EBV Antibodies and the Risk of Associated Malignancies
EBV Antibodies and the Risk of Associated Malignancies
GC represents another EBV-associated malignancy that arises in epithelial cells, although unlike NPC, evidence of a link between antibodies against EBV and GC risk is inconsistent (Table 1, Web Table 1 http://aje.oxfordjournals.org/content/180/7/687/suppl/DC1 (available at http://aje.oxfordjournals.org/)). One important contrast between GC and NPC is that only a minority of GC cases are associated with EBV infection, with approximately 7%–10% of tumors classified as EBV-related.
We identified 3 prospective cohort studies and 1 case-control study that evaluated the relationship between GC and EBV serological markers, with sample sizes ranging from 54 to 185 GC cases. Two of these 4 studies did not make the important distinction between EBV-positive and EBV-negative GC but rather included a single case group. No statistically significant increases in GC risk were seen in subjects with elevated antibody titers against either structural (VCA) or nonstructural (EBNA1, EA) EBV proteins in these 2 prospective studies. Investigators in the Chinese study (n = 185 cases) instead reported an inverse association between elevated VCA IgG antibody titers measured before diagnosis and GC risk, an association that was more pronounced after analyses were restricted to cases who were diagnosed at least 2 years after blood draw (odds ratio = 0.60, 95% CI: 0.36, 0.99). This inverse association between higher VCA IgG titer and lower GC risk was 1) more pronounced for cardia GC cases than for noncardia cases and 2) in the opposite direction of that observed between EBV serological markers and risk for all other EBV-associated malignancies.
The other 2 studies did make the important distinction between EBV-positive and EBV-negative GC tumors. In a prospective cohort of Japanese men in whom anti-EBV antibodies were measured in serum collected an average of 13.7 years (range, 2.7–21.3 years) before GC diagnosis, EBV-positive cases (n = 14) had higher geometric mean titers of IgG antibodies to both structural (VCA) and nonstructural (EBNA1) proteins than did EBV-negative cases (n = 40) and controls (n = 54). A second Japanese study in which antibodies were measured at the time of GC diagnosis also found higher VCA IgG geometric mean titers in EBV-positive cases (n = 64) than in EBV-negative cases (n = 59) and controls (n = 73). Additionally, seropositivity rates for VCA IgA and EA IgG in that case-control study were significantly higher in EBV-positive cases than in EBV-negative cases (odds ratio ≈7 for VCA IgA and odd ratio ≈20 for EA IgG).
Although both studies reported increased risk of EBV-positive GC in subjects with higher VCA antibody titers, the sample size in the earlier study was limited (e.g., fewer than 20 EBV-positive cases). In addition, the data did not elucidate the importance of the timing of antibody measurement, with one study collecting blood at the time of GC diagnosis and the other measuring antibodies in blood collected 2.7–21.3 years before diagnosis. Of note, results from both of these studies contrasted with the inverse association observed between VCA titers and GC risk in the larger prospective study (n = 185 cases) that did not consider EBV-positive and EBV-negative GC tumors separately.
Unlike other EBV-associated malignancies, GC has potential precursor lesions that have been identified and can be evaluated in relation to EBV serological markers. In a longitudinal Chinese study of gastric lesions, persons with elevated baseline VCA IgG and EBNA IgG titers had a higher likelihood of progressing to more severe gastric dysplasia 2 years later, particularly subjects with baseline diagnoses of intestinal metaplasia. Ascertainment of varying gastric neoplastic states of disease could allow for larger statistically powered studies to evaluate the link between EBV serological markers and gastric carcinogenesis.
Gastric Carcinoma
GC represents another EBV-associated malignancy that arises in epithelial cells, although unlike NPC, evidence of a link between antibodies against EBV and GC risk is inconsistent (Table 1, Web Table 1 http://aje.oxfordjournals.org/content/180/7/687/suppl/DC1 (available at http://aje.oxfordjournals.org/)). One important contrast between GC and NPC is that only a minority of GC cases are associated with EBV infection, with approximately 7%–10% of tumors classified as EBV-related.
We identified 3 prospective cohort studies and 1 case-control study that evaluated the relationship between GC and EBV serological markers, with sample sizes ranging from 54 to 185 GC cases. Two of these 4 studies did not make the important distinction between EBV-positive and EBV-negative GC but rather included a single case group. No statistically significant increases in GC risk were seen in subjects with elevated antibody titers against either structural (VCA) or nonstructural (EBNA1, EA) EBV proteins in these 2 prospective studies. Investigators in the Chinese study (n = 185 cases) instead reported an inverse association between elevated VCA IgG antibody titers measured before diagnosis and GC risk, an association that was more pronounced after analyses were restricted to cases who were diagnosed at least 2 years after blood draw (odds ratio = 0.60, 95% CI: 0.36, 0.99). This inverse association between higher VCA IgG titer and lower GC risk was 1) more pronounced for cardia GC cases than for noncardia cases and 2) in the opposite direction of that observed between EBV serological markers and risk for all other EBV-associated malignancies.
The other 2 studies did make the important distinction between EBV-positive and EBV-negative GC tumors. In a prospective cohort of Japanese men in whom anti-EBV antibodies were measured in serum collected an average of 13.7 years (range, 2.7–21.3 years) before GC diagnosis, EBV-positive cases (n = 14) had higher geometric mean titers of IgG antibodies to both structural (VCA) and nonstructural (EBNA1) proteins than did EBV-negative cases (n = 40) and controls (n = 54). A second Japanese study in which antibodies were measured at the time of GC diagnosis also found higher VCA IgG geometric mean titers in EBV-positive cases (n = 64) than in EBV-negative cases (n = 59) and controls (n = 73). Additionally, seropositivity rates for VCA IgA and EA IgG in that case-control study were significantly higher in EBV-positive cases than in EBV-negative cases (odds ratio ≈7 for VCA IgA and odd ratio ≈20 for EA IgG).
Although both studies reported increased risk of EBV-positive GC in subjects with higher VCA antibody titers, the sample size in the earlier study was limited (e.g., fewer than 20 EBV-positive cases). In addition, the data did not elucidate the importance of the timing of antibody measurement, with one study collecting blood at the time of GC diagnosis and the other measuring antibodies in blood collected 2.7–21.3 years before diagnosis. Of note, results from both of these studies contrasted with the inverse association observed between VCA titers and GC risk in the larger prospective study (n = 185 cases) that did not consider EBV-positive and EBV-negative GC tumors separately.
Unlike other EBV-associated malignancies, GC has potential precursor lesions that have been identified and can be evaluated in relation to EBV serological markers. In a longitudinal Chinese study of gastric lesions, persons with elevated baseline VCA IgG and EBNA IgG titers had a higher likelihood of progressing to more severe gastric dysplasia 2 years later, particularly subjects with baseline diagnoses of intestinal metaplasia. Ascertainment of varying gastric neoplastic states of disease could allow for larger statistically powered studies to evaluate the link between EBV serological markers and gastric carcinogenesis.
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