Novel test detects hard-to-find cervical cancers

Scientists at the National Cancer Institute-designated Montefiore Einstein Cancer Center (MECC) have developed a test for detecting a type of cervical cancer that Pap tests often miss.

Described in the Journal of the National Cancer Institute (JNCI), the novel test appears sensitive for detecting cervical adenocarcinoma (ADC) — which accounts for up to 25% of cervical cancer cases — as well as its precursor lesions, adenocarcinoma in situ (AIS), which often develop into ADCs.

“Because ADCs are often missed by current screening methods, they have higher mortality rates than the more common cervical squamous cell cancer,” said Professor Howard Strickler, co-senior author of the paper. “Our goal is to catch the disease early, before it develops into cancer.”

The widespread use of the Pap test, 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 incidence of ADC has not decreased, probably because the Pap test is less effective at detecting it.

In recent years, testing for human papillomaviruses (HPVs) — which cause virtually all cases of cervical cancer — joined the Pap test as a standard screening tool for cervical cancer. Although there are more than 100 types of HPV, three types — HPV 16, 18 and 45 — account for more than 70% of all cervical cancer cases and more than 90% of ADC cases. The current HPV tests cover all three types and can alert infected women that they face a high risk for developing cervical cancer. The MECC-developed HPV test assessed HPV 16, 18 and 45 in a novel way: by specifically looking at methylation levels.

“The advent of next-generation genetic testing has opened up opportunities for us to more accurately detect oncogenic HPV strains and patterns in the genomes that correspond with the development of AIS and ADC,” said Professor Robert D Burk, who co-led the study.

Methylation — the addition of methyl (CH₃) groups to a region of DNA — is a routine occurrence in DNA, both viral and human, and plays a critical role in altering gene expression. The new study investigated methylation levels in cervical tissue samples from 1400 women who had undergone cervical cancer screening at Kaiser Permanente Northern California before 2014 and whose cervical cancer status was known.

In assessing the HPVs in the cytological samples, the researchers tallied up the methylation percentages for each of 35 different viral-genome sites, with each sample receiving a final ‘methylation score’ equal to the average methylation percentage across all 35 sites. Those women with methylation scores in the upper 25% had very high odds for having developed either ADC or AIS.

“Our findings, if confirmed by clinical trials, suggest that women with a high methylation score may benefit from colposcopy and specialised tissue evaluation, beyond just a Pap test, which could lead to early diagnosis and treatment for ADC or the removal of AIS lesions before they develop into ADC,” Burk said.

Cervical cancer remains the fourth most common type of cancer in women, with the burden significantly higher in lower- and middle-income countries. Strickler noted that, given that the test uses equipment that could be simplified, it has the potential to expand testing in these lower-resourced countries.

“Ideally, the new HPV methylation test would only need to be done once every three to five years,” he added. “We are hopeful that this test will be able to increase cervical cancer screening equity in the US as well.”

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