Cytomegalovirus and Epstein-Barr virus in breast cancer

Abstract

Findings of polymerase chain reaction (PCR) studies of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) and breast cancer vary, making it difficult to determine whether either, both, or neither virus is causally associated with breast cancer. We investigated CMV and EBV in paired samples of breast cancer and normal breast tissue from 70 women using quantitative PCR. A serum sample from each woman was tested for CMV and EBV IgG. To place our results in context, we reviewed the existing literature and performed a meta-analysis of our results together with previous PCR studies of EBV, CMV, and breast cancer. Of the serology samples, 67 of 70 (96%) were EBV IgG positive and 49 of 70 (70%) were CMV IgG positive. QPCR detected EBV in 24 (34%) of the tumour and 9 (13%) of the paired normal specimens and CMV in 0 (0%) of the tumour and 2 (3%) of the paired normal specimens. Our findings, together with earlier results summarised in the meta-analysis, suggest several possibilities: variable findings may be due to limitations of molecular analyses; 'hit and run' oncogenesis may lead to inconsistent results; one or both viruses has a role at a later stage in breast cancer development; infection with multiple viruses increases breast cancer risk; or neither virus has a role. Future studies should focus on ways to investigate these possibilities, and should include comparisons of breast cancer tissue samples with appropriate normal tissue samples.

Fig 1. Meta-analysis of EBV positivity in breast cancer tissue samples.

Random effects meta-analysis was performed on the proportions of samples that were positive for EBV rather than relative risks, because only six studies (including ours) included paired normal samples. Proportions had 95% confidence intervals derived from the Normal approximation to the binomial with 0.5 added to zero counts. Estimates of the average proportion positive were calculated for all studies and for each assay type that was used in multiple studies. Results of studies that analyzed breast tissue samples for EBV are shown according to the method of analysis. The overall strength of association for each type of analysis, and the overall strength of association for all studies are shown at the bottom of the figure. There was considerable heterogeneity in the EBV analyses (I² = 98.6%).

Fig 2. Meta-analysis of CMV positivity in breast cancer tissue samples.

Random effects meta-analysis was performed on the proportions of samples that were positive for CMV. Proportions had 95% confidence intervals derived from the Normal approximation to the binomial with 0.5 added to zero counts. Estimates of the average proportion positive were calculated for all studies and for each assay type that was used in multiple studies. Results of studies that analyzed breast tissue samples for CMV are shown according to the method of analysis. The overall strength of association for each type of analysis, and the overall strength of association for all studies are shown at the bottom of the figure. There was considerable heterogeneity in the CMV analyses (I² = 99.6%). Footnote to Fig. 2: PCR results for Harkins et al were not included in this meta-analysis because nested PCR was performed on only 8 specimens, all of which were positive on IHC (please see S1 Table).