Pioneers of Promise
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Pinpointing the Cause of Cervical Cancer
By Melissa Hendricks
In 1842, Italian investigator D. Rigoni-Stern reported that prostitutes had an unusually high rate of cervical cancer, while nuns had virtually no cases of the disease. He hypothesized that cervical cancer was sexually transmitted.
In the years since Rigoni-Stern's observations, researchers have accumulated more evidence in support of his hypothesis, and last year an international group of scientists reported that virtually every case of cervical cancer stems from the sexually transmitted human papillomavirus (HPV). The finding marks the first time a virus has been shown to account for every case of a cancer. Even the relationship between tobacco and lung cancer is not as strong.
Hopkins virologist Keerti Shah (MPH '57, PhD '63) co-authored the recent paper and has investigated the HPV–cervical cancer connection for 20 years. He is a reserved man, who stresses that "many, many people were involved--it was a worldwide effort." His colleagues at the School of Public Health, however, say Shah figured prominently in building the case against the virus.
"He is somebody who has dogged this, pushed this, studied this from the very beginning," says Al Sommer, dean of Public Health. "It was Shah and the postdocs he hired and others who worked with him who kept the momentum going. He's been there all along at every critical juncture."
Shah became involved in HPV research in the late 1970s when a colleague sent him a sample thought to contain a poliomavirus--a group of viruses that Shah had been studying. Shah determined that the sample actually was not a poliomavirus but HPV.
About the same time, investigators elsewhere had identified HPV in specimens taken from the genital tracts of women with cervical cancer and had floated theories that HPV could have caused the disease. "I was always interested in the causes of disease," says Shah. So he decided to learn more about the HPV sample. Eventually, he began collaborating with other scientists who shared his curiosity.
Their investigations were complicated by the fact that virologists had identified several types of viruses from women with cervical cancer, including the herpes virus. Researchers had heated debates as to whether HPV, herpes, or some other agent was to blame for the disease. To make matters even more complicated, there were many different types of HPV. (Scientists to date have identified about 100 HPV types, including about 20 that reside in the genital tract.)
In the lab, researchers had found that when they infected healthy cells with HPV, the cells took on the features of a cancer cell. But that was not sufficient evidence to incriminate HPV. "Viruses do all sorts of things in the lab that you don't see in real life," says Shah.
To build a convincing case, the researchers would need a thorough epidemiological study. So Shah and an international team designed a rigorous, case-controlled study involving hundreds of women with and without cervical cancer.
The researchers incorporated many different controls into their study design. They enrolled volunteers from Spain, a country with very little cervical cancer, and Colombia, which has a rate about eight times that of Spain's. They collected cervical-swab specimens from each woman and applied three different DNA-based assays to test for HPV. They also "blinded" the samples, to hide whether the sample came from a woman with or without cervical cancer.
After collecting all their data, Shah and his colleagues tore open the envelope that held the key to the blinding code. "It was very clear," says Shah. Regardless of which assay had been used, at least 60 percent of cervical cancers were associated with HPV. Shah suspected the true figure was actually higher.
In further studies, he and collaborators investigated the prevalence of HPV in women from 22 countries, ultimately demonstrating that HPV accounts for 99.7 percent of cervical cancers. They reported their findings last year in the Journal of Pathology.
Most women who are infected with HPV will not develop cervical cancer, the second most common cancer in women. HPV infections usually disappear on their own within a year. When cervical cancer does develop, it generally takes a decade or longer. HPV is the trigger, but other factors--other infections, smoking, and multiple pregnancies have all been flagged as potential risks-- are required for the infection to progress to cancer, says Shah.
The veteran investigator is gratified by the clinical applications that are arising from his and his colleagues' research. These include cervical cancer diagnostic tests that assay for HPV and may be used in combination with or instead of the Pap smear. The HPV test is simpler and may even one day lead to a home screening test for the virus. Simpler testing would be an enormous boon to reduce cervical cancer worldwide, especially in developing countries where rates are highest. Research is also under way at Hopkins and elsewhere for a vaccine aimed at preventing HPV infections or treating cervical cancer.
"If we combine screening and vaccines, tools that I think will be in our hands in five years, then there will definitely be a reduction in the burden of cervical cancer," says Shah. "I think there is a lot of hope."
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