The HPV16 genome is stable in women who progress to in situ or invasive cervical cancer: a prospective population-based study.

The human papillomavirus (HPV) rate of evolution is essential for cancer-preventive strategies targeting HPV. We analyzed variability over time in a prospective, population-based nested case-control study of in situ (CIS) and invasive squamous cervical cancer (SCC). Among 757690 women who participated in cervical screening in Sweden during 1969-2002, 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=59), SCC (n=32) or remained healthy (n=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 7906 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 (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 HPV-based screening and HPV vaccination.