Genetic Risk for Cervical Cancer

Women carrying two copies of a variant of the p53 gene are seven times more likely to develop cervical cancer than patients with only one copy. The finding, reported in today's issue of Nature, helps to explain the link between the disease and human papillomavirus (HPV), a common genital-tract infection in women.

"The importance of this study is that it suggests another risk factor" for cervical cancer, says Kathleen Cho, a gynecological pathologist at Johns Hopkins School of Medicine. "This makes sense in the context of what we understand about how HPV contributes to cervical cancer." Cho says the findings could lead to the development of a genetic test that would identify those at higher risk for cervical cancer.

Cervical cancer kills more women worldwide than any cancer except breast cancer. For over 20 years, researchers have known that of the several million women whose genital tract becomes infected with certain types of HPV, a few thousand will develop cervical cancer. HPVs make proteins that inactivate cellular tumor suppressor proteins. One of these HPV proteins, called E6, inactivates the protein p53, which acts as an emergency brake to stop cells that have suffered genetic damage from dividing.

In the late 1980s, researchers discovered that the gene that produced p53 had two different alleles. One used the amino acid arginine, while the other used proline. A team led by Alan Storey of the Imperial Cancer Research Fund in London wondered whether the appearance of these forms could affect an individual's susceptibility to cervical cancer.

In test tube experiments, the researchers studied the effect of the HPV-18 strain's E6 protein on human cells that expressed either type of the p53 protein. They found that while HPV-18 destroyed p53 arginine, it left p53 proline intact. The researchers then compared the frequency of both alleles in tumor and control cells and found that an individual who carries two copies of the arginine form of the p53 gene is seven times more susceptible to HPV-induced cancer than those who do not.

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