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Page 137 Hjalgrim et al. J Transl Genet Genom 2022;6:134-46 https://dx.doi.org/10.20517/jtgg.2021.46

[24]
Here, the suspicion has been the strongest against EBV . EBV is a ubiquitous lymphotropic human
[25]
herpesvirus, which was first isolated from Burkitt lymphoma cell lines . Depending on the socio-economic
setting, primary infection with EBV typically occurs in early childhood (in deprived settings) or in
adolescence (increasingly often in affluent settings), in which case it is then often accompanied by infectious
mononucleosis . Following primary infection, EBV latently infects B-lymphocytes to escape immune
[26]
surveillance, with occasional lytic activations normally culled by the host’s immune system .
[27]
Following early demonstrations of EBV nucleic acids and gene products in malignant HRS cells in seminal
papers in the late 1980s [28-31] , we now know that only a subset of cHLs is EBV-positive and that the
prevalence of EBV in cHL varies somewhat systematically with sex, age, and histology. Specifically, EBV
prevalence is higher in cHLs diagnosed in males compared with females, in children and older adults
compared with AYAs; in MC compared with NS cHL, and in deprived compared with affluent settings [21,32] .

Importantly, although the prevalence of EBV in cHL correlates independently with both age at diagnosis
and with histological types of cHL, none of the three captures the other two accurately and they likely
represent different phenomena in the natural history of cHL . Consequently, studies lacking any of the
[2]
three characteristics may therefore be interpretationally challenging.

In addition to being biologically credible (see below), a variety of differences between EBV-positive and
EBV-negative cHLs suggests that HRS EBV status distinguishes between aetiologically separate cHL
entities . For instance, epidemiological risk factors differ between EBV-positive and EBV-negative cHL. In
[24]
particular, increased risks of HL following EBV-related infectious mononucleosis seem predominantly or
even exclusively restricted to EBV-positive cHL as it is the case for the increased HL risk associated with
immune deficiencies such as HIV infection and organ transplantation [2,16] . Other examples of exposures
suspected of having different effects on the risk of EBV-positive and EBV-negative cHL include number of
older and younger siblings and smoking [2,16] . These observations are supplemented by prospective
serological analyses, which indicate that aberrant EBV-antibody patterns precede diagnosis of EBV-positive
cHL, but not diagnosis of EBV-negative cHL .
[33]

Finally, genome-wide association studies have identified loci associated with risks of cHL irrespective of
tumour EBV-status, as well as loci specific to EBV-positive and EBV-negative cHL (genetic studies are
thoroughly reviewed and interpreted in Ref. ). Loci associated with cHL have been found both inside and
[16]
outside of the HLA region and very strong associations between HLA-type and EBV-positive cHL have
been known for a long time [34-37] . The association between some of the loci and cHL also varies by histology
[38]
independently of tumour EBV status .
Nevertheless, neither HLA nor non-HLA loci has so far been used in treatment risk stratification and
epidemiologically the most intriguing observation from genetic studies in HL to date may be the realisation
that cHL has a much larger genetic overlap/similarity to autoimmune diseases than solid cancers .
[39]

In combination, these different lines of evidence have led to the formulation of a pathogenic model
according to which EBV may lead to EBV-positive cHL either in direct continuation of the primary
infection, be it in childhood or in AYA or because illness and/or immune senescence result in loss of
immunological control of the normal latent stage of infection [24,40] .