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Researchers at the Montefiore Einstein Cancer Centre (MECC), designated by the National Cancer Institute (NCI), have developed a groundbreaking test to detect a type of cervical cancer that often goes unnoticed by traditional Pap tests. This discovery has significant implications for cervical cancer screening. The study’s findings were recently published in the Journal of the National Cancer Institute (JNCI). Dr. Howard Strickler, the co-senior and corresponding author of the JNCI paper and a member of MECC, explained, “Our innovative test demonstrates a high sensitivity for detecting cervical adenocarcinoma (ADC), which now accounts for up to 25 percent of cervical cancer cases, along with its precursor lesions, adenocarcinoma in situ (AIS), which often progress into ADCs.” Cervical adenocarcinomas have higher mortality rates compared to the more common cervical squamous cell cancers since they are frequently missed by current screening methods. Dr. Strickler’s goal is to identify the disease at an early stage, before it evolves into cancer. Dr. Strickler also serves as a professor and heads the division of epidemiology at the Albert Einstein College of Medicine. The Pap test, a method in which a pathologist examines tissue samples for abnormal cells, has significantly reduced the incidence of cervical squamous cell cancer over the past six decades. However, the prevalence of ADC has not decreased due to the Pap test’s limited effectiveness in detecting it. In recent years, HPV testing, which identifies the human papillomaviruses (HPVs) responsible for nearly all cervical cancer cases, has become a standard screening tool alongside the Pap test. Although there are over 100 HPV types, three specific types (HPV 16, 18, and 45) account for more than 70 percent of all cervical cancer cases and over 90 percent of ADC cases. Current HPV tests cover these three types and can alert infected women to a high risk of developing cervical cancer. While vaccines like Gardasil-9 offer protection against nine HPV types, several generations of women are now beyond the eligible age for vaccination. Therefore, screening and preventive treatment for cervical cancer will remain crucial for decades. The MECC-developed HPV test takes a novel approach by examining methylation levels in HPV 16, 18, and 45. Dr. Robert D. Burk, a co-leader of the study and a member of Einstein and MECC, explained, “Next-generation genetic testing has provided us with opportunities to more accurately detect oncogenic HPV strains and identify genomic patterns associated with the development of AIS and ADC.” Methylation, the process of adding methyl groups (CH3) to DNA, is a common occurrence in both viral and human DNA, playing a crucial role in altering gene expression. The study, conducted in collaboration with the NCI, analyzed methylation levels in cervical tissue samples from 1,400 women who underwent cervical cancer screening at Kaiser Permanente Northern California before 2014, with known cervical cancer statuses. By assessing HPV in these samples, researchers calculated methylation percentages at 35 different viral-genome sites, providing each sample with a “methylation score” based on the average methylation percentage across these sites. Women with methylation scores in the top 25 percent had significantly increased odds of developing ADC or AIS. Dr. Burk emphasized, “If our findings are confirmed in clinical trials, women with a high methylation score may benefit from more extensive evaluation, such as colposcopy and specialized tissue examination, in addition to Pap tests. This could lead to early diagnosis and treatment for ADC or the removal of AIS lesions before they progress to ADC.” Dr. Strickler noted that the test’s equipment could potentially be simplified, making it suitable for broader use in resource-limited countries. Cervical cancer remains the fourth most common cancer among women, with a disproportionately higher burden in lower- and middle-income countries, especially those in Sub-Saharan Africa where HIV-HPV co-infections are prevalent. Significant disparities also exist within the United States, with the Bronx, one of the nation’s poorest urban congressional districts, experiencing cervical cancer rates 50 percent higher than Manhattan. More frequent and effective screening could help bridge this healthcare disparity. “Ideally, the new HPV methylation test would only need to be done once every three to five years,” added Dr. Strickler, expressing hope that the test could enhance cervical cancer screening equity in the U.S. and beyond.