Wednesday, April 2, 2025
4/2/2025
Molecular Markers for Tumors Associated with Extrachromosomal HPV - 3URMHFW 6XPPDU In the classical paradigm for cervical cancer, keratinocytes are infected with high-risk HPV (HR-HPV) genomes which become integrated (“iHPV”) into human chromosomes, and facilitate progression to invasive cancer. However, the concept of HPV integration is not routinely used in clinical practice. Intriguingly, we and others have shown that at least 25% of HPV-positive (HPV+) cancers harbor only “extrachromosomal” HPV (“eHPV”), and there are reports of “hybrid” tumors with both eHPV and iHPV. We have also shown that there is no difference in the distribution of clinical stage between patients with eHPV versus iHPV tumors, even though patients with eHPV tumors have better clinical outcomes. Based on this, we posit that eHPV and iHPV tumors have distinct molecular drivers and may require different treatment strategies. Investigation of novel diagnostic and therapeutic strategies in cervical cancer remains highly significant despite the advances in screening and vaccination. The successes of these prevention programs in the “West” have not been replicated in resource-poor countries with the greatest disease burden, and even in the United States, disparities in vaccine uptake still exist with millions still at risk of developing cervical cancer. We were the first to discover r ecurrent somatic ERK2-E322K mutations in primary cancers (8% o f cervical cancer). We have now shown that ERK2-E322K mutations are 9 times mo re likely to occur in eHPV tumors compared with iHPV tumors. We have also identified specific viral spliced transcripts (VSTs) that distinguish eHPV and iHPV primary HPV16-positive cervical tumors, and we have shown using VSTs that the expression of HPV E5, which is known to promote angiogenesis, is a hallmark of eHPV status. Our overall hypotheses are that eHPV-tumors and iHPV-tumors have distinct host and viral genomic classification markers, that patients with eHPV tumors respond better to therapy with the angiogenesis inhibitor bevacizumab than those with iHPV tumors, and that ERK2-E322K mutation enhances the growth of eHPV tumors more than iHPV tumors. Our specific aims to: (i) characterize host molecular markers that distinguish eHPV-tumors from iHPV-tumors, (ii) investigate the diagnostic and therapeutic utility of HPV viral spliced transcripts in cervical cancer, and (iii) investigate the effect of ERK2E322K mutation on the growth of eHPV versus iHPV tumors. We expect our research contribution to be significant and impactful for patient diagnosis and treatment. We will p. rovide translational utility for HPV integration (or the lack thereof) by identifying host and viral markers for the classification of eHPV and iHPV tumors, and for treatment-related patient stratification.
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