Factors that favour a proportion of HPV16 infections to progress to cancer are still poorly understood, but an increasing number of studies have implicated a role of HPV16 variants in cervical cancer risk.
An HPV variant is a genome defined by a unique combination of single nucleotide polymorphisms (SNPs). A recent proposal defines major variant lineages by a 1.0% difference between full genomes of the same HPV type, with differences of 0.5 to 0.9% defining sub-lineages. Based on whole HPV genome sequencing, HPV16 variants have been classified into four major lineages: (1) A, that includes sub-lineages A1–3 (previously named European), and A4 (Asian); (2) B (African 1); (3) C (African 2); and (4) D (including Asian–American [AA] and North-American [NA]) (Burk et al., 2013).
The distribution of HPV16 variant lineages around the world is highly geographically and ethnically specific, which limits the extent to which data can be easily combined across countries and interpreted soundly. Nevertheless, some consistent findings in case:control comparisons in multiple geographic settings do appear to exist, namely :
D (North American/Asian-American) variant lineages appear to be associated with HPV16 persistence and CIN3+/cervical cancer development (Berumen et al., 2001; Xi et al., 2007; Schiffman et al., 2010; Cornet et al, 2013).
A4 (Asian) variant lineage shows association with cervical cancer, particularly in East Asian populations where they are common (Cornet et al, 2013; Chang et al 2013; Hang et al, 2016).
It is not yet clear which of the many correlated lineage-defining SNPs are at the cause of these differential risks, but work is currently moving to the finer level of genetic analysis by performing whole HPV16 genome sequencing in an appropriately large number of HPV16-positive cases and controls (see 17/06 session: “new advances in genomics”).
To date, little is known about the distribution of variant lineages in HPV16 infection and cancer at other sites of the anogenital tract or head and neck, but there is no striking evidence or biological plausibility why it should be any different from that in the cervix.
Although our findings suggest that HPV16 variant analysis has no clinical application at present (all variant lineages are commonly found in cervical cancer), understanding the genetic basis of differences in the carcinogenicity of HPV16 variants may help us unravel important biological and/or immunological interactions between virus and host that could lead to better tools to control HPV infection and its malignant consequences.