Adrenal_tumor

ciHHV-6 found in adrenocortical tumors

In All, Cancer, ciHHV-6 by hhv6foundation

Since the discovery of chromosomally integrated HHV-6 (ciHHV-6), investigators have wondered about the potential consequences of having chromosome integrated HHV-6 in the genome.

Emilia Pinto and colleagues at St. Jude Children’s Research Hospital in Memphis reported in Nature Communications that chromosomally integrated HHV-6 was found in 2 of 37 (5.47%) pediatric adrenocortical tumors. Furthermore, the site of integration was chromosome 11p, a chromosome that plays an important role in the adrenocortical tumors.

Emilia Pinto

Emilia Pinto

Pediatric adrenocortical tumors are very rare and deadly. They are associated with chromosomal instability. Moreover, with these tumors, an early event that triggers tumorigenesis typically occurs with loss of chromosomes 11p and 17p.

Pinto and colleagues found HHV-6 by doing whole-genome sequencing and were surprised to find the entire genome of HHV-6 turn up in the testing.

Although the authors do not suggest a link between ciHHV-6 and pathogenesis of the tumor, the finding such a high incidence of integrated full genome of HHV-6 on a chromosome critical to the disease process, has piqued the curiosity of investigators in the field. In addition to the two ciHHV-6 positive tumors reported, an additional four cases were positive for HHV-6 by qualitative PCR. (See interview below).

“The paper about pediatric adrenocortical tumors by Pinto and colleagues, gives a fascinating insight into the underlying molecular biology of these tumors,” said Nicola Royle, an expert in genetics who studies telomere stability. In an earlier study, Royle and colleagues at University of Leicester, UK showed that individuals with ciHHV-6 (about 1% of the population) have telomeres that are less stable, and prone to sudden deletions (Huang 2013).

Adrenocortical tumors have a bimodal distribution with most cases occurring in children under 5 and in adults who are 30-40 years old. Typical symptoms include virilization, Cushing’s syndrome or precocious puberty. Several genes important for fetal growth and development are located on chromosome 11p, including h19, insulin-like growth factor II and p57. Infections of CMV, EBV and HSV1 and 2 have been described in adrenal tumors, but HHV-6 infection in the adrenal gland has not been studied or noted previously.

“I hope the authors will be able to follow up this very interesting observation,” added Royle. “It would be great to know if the two children have inherited the integrated HHV-6B at 11p from a common ancestor, perhaps many generations ago. Alternatively two independent integration events into the 11p telomere by different HHV-6B strains could have occurred. As the authors point out, it is not clear yet whether the presence of the viral genome or a possible effect on the telomere have contributed to the tumor formation.”

Interview with Emilia Pinto on ciHHV-6 & adrenocortical tumors

We asked Emilia Pinto and her team, Dr. Raul Ribeiro and Gerard Zambetti at St. Jude’s Research Hospital to answer a few questions about their intriguing study.

Q: You have found chromosomal integration at 11p in two of 37 adrenocortical tumors. Is there any chance that this could have been a coincidence?

A: The ciHHV-6 observed in these two adrenocortical cases with very quiet genome and no detected predisposing gene mutations suggest that ciHHV-6 might have a role in chromosomal instability and in our cases selecting against maternal chromosome 11.

Q: How would you summarize the significance of your findings as they relate to ciHHV-6?

A: ciHHV-6 is a rare etiological event in pediatric adrenocortical tumorigenesis, where germline TP53 mutation and 11p alterations are more prevalent. We postulate that telomeres with HHV-6 integration tend to be unstable and short as previously suggested by a study headed by Nicola Royle. In this context, HHV-6 integration in the 11p region, as demonstrated in our study, might result in chromosomal 11 instability, selecting clones that overexpress IGF2.

Q: You found 5.4% of the 37 samples positive for ciHHV-6. Were any of the other samples positive for HHV-6? If yes, how many were there and how would you describe the viral load?

A: Yes, we have few samples more (06) that were shown to be positive for HHV-6 by qualitative PCR. Viral load by qPCR was not performed in these cases.

Q: Was the ciHHV-6 type you found A or B?

A: The probe (FISH) used for this study could target both types (Dr. Troy Lund, at University of Minnesota Medical School, personal communication). However, molecular studies identified the presence of the Human herpesvirus 6B DNA, complete genome, strain: HST in the case submitted to whole genome sequencing.

Q: Did you test for other herpesviruses and if so, were any of them positive?

A: The only herpesvirus that was demonstrated to have whole genome integrated in pediatric adrenocortical tumors studied by whole genome sequencing was HHV-6.

Q: You state in the discussion of the paper that the question of whether chromosomal integration leads to IGF2 over expression remains to be determined. Do you plan to do any additional investigation on this question?

A: We do not believe ciHHV-6 directly induces IGF2 overexpression. It is possible that telomeric integration of HHV-6 result in telomeric dysfunction. Because IGF2 in chromosome 11 is differentially methylated (silent in the maternal chromosome 11 and active in the paternal), loss of the maternal chromosome 11 and duplication of the paternal results in overexpression of IGF2. Our hypothesis is that HHV-6 integration in chromosome 11 causes “localized aneuploidy” likely mediated by telomeric dysfunction. We hope our results stimulate investigators to work on this hypothesis.

For more information, read the full paper here.