High Prevalence of Human Cytomegalovirus in Brain Metastases of Patients with Primary Breast and Colorectal Cancers

Abstract

BACKGROUND: Brain metastases (BMs) develop by largely unknown mechanisms and cause major morbidity and mortality in patients with solid tumors. Human cytomegalovirus (HCMV) is frequently detected in tumor tissue from patients with different cancers. Here, we aimed to determine the prevalence and potential prognostic role of HCMV in BMs. METHODS: We obtained archived samples of BMs from 41 patients with breast cancer and 37 with colorectal cancer and paired primary tumor tissues from 13 and 12 patients in each respective group. In addition, primary breast cancer tissues from 15 patients were included. HCMV proteins were detected with an immunohistochemical technique and Western blot. HCMV nucleic acids were detected with TaqMan polymerase chain reaction (PCR) assay. RESULTS: HCMV proteins were abundantly expressed in 99% of BM specimens, and in 12 of 13 (92%) paired primary breast cancer specimens. All 12 paired colon cancer samples were positive for HCMV proteins. Protein staining was mainly confined to neoplastic cells. Western blot analysis detected an HCMV-IE reactive protein in 53% of breast cancer specimens, and PCR detected the presence of HCMV DNA and transcripts in 92% and 80% of samples, respectively. Patients with high-level expression of HCMV-IE proteins in their tumors had a shorter time to tumor progression and shorter overall survival. CONCLUSIONS: The prevalence of HCMV proteins and nucleic acids is very high in primary and metastatic tumors and may drive the development of metastatic brain tumors; therefore, this virus may represent a potential therapeutic target in metastatic cancer.

Low Expression of Estrogen Receptor-α and Progesterone Receptor in Human Breast Cancer Tissues Is Associated With High-Grade Human Cytomegalovirus Protein Expression

“…In this study, we detected HCMV proteins and nucleic acids in all BC specimens, consistent with previous reports 21,25,39 . HCMV-IE protein was present in all infiltrating BC, DCIS, and adjacent normal breast tissues, whereas HCMV-LA expression was absent in 25% of infiltrating BC, 53% of DCIS, and 33% of adjacent normal tissue.…”

The impact of inflationary cytomegalovirus‐specific memory T cells on anti‐tumour immune responses in patients with cancer

“…Emerging evidence suggests that CMV is highly prevalent in patients with breast, colon, prostate, liver, and cervical cancers, rhabdomyosarcoma, salivary gland tumours, or brain tumours . Most neoplastic cells in the sentinel lymph nodes of > 90% of patients with breast cancer have been shown to be CMV‐positive, whereas 98% of brain metastases of colon and breast cancers contain CMV proteins and/or nucleic acids . Conversely, CMV proteins are not detected in healthy tissues surrounding CMV‐positive tumours or metastases.…”

Frequent occurrence of therapeutically reversible cmv-associated encephalopathy during radiotherapy of the brain.

“…CMV particles have been shown to exist in the tissue of a high number of high-grade gliomas 6,8 and brain metastases, 9 but not in surrounding nontumorous tissue or benign brain tumors. 8,10 In high-grade gliomas, immunoreactivity to immediate-early (IE)1 -72, a CMV-encoded antigen, has been detected in more than 90% of the specimens (Mitchell et 6 and 78% (28/36) 10 of the cases.…”

“…One could hypothesize that RT of tumor masses known to contain at least particles of the virus (80% -99% for high-grade gliomas 6,30 and 92% -100% for brain metastases 9 ) can lead to local infection: encephalitis and systemic viremia. This is supported by the fact that all anti-CMV IgG positive glioblastoma patients in our study with macroscopic tumor developed CMV encephalopathy during RT.…”