As a virologist, I assumed that the name “Pap smear” was somehow related to the infectious agent that is associated with 99.7% of cervical cancers: human papillomavirus (HPV). However, it turns out that the similarity is just a coincidence; the Pap smear is named after its originator, Dr. George Papanicolaou.
Fun fact: George’s wife, Mary, collected samples from herself for years for her husband’s research and convinced friends and colleagues to do the same. Ultimately, samples from a colleague who had cervical cancer led Dr. Papanicolaou to develop the Pap test.
Unfun fact: HPV doesn’t just cause cervical cancer. Chronic infections with some of the high-risk HPV strains are associated with anal, penile, throat, vaginal, and vulvar cancers. Although cervical cancer rates are dropping in the US—in no small part due the HPV vaccine—incidence of other HPV-caused cancers is rising.
Consider anal cancers, which are on the rise and almost always associated with chronic infection by high-risk strains of HPV. While anal cancer is rare overall, risk escalates precipitously for people living with HIV (PLWH), who are 40 times more at-risk of developing anal cancer.
Screening for anal cancer has some parallels to screening for cervical cancer: testing for HPV infection, especially with the high-risk strains, identifies patients who need additional follow-up such as cytological screening. Anoscopies and anal cytology—where cells are collected and stained similarly to a Pap smear—can be used to detect precancerous changes called high-grade squamous intraepithelial lesions (HSIL). Treatment of HSIL can prevent progression to anal cancer if they are caught in time.
Unfortunately, this way of screening has its limitations. Testing for HPV is not very specific, as HPV infection is incredibly common and not everyone with HPV will develop HSIL or anal cancer. Anal cytology, on the other hand, is not very precise and often require confirmation with other, more sensitive, tests.
“That leads to a lot of unnecessary follow-up procedures," says Faiza Faria, a public health researcher in the Clinical Research Division. She, along with Rachel Winer, Professor in the Department of Epidemiology at the UW School of Public Health and other colleagues at UW, wanted to find a biomarker that could better identify patients at high risk of HSIL. Their results were recently published in Cancer, Epidemiology, Biomarkers & Prevention.
“Currently, US anal cancer screening guidelines for PLWH recommend high resolution anoscopy (HRA), which requires specialized equipment and trained professionals,” Ms. Faria continues. “Identifying biomarkers that can be collected with an anal swab for risk stratification may allow low-risk patients to be monitored with less invasive approaches and at less frequent intervals.” It also would hopefully motivate those at higher risk to seek out high-resolution anoscopies more regularly.
One promising candidate to detect HSILs is oncoprotein E6, which, among other things, hijacks cellular DNA damage repair pathways and predisposes cells to cancer. E6 showed high specificity as a biomarker for detecting cervical HSILs—that is, patients who were positive were very likely to have HSILs.
To determine whether E6 could also be a biomarker for anal cancer screening, Ms. Faria and her team used samples collected from 85 patients undergoing anal cancer screening or treatment at Harborview Research Center. All patients were assigned male at birth and living with HIV. Anal brush specimens were tested for HPV DNA by PCR and for E6 expression, and the results were compared with clinical cytology and histology looking for presence and extent of HSILs.
“Our study found that the E6 oncoprotein test is extremely specific—it only turned positive in people who had pre-cancerous lesions,” says Ms. Faria. “That means it could help providers to focus their attention on those who need it most, while avoiding unnecessary procedures for others.”
Although the positive predictive value of the E6 oncoprotein test was 100% (meaning a positive test result always correlated with HSIL lesions), a negative result was less conclusive. “The test had very low sensitivity for pre-cancerous lesions, meaning that it would not be good as a standalone screening test,” says Ms. Faria. Positive results tended to correlate with larger or more clinically relevant HSILs.
The authors say that more work is needed on ways to overcome the limitations of this test. “Since the E6 test missed many high-grade lesions, future studies should explore whether combining it with other biomarkers can create a better overall screening strategy,” says Ms. Faria. Future work should also take a longitudinal approach to see if E6 positivity correlates directly with progression to anal cancer. “This is an important step toward smarter, more targeted anal cancer screening strategies in a high-risk population,” says Ms. Faria.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Stephen Hawes and Rachel Winer contributed to this research.
The spotlighted research was funded by the National Institute of Allergy and Infectious Diseases.
Faria F, Hawes SE, Lin J, Schouten J, Stankiewicz Karita HC, Cherne S, Vasavada A, Barnabas RV, Wasserheit JN, Feng Q, Winer RL. The Role of Human Papillomavirus E6 Oncoprotein as a Biomarker in Anal Cancer Screening in Persons Living with HIV. Cancer Epidemiol Biomarkers Prev. 2025 Sep 2;34(9):1656-1662.
Hannah Lewis is a postdoctoral research fellow with Jim Boonyaratanakornkit’s group in the Vaccine and Infectious Disease Division (VIDD). She is developing screens to find rare B cells that produce protective antibodies against human herpesviruses. She obtained her PhD in molecular and cellular biology from the University of Washington.
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