A broadscale investigation of the ovarian cancer oncobiome using a microarray system called PathoChip and next-generation sequencing found HHV-6A sequences at or near genes associated with tumorigenesis in ovarian cancer tissue samples while the viral sequences were undetected in controls.
Both HHV-6A and HHV-6B have been investigated as potential oncogenic agents. Determining whether the viruses cause cancer, serve as cofactors, or are simply innocent bystanders has been difficult owing to their ubiquitous nature, but as more specific detection methods are increasingly utilized to detect HHV-6 activity in cancers, a clearer view of the involvement of HHV-6 in tumorigenesis emerges. In this study, the results from screening 99 ovarian cancer samples revealed that several species of bacteria, fungi, and parasites were found to predominate in cancer tissue when compared to control tissue. Similarly, the viral profile of cancerous samples differed from normal ovaries. Not only was the average hybridization signal detected for the viral families lower in cancer specimens, but different viral species were present.
In particular, conserved and specific probes for both HHV-6A and 6B were found in the cancer biopsies but were absent in the 20 matched ovarian tissue samples and 20 non-matched ovarian biopsies. Ten instances of HHV-6A integration in various chromosomes were detected, with U47, encoding envelope glycoprotein O, identified as the most commonly inserted viral sequence. Most integrations were found in intronic or intergenic regions, but some were present at exonic and sub-telomeric loci. Of the genes that HHV-6A sequences were found to be integrated into or located near, most were significantly associated with cancers, and six, including CPLX1, IGFBP3, and the oncogene SH3RF2 were associated with malignant tumor formation at a p value of 8.45E-07. Probes for EBV, CMV, and HHV-8 were detected in both cancer and control samples, and HSV-2 was detected more frequently in controls than in cancers.
While the results of this study do not point to any one causative agent in the development of ovarian cancer, there appears to be dysregulation of the microbiome, and even if HHV-6 is not directly oncogenic, it could well be involved in the progression of this dysregulation. Of course, it is also possible that the altered microenvironment resulting from tumor development provides conditions that favor HHV-6 infiltration and integration. However, although HHV-6A was one of many pathogens found more commonly in the cancer tissues than in matched controls, the association between the genes that the virus integrated into or near to and the development of cancer, as well as the lack of HHV-6 in non-cancerous samples, makes a case for closer examination of HHV-6 in ovarian cancer.
While the virus has not been detected in the uterus of fertile women, HHV-6A has been found in the endometrium of 43% of women with unexplained infertility (Marci 2016). Moreover, the infertile women who were HHV-6A positive had endometrial natural killer cell and cytokine profiles that differed from those of both fertile controls and infertile, HHV-6A negative women. Though few studies have been performed to examine how HHV-6A interacts with the female reproductive system, the data that is available is intriguing and suggests that the virus may disrupt several aspects of its microenvironment, which could have far-reaching consequences.
Find the full paper here: Banerjee 2017.