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Principal Investigator: JEANNE ANN JORDAN
Organization: GEORGE WASHINGTON UNIVERSITY
Fiscal Year: 2021
Award: $359,399
Funding agency: National Cancer Institute
ABSTRACT
Human papillomavirus (HPV) infections are highly prevalent in men and women. High-risk (HR) HPV types 16
& 18 (HPV16/18) are responsible for ~90% of all anal cancers, whose incidence has risen by 96% in the last 2-
3 decades primarily because of the HIV/AIDS epidemic. Indeed, HIV-infected men who have sex with men
(HIV+MSM) are the population at highest risk of anal cancer with an incidence rate of 137 per 100,000
compared with 2 per 100,000 among HIV-uninfected men. Current anal cancer screening begins with an anal
Papanicolaou (Pap) test to look for abnormal cytology, and in some clinics include HR-HPV DNA testing, which
detects infection. If cytologic abnormalities of atypical squamous cells of unknown significance or higher are
found on the anal Pap, patients are referred for high-resolution anoscopy (HRA), an invasive procedure to
visualize and remove abnormal tissue for histology. Unfortunately, anal Pap screening under-estimates the
grade of dysplasia compared to histology. Furthermore, HR-HPV DNA screening has limited utility among the
HIV+MSM population because prevalence of anal HPV infection is so high (~80%). Screening individuals for
HR-HPV DNA, although sensitive for detecting infection, is not specific for predicting risk of anal dysplasia. A
more specific companion diagnostic is urgently needed to help determine when someone should be referred
for HRA or not. To that end, we will be the first to assess the following combined measures of HPV gene
expression from anal specimens: a) methylation status of all 15 CpG sites within the long control region (LCR)
upstream of E6/E7 oncogenes, b) intra-epithelial levels of HR-HPV E6/E7 mRNA, and c) HPV 16/18 E6 protein
expression. We hypothesize that combining 1 or more of these biomarkers with the anal Pap test, rather than
the HR-HPV DNA test, would improve specificity for predicting AIN2+. To evaluate this, we will conduct a
cross-sectional study of a diverse population of HIV+MSM with abnormal anal Pap results, who are undergoing
HRA at clinics here in the District of Columbia, the city with the highest HIV prevalence rate in the U.S. Prior to
the HRA procedure, 3 anal swabs will be collected: DNA will be extracted from one and used to assess CpG
methylation patterns, an epigenetic biomarker, in HPV16/18 LCR, while the 2nd will be placed into liquid-based
cytology media for HPV DNA genotyping, HR-HPV E6/E7 mRNA expression, and HPV16/18 E6 oncoprotein
detection, and the 3rd will be analyzed directly for HPV16/18 E6 oncoproteins. Results of these tests will be
compared independently for their ability to predict AIN2+ from HRA guided biopsies. HPV DNA genotyping
data will permit us to characterize distribution of anogenital HPV types found in HIV+MSM here in DC.
Identifying a more specific biomarker will improve the accuracy of predicting anal dysplasia in this high-risk
group by providing stronger evidence to justify HRA if positive, or reduce the rate of unnecessary HRA if
negative. Discovering a better companion diagnostics remains important in the HPV vaccine era because
many HIV+MSM were never vaccinated and vaccine uptake continues to be lower than the target goals.
Terms: <AIDS Virus><AIDS/HIV><AIDS/HIV problem><Ablation><Abscission><Acetic Acids><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Algorithms><Anal><Anal Cancer><Anal Cancers><Anal Intraepithelial Neoplasia><Anal canal><Anus><Anus Cancer><Atypical Squamous Cell><Biological Markers><Biopsy><Body Tissues><Cancer Genes><Cancer Screening for Patients><Cancer-Promoting Gene><Cancers><Cell Cycle><Cell Cycle Control><Cell Cycle Regulation><Cell Division Cycle><Characteristics><Cities><Clinic><Cross Sectional Analysis><Cross-Sectional Analyses><Cross-Sectional Studies><Cross-Sectional Survey><Cytology><D.C. Washington><DC Washington><DNA><Data><Deoxyribonucleic Acid><Detection><Development><Diagnostic><Disease Frequency Surveys><District of Columbia><Dysplasia><Early Diagnosis><Epidemic><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial><Excision><Extirpation><Gene Expression><Genome><Genotype><Goals><HIV><HIV/AIDS><HIV/AIDS problem><HPV><HPV 16><HPV Vaccine><HPV infection><HPV oncogene><HPV-16><HPV-High Risk><HPV16><Health><Healthcare><High Risk Oncogenic HPV><High risk HPV><High risk Human Papillomavirus><High risk Human papilloma virus><Histologic><Histologically><Histology><Human Immunodeficiency Viruses><Human Papilloma Virus><Human Papilloma Virus Vaccine><Human Papillomavirus><Human papilloma viral oncogene><Human papilloma virus infection><Human papilloma virus type 16><Human papillomavirus 16><Human papillomavirus Vaccine><Human papillomavirus infection><Human papillomavirus type 16><Incidence><Individual><Infection><Infectious Human Wart Virus><LAV-HTLV-III><Lateral><Lesion><Liquid substance><Lymph Node Involvement><Lymphadenopathy-Associated Virus><MSM><Malignant Anal Neoplasm><Malignant Anal Tumor><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Anus><Malignant neoplasm of anus><Measures><Messenger RNA><Methylation><Oncogene Products><Oncogene Proteins><Oncogenes><Oncoproteins><Outcome><Pap Test><Pap screening><Pap smear><Papanicolaou Smear><Papanicolaou Test><Participant><Pathologist><Patients><Performance><Physicians><Population><Population Heterogeneity><Predictive Value><Prevalence><Procedures><Prognosis><Randomization trial><Removal><Research Specimen><Resolution><Risk><Screening for cancer><Sensitivity and Specificity><Severities><Site><Specificity><Specimen><Surgical Removal><Swab><Test Result><Testing><Tissues><Transforming Genes><Triage><United States><Vaccinated><Virus-HIV><Woman><accept vaccination><accept vaccine><anal squamous cell carcinoma><anus intraepithelial neoplasia><base><bio-markers><biologic marker><biomarker><bisulfite><companion diagnostics><developmental><diverse populations><dyscrasia><early cancer detection><early detection><epigenetic biomarker><epigenetic marker><fluid><health care><heterogeneous population><high risk><high risk group><high risk population><human papilloma virus 16><human papilloma virus oncogene><human papillomaviral oncogene><human papillomavirus oncogene><hydrogen sulfite><hydrosulfite><improved><intraepithelial><liquid><mRNA><mRNA Expression><malignancy><men><men who have sex with men><men who have sex with other men><men's><methylation pattern><neoplasm/cancer><overexpress><overexpression><population diversity><precancerous><predictive assay><predictive test><premalignant><prevent><preventing><protein expression><pyrosequencing><racial diversity><racially diverse><randomized trial><resection><screening><specific biomarkers><tumor><type 16 Human papilloma virus><type 16 Human papillomavirus><vaccination acceptability><vaccination acceptance><vaccination confidence><vaccination uptake><vaccination willingness><vaccine acceptability><vaccine acceptance><vaccine confidence><vaccine uptake><vaccine willingness><viral DNA><virus DNA><wart virus>