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Enhanced HPV16 Diversity Suspected of Protecting Against Cervical Cancer

NEW YORK (GenomeWeb) – Variation in the human papillomavirus type 16 (HPV16) genome appears to be linked to forms of the virus that are less likely to lead to cervical cancer or precancerous conditions, according to a study published online today in Cell.

Researchers from the US, France, Hong Kong, and Costa Rica considered genome sequence data for 5,570 HPV16 isolates from infected individuals. Along with high levels of genetic diversity in general, they found that variation was over-represented in individuals who did not have cancer or precancerous lesions, particularly across the E7 oncogene. On the other hand, conservation in E7 sequences tended to coincide with the cancer or pre-cancer infection cases.

"[O]ur findings suggest that within-lineage hypovariation in specific regions of the viral genome is important for HPV16 carcinogenicity," corresponding author Lisa Mirabello, a cancer epidemiology and genetics researcher at the National Cancer Institute, and her co-authors wrote. "It will be important to follow-up our E7 findings, and other implicated regions, in subsequent studies to characterize genetic variation in these regions in more depth."

The researchers did whole-genome sequencing on 3,215 HPV16 isolates from specimen transport medium for Pap samples collected from women in California, along with multiple cervical, anal, and/or oral isolates in scrape, swab, or rinse samples from 58 Costa Rican women.

In the first 3,215 HPV16 genomes, they detected 2,445 subtly different versions of the virus, along with shared sequences for 770 HPV16 isolates. Similarly, almost 85 percent of the Costa Rican viruses — or 49 of the isolates — were distinct. In a handful of cases, that diversity extended to samples from different body sites in the same individual, though more than 81 percent of paired samples from a single individual matched one another genetically.

The team then performed a case-control comparison of HPV16 genome patterns in symptom-free HPV-infected women and women who had cervical intraepithelial neoplasia, or CIN, features associated with cervical pre-cancer — an analysis that included genome sequences for HPV16 isolates from another 688 women pre-cancerous lesions classified as at least grade 2 CIN and 1,609 HPV16-infected women with invasive cervical cancer.

A few dozen SNPs showed potential associations with CIN in the so-called A1 or A2 sub-lineages of HPV16, the researchers reported. But more broadly, they found that non-synonymous and nonsense mutations were more common in viral samples from the control individuals than they were in HPV16 sequences from individuals with cancer or pre-cancer. That was especially true of the E7 gene, which showed strong sequence conservation in the viruses obtained from high-grade CIN samples or cervical cancers.

"A priority should be to conduct functional studies to understand how the particular E7 genetic sequence apparently common to virtually all cervical cancers caused by HPV16 worldwide is linked to this type's unique carcinogenicity and might be an appropriate target for therapeutic intervention," Mirabello and her co-authors concluded.