Cervical carcinogenesis includes the following necessary steps: infection with one of 13 evolutionarily related carcinogenic human papillomavirus (HPV) types, viral persistence linked with progression to cervical precancer (cervical intraepithelial neoplasia grade 3, CIN3), and invasion. There are extremely large differences in carcinogenic behavior among the types that can cause cervical cancer, despite highly conserved organization in their very small (8,000 base pair) genomes. If persistently detectable, the genotype HPV16 is one of the most potent human carcinogens known, whereas HPV genotypes in the same species are rarely if ever carcinogenic. Even variant lineages of genotypes, including HPV16, which differ by only 200 SNPs, can differ in carcinogenicity by 5-100 fold. DCEG cohort studies, which have stored 100,000 HPV isolates with known natural history, confer substantial statistical power to determine which nucleotides or combinations of nucleotides confer HPV16s unique risk. By interrogating whole genomes of sufficiently large numbers of cases (n.b., we have access to tens of thousands), we anticipate making substantial progress in understanding the viral genetic basis of HPV carcinogenesis. Because the HPV genome is so small and because variants of each of the HPV types differ by only about 200 base pairs, we predict that it will be possible to identify specific viral genetic variations associated with carcinogenicity. We will be able to identify targets and or biochemical functions within the host which are perturbed in the cascade to cancer. The ultimate translational goal is to identify sequence-specific differences that provide clues about the biological basis of HPV carcinogenicity, and eventually identify therapeutic antiviral targets. What we learn about HPV genomics and HPV-associated cancer pathogenesis could inform our understanding of other disease-associated viruses (e.g., HIV).
| Mirabello, Lisa; Clarke, Megan A; Nelson, Chase W et al. (2018) The Intersection of HPV Epidemiology, Genomics and Mechanistic Studies of HPV-Mediated Carcinogenesis. Viruses 10: |
| Mirabello, Lisa; Yeager, Meredith; Yu, Kai et al. (2017) HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis. Cell 170:1164-1174.e6 |
| Mirabello, Lisa; Yeager, Meredith; Cullen, Michael et al. (2016) HPV16 Sublineage Associations With Histology-Specific Cancer Risk Using HPV Whole-Genome Sequences in 3200 Women. J Natl Cancer Inst 108: |
