Discussion
Cytomegalovirus is wreathed in mystery, a Gordian knot of biological
knowledge and understanding [82]. Cytomegalovirus had evolved a
peculiar virus-host symbiosis by a taciturn tactic that co-opts or
escapes immune pathways in order to arrange its persistence in the host.
A strong inverse statistical correlation between the incidence of cancer
and CMV seroprevalence covers quite a swath of cancer spectra and
territorial ranges. Although correlation does not categorically infer
causation, this one may underscore a causal meaning. Besides the
benefits of vaccine against CMV [53], it may suggest an impeded
carcinogenesis by generating the CMV-induced tumoricidal T cells.
CMV-based vaccine antagonistic to tumorigenesis would possibly result in
a global regression of cancer. Comparing non-Whites to Whites, Cannonet al. [2] evaluated that CMV seroprevalence is consistently
20-30 percent points higher in the former than in the latter (summary
PR=1.59, 95% CI=1.57-1.61). Some ethnic groups had CMV seroprevalence
~ 100% (Fig. 4A in [2]). In agreement with the
current work, Fowler et al. [32] discounted the importance of
ethnicity per se as a risk factor for the CMV infection. Similar
conclusions were reached by Lantos et al. [54], Rook
[55], and Dowd et al. [56,57].
Elimination of health disparities as a consequence of racial and ethnic
differentials has been earlier recognized as important [47,48,83].
Socioeconomic disparities across race/ethnicity categories impact the
level of CMV seroprevalence [83]. These may have biased lower
estimates of cancer incidence at the time. Rather than the race/ethnic
divides of themselves, we propose CMV infection as an oncopreventer both
of some hematologic malignancies at our clinic and of cancers worldwide
[13]. Although CMV prevalence and education level, SES, and
household income are associated with race and ethnicity, we speculate
here that latent CMV infection is a fundamental cause underlying
disparities in cancer incidence among race/ethnic groups in the U.S. and
worldwide. The NHANES III data (the U.S. 2011-2012) report CMV
prevalence (race/minority) in children 1-5 years of age as 37% among
non-Hispanic other/multiracial, 31% among Hispanic, 15.9% among
non-Hispanic Black, and 10.6% among non-Hispanic White ethnicities
[33]. This data is inversely proportional to the incidence of all
cancers (combined) in populations of these youths, indicative of a
higher risk of cancer in CMV seronegative populations in the U.S. Also,
unlike Hispanos, cancer rates in Cubans were comparable to non-Hispanic
Whites, and Puerto Ricans and Cubans in Florida had rates of some solid
cancers similar to non-Hispanic Whites despite the rates of these
cancers being significantly lower in their countries of origin [22].
High incidence of cancer despite a high prevalence of CMV in the Inuit
(Eskimos) may be a consequence of deficient T cell immunity in this
ethnic population [23,24]. This is to be expected and, indeed, we
found no global correlation between the incidence of Kaposi’s sarcoma
(mostly diagnosed in HIV-positives with compromised T cell immunity) and
the prevalence of CMV (Fig. 5 ). CMV does not exert protection
unless T cell immunity is functional.
Immigrants to U.S. experience decreasing incidence rates of cancer of
infectious origin (hepatitis B virus, Helicobacter pylori , human
papillomavirus) which are prevalent in their countries of origin. On the
contrary, incidence rates of lung, breast, colorectal and prostate
cancer have been on the rise despite remaining relatively low in the
host nations [57-59].
The statistical analysis indicates an inverse correlation between CMV
pervasiveness and the race-specific cancer incidence, a valuable hint at
a possible oncoprotective effect of the pathogen. Previously, we
speculated that CMV may confer a protection against B cell dyscrasias
[13]. For example, there is a highly significant inverse link
(Fig. 1 . Spearman’s ρ = -0.754;p <0.001) between all invasive cancers combined (both
genders, all ages) and the country specific CMV prevalence profile
across the mainland and sea-coastal regions of 73 countries
(Table 3 ). We draw attention to a possible protective effect of
the CMV infection as an unappreciated factor which may subvert
oncogenesis.
We sought to grasp a better understanding of fluctuating incidence of
new cancers among immigrant and established indigenous populations by
consulting relevant reports. We envision that dilution of the prevalence
of CMV, due to a progress in economic opportunity and an open access to
competent medical patronage, may have resulted in increased cancer
rates, indeed the epidemics of neoplasms [60]. Societal development
aside, poverty remains a considerable medical concern [30,33,62,72].
Higher prostate and lung cancer rates are reported in established
immigrant enclaves from Japan and China in the U.S. than are found in
Japan and China, probably because improved SES in the U.S. (i.e. a
better hygiene and improved medical care) with a consequent decline of
CMV-mediated oncoprotection in the U.S. Also, individuals with low SES
have higher antibody titers to CMV [31] and presumably more
protection against cancer.
Crucially, CMV induces a specific, CMV-determined, T cell mediated
antitumor effect in immunocompetent persons but fails in patients with
inoperative T cell immune surveillance, like Kaposi sarcoma
(Fig. 5 ). The role of CMV acquisition and the consequent T
lymphocyte-specified inhibition of tumorigenesis may prove of importance
in pre-empting various malignancies, particularly those that can be
detected at an early stage, such as breast and colon cancers.
Disaggregation (decomposition) of ethnic data in racial/multiethnic
studies of cancer vs. rates of cancer cases combined and the CMV
prevalence may, while quite information-rich, also be a source of bias
due to unmeasured confounders or mediators [79]. Disaggregation may
mask true biological linkages which would be more accented if global
bulk of data were analyzed. Hoshiba et al. [61] examined the
long-term (1980-1998) dynamics of CMV seroprevalence in pregnant women
in Japan. Complement-fixing antibody and specific IgG antibody, as
measured in sera, decreased gradually from 93.2% to 66.7%. CMV-IgG
seropositive rates were 87.4% in 1985, and 75.2% in 1996 to 1997. This
provides a separate hint at a possible protective effect of CMV in this
population. Of note, the incidence of cancer increased in parallel to
decrease of CMV seropositivity in this Japanese population.