title: Loss of Dependence on Continued Expression of the Human Papillomavirus 16 E7 Oncogene in Cervical Cancers and Precancerous Lesions Arising in Fanconi Anemia Pathway-Deficient Mice.
abstract: Fanconi anemia (FA) is a rare genetic disorder caused by defects in DNA damage repair. FA patients often develop squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) are known to cause cancer, including the cervix. However, SCCs found in human FA patients are often HPV negative, even though the majority of female FA patients with anogenital cancers had preexisting HPV-positive dysplasia. We hypothesize that HPVs contribute to the development of SCCs in FA patients but that the continued expression of HPV oncogenes is not required for the maintenance of the cancer state because FA deficiency leads to an accumulation of mutations in cellular genes that render the cancer no longer dependent upon viral oncogenes. We tested this hypothesis, making use of Bi-L E7 transgenic mice in which we temporally controlled expression of HPV16 E7, the dominant viral oncogene in HPV-associated cancers. As seen before, the persistence of cervical neoplastic disease was highly dependent upon the continued expression of HPV16 E7 in FA-sufficient mice. However, in mice with FA deficiency, cervical cancers persisted in a large fraction of the mice after HPV16 E7 expression was turned off, indicating that these cancers had escaped from their dependency on E7. Furthermore, the severity of precancerous lesions also failed to be reduced significantly in the mice with FA deficiency upon turning off expression of E7. These findings confirm our hypothesis and may explain the fact that, while FA patients have a high frequency of infections by HPVs and HPV-induced precancerous lesions, the cancers are frequently HPV negative. IMPORTANCE  : Fanconi anemia (FA) patients are at high risk for developing squamous cell carcinoma (SCC) at sites where high-risk human papillomaviruses (HPVs) frequently cause cancer. Yet these SCCs are often HPV negative. FA patients have a genetic defect in their capacity to repair damaged DNA. HPV oncogenes cause an accumulation of DNA damage. We hypothesize, therefore, that DNA damage induced by HPV leads to an accumulation of mutations in patients with FA deficiency and that such mutations allow HPV-driven cancers to become independent of the viral oncogenes. Consistent with this hypothesis, we found that cervical cancers arising in HPV16 transgenic mice with FA deficiency frequently escape from dependency on the HPV16 oncogene that drove its development. Our report provides further support for vaccination of FA patients against HPVs and argues for the need to define mutational profiles of SCCs arising in FA patients in order to inform precision medicine-based approaches to treating these patients.
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Soyeong
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Jung Wook
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Pitot
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA plambert@wisc.edu.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000235:genetics / Q000821:virology*; D004260:DNA Repair; D005199:Fanconi Anemia / Q000150:complications / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D064168:Minichromosome Maintenance Complex Component 7 / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000150:complications / Q000235:genetics / Q000821:virology*
chemical_list: D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; C491086:Mcm7 protein, mouse; D064168:Minichromosome Maintenance Complex Component 7