The HPV16 Genome Is Stable in Women Who Progress to In Situ or Invasive Cervical Cancer: A Prospective Population-Based Study

Abstract

The human papillomavirus (HPV) rate of evolution is essential for cancer-preventive strategies targeting HPV. We analyzed variability over time in a prospective, populationbased nested case-control study of in situ (CIS) and invasive squamous cervical cancer (SCC). Among 757,690 women who participated in cervical screening in Sweden during 1969 to 2002, we identified 94 women who had HPV16 persistence in two serial cervical screening samples (median 24 months apart, range 0.5-178 months) and later were diagnosed with CIS (n ¼ 59), SCC (n ¼ 32), or remained healthy (n ¼ 3). Whole-HPV16-genome sequencing and comparison of sequences in the serial samples revealed that all women had the same HPV16 lineage, particularly lineage A, in both serial smears. Fifty-six percent of women had an identical 7,906 base pair HPV16 sequence in both samples, and no woman had more than 15 nucleotide substitutions. The median substitution rate was 0 substitutions/site/year (95% confidence interval, 0-0.00008), with no variation between quartiles of follow-up. We concluded that in most women with HPV16 persistence preceding disease, the nucleotide substitution rate was not measurable within up to 15-years follow-up. This slow rate of evolution has important implications for both HPVbased screening and HPV vaccination. Significance: These findings show there is no genomic variation over time in HPV16 infectionsprogressing tocervical cancer, which could influence risk stratification of women when screening for cervical cancer and inform HPV vaccination strategies.

HPV16 and HPV18 type-specific APOBEC3 and integration profiles in different diagnostic categories of cervical samples

“…We found a total of 3747 MNVs in the 131 samples, being in line with studies reporting a high number of HPV variation at the population level [20,42,43], within infected hosts [10,11,30]. A recent study on HPV16 genome stability analysed possible HPV16 sublineage co-infections and observed 20-38 variants in each sample [44], corresponding to the mean numbers of MNVs in this study. The variation was reported not to be due to co-infections but interpretation of the nucleotide variation source was not further elaborated [44].…”

“…A recent study on HPV16 genome stability analysed possible HPV16 sublineage co-infections and observed 20–38 variants in each sample [44], corresponding to the mean numbers of MNVs in this study. The variation was reported not to be due to co-infections but interpretation of the nucleotide variation source was not further elaborated [44].…”

HPV16 and HPV18 type-specific APOBEC3 and integration profiles in different diagnostic categories of cervical samples

“…We found a total of 3669 MNVs in the 131 samples, being in line with studies reporting a high number of HPV variation at the population level [ 24 , 46 , 47 ], within infected hosts [ 11 , 12 , 34 ]. A recent study on HPV16 genome stability analysed possible HPV16 sublineage co-infections and observed 20–38 variants in each sample [ 48 ], corresponding to the mean numbers of MNVs in this study. The variation was reported not to be due to co-infections, but interpretation of the nucleotide variation source was not further elaborated [ 48 ].…”

“…A recent study on HPV16 genome stability analysed possible HPV16 sublineage co-infections and observed 20–38 variants in each sample [ 48 ], corresponding to the mean numbers of MNVs in this study. The variation was reported not to be due to co-infections, but interpretation of the nucleotide variation source was not further elaborated [ 48 ]. The prevalence of sub-lineage co-infections is expected to be low [ 49 ].…”

High Levels of Within-Host Variations of Human Papillomavirus 16 E1/E2 Genes in Invasive Cervical Cancer

“…A recent study including genomic analysis of HPV16 on serial cervical samples from precancer/cancer cases revealed that 56% of the women tested had an identical viral genomic sequence in two consecutive samples (the median time between sampling was 24 months) (Arroyo-Muhr et al, 2019). Moreover, the estimated substitution rate was almost zero substitutions/site/year, suggesting that HPV16 genomic sequences are extremely stable in most cases of persistent infections.…”