated for the mumps. Conversely, several of the key studies (which had looked at other associations besides the mumps) confirmed well-established findings, like protection with pregnancies and oral contraceptive use [3
]. While prospective studies related to mumps would have been desirable, studies two through eight are likely to constitute the only pre-vaccination era epidemiologic data we will ever have related to this association.
Despite the epidemiologic evidence that mumps might reduce the risk of ovarian cancer, this association has largely been ignored, probably due to the lack of a plausible biologic explanation. We have presented data here in support of an immunological basis for the association. A protective effect of mumps parotitis on ovarian cancer risk can be explained under a model related to immunity against the surface glycoprotein, MUC1. Events affecting tissues that normally express MUC1 might confer protection because of injury to the tissue causing expression and presentation of a tumor-like (less glycosylated) form of MUC1 to the immune system [10
]. This would allow immune recognition of the protein core of MUC1 and generation of an immune response similar to that which occurs with cancer [15
]. Since MUC1 is expressed in normal salivary glands, acute inflammation of this tissue with mumps would be expected to induce changes in MUC1 expression and glycosylation similar to that which has been reported for other tissues undergoing inflammation [17
]. Thus, our observation that anti-MUC1 antibodies are elevated in individuals with mumps is consistent with the interpretation that mumps infection could elicit an immune response to later protect against ovarian cancer.
We began this study with the expectation that, in mumps cases with paired sera, we would find higher MUC1 levels in the acute specimen and higher anti-MUC1 antibody levels in the convalescent specimen. The fact that neither was observed may reflect lack of detail on the timing of blood collections in relation to onset of symptoms. Alternatively, the fact that anti-MUC1 antibody levels were similar (but higher than controls) in both the acute and convalescent sera could be explained if this were not the first time that the mumps cases had seen an inflammatory type of MUC1. In this circumstance, a much more rapid immune response would be expected and might have occurred because of prior inflammatory conditions involving the genito-urinary, respiratory, digestive tract, or breast ducts—tissues which all express MUC1. MUC1 antigen itself was not elevated in cases compared to controls in either the acute or convalescent specimens. Saliva, if it had been available, might have been a better body fluid to look for MUC1, but it is also possible that the presence of anti-MUC1 antibodies interfered with measurement of MUC1 since immune complexes involving MUC1 and antibodies against it have been described [22
]. Supporting this possibility was an inverse correlation between anti-MUC1 antibody levels and MUC1 antigen levels in cases (but not controls) noted in our presentation of the results of . Interestingly, CA 125 was significantly elevated in sera from the mumps cases compared to controls. CA 125 is expressed in salivary gland tumors [23
], but we could find no reports of its expression in normal salivary glands. The low volume of mumps specimens precluded measurement of immune complexes or anti-CA125 antibody levels.
There are many limitations of this study, not the least of which was the difficulty of obtaining specimens from individuals with mumps parotitis which limited the size of this study. The samples we obtained were collected between 2000 and 2008 in various public health agencies and were stored under variable conditions (). Although mumps is now reportable in many regions, we have no way of knowing whether the cases that come to public health attention are representative of mumps infection in the community or a more selected group. Information on precisely when during the course of the infection the samples were collected was limited, and titer data were available from only two sites (London and Edinburgh). Because of the anonymized nature of the case and control specimens, we were unable to correct for potential confounders, other than age and gender. Age could be a key confounder, since we previously reported that anti-MUC1 antibody levels may decline with age [10
]. While cases were more likely than controls to be younger and to be male, adjustment by these variables revealed that confounding by age and sex did not account for the relationships between mumps and anti-MUC1 antibodies, CA125, or MUC1 levels. The small size of this study should not have produced an artifactual association between mumps and anti-MUC1 antibody (or CA125 levels) but certainly could have affected the precision of our estimate of the effect.
Regarding controls, we are certain they did not have an active mumps infection, but it was a diverse group which included university volunteers for the London cases in batch 1 and, in batch 2, individuals without mumps in Illinois who were tested for immunity and blood bank controls from Boston. Community-matched controls were only available for the Nova Scotia subjects in batch 2. Despite this, the levels of anti-MUC1 antibodies in all control groups from batch 2 were very similar and nearly identical to the Nova Scotia controls.
Another limitation was variability in the assay from batch 1 to batch 2. To decrease inter-plate variability after running batch 1, we increased the number of unique specimens per plate for batch 2, which may have contributed to the batch differences. However, despite batch variation, both batches suggested higher antibody levels in mumps cases compared to controls. Moreover, analyses including and excluding batch 1 yielded a similar result.
The epidemiology of mumps parotitis has obviously changed dramatically in the last 40 years. Mumps parotitis was a very common illness in infants and children prior to 1970. With now close to universal vaccination except in the third world, mumps has become a disease of adults who were either born too early for routine vaccination or who have lost immunity after vaccination. For this reason, inferences about the consequences of parotitis on MUC1 immunity based on observations from the specimens tested here may not be generalizable to what might have occurred with childhood infection before vaccination programs began. We point out, however, that the anti-MUC1 antibody response was most robust in younger women suggesting that childhood infection, as would have occurred in the past, might have been the optimum time for engendering immunity against ovarian cancer.
Clearly, mumps vaccination only creates anti-viral antibodies and would not lead to anti-MUC1 antibodies, which we show here require an active parotitis. If it is true that symptomatic mumps protected against ovarian cancer through an immune reaction, a logical consequence is that we might expect an increased incidence of ovarian cancer as symptomatic mumps parotitis infections have decreased through vaccination. In a paper examining incidence patterns for ovarian cancer from 1978 to 1998, rates of invasive serous, endometrioid, and clear cell tumor increased over this time period among white females [24
]. Endometrioid and clear cell cancers are the types of ovarian cancer that we found were most strongly linked to the conditions we proposed might be mediated through anti-MUC1 antibodies [10
]. The above incidence data may be confounded by diagnostic trends, but re-examination of these disease rates with more recent data and a focus on the birth cohorts most likely to have been vaccinated should be undertaken.
Prior to vaccination, mumps was generally a mild illness but could have serious sequelae including orchitis and sterility, meningitis and deafness, and pancreatitis. Nevertheless, our study suggests there could also have been unanticipated long-term anticancer benefits of a mumps infection, such as we have described in this paper. Understanding the scope of and basis for the potential benefits of childhood infections may allow immunologists to duplicate the beneficial effects at the same time that vaccination provides the means for avoiding a natural infection and its possible immediate consequences. Further study of individuals going through a mumps infection, especially with a focus on mucin immunity, may provide clues to mechanisms for duplicating the beneficial effects of mumps parotitis suggested by this study.