LONDON - Women who have inherited a particular form of the tumor suppressor protein p53 may be up to seven times more likely to develop cervical cancer than others, an international group of researchers has found.

The discovery suggests there may be a subgroup of women who would benefit from more intensive screening for precancerous changes in the cervix, or who might in the future gain greater benefit from a vaccine to protect against the human papillomavirus (HPV), which is present in more than nine out of 10 cervical tumors.

Alan Storey, team leader at the Skin Tumour Laboratory of the Imperial Cancer Research Fund, one of the U.K.'s leading cancer research charities, said the finding sheds light on how HPV turns normal cells into tumor cells.

Storey and his colleagues reported results of their research in a paper in Nature, May 21, 1998, titled “Role of a p53 polymorphism in the development of human papilloma-virus-associated cancer.“

Storey's colleagues included researchers from his laboratory; from the department of medical microbiology at St. Bartholomew's and the Royal London Hospital School of Medicine and Dentistry, in London; from the International Centre for Genetic Engineering and Biotechnology, in Trieste, Italy; and from the Institute for Parasitology and the McGill Cancer Centre, in Quebec.

Each year, more than 1,500 women in the U.K. die from cervical cancer. The development of cervical cancer is closely linked to infection with HPV. In more than 95 percent of cervical cancers, HPV types 16 and 18, together with a handful of others, are present.

HPV 16 and HPV 18 are known to produce two proteins that play a key role in the development of cancer, called E6 and E7. E7 binds to and inactivates the cellular tumor suppressor protein Rb, while E6 binds to p53, also a cellular tumor suppressor protein, and causes the cell to break it down.

Virus Disarms P53

Although p53 is often mutated in various kinds of cancer, it is often normal in cancers caused by HPV. Instead, the virus itself inactivates this protective protein.

Storey explained, “P53 acts like a molecular policemen, monitoring the state of our genetic information. If our DNA is damaged, p53 accumulates, preventing the cell from dividing and allowing time for the damage to be repaired. If the repair process fails, p53 triggers programmed cell death so that the damaged cell is eliminated.“

This is why, he added, it is so important for HPV to knock out p53. If the virus triggered the repair process, the cell's growth could come to a halt or the cell might be eliminated, and the virus would not be able to replicate.

When p53 was first isolated, it was found to be present in the general population in two forms. The amino acid present at position 72 in the protein is either a proline or an arginine. Depending on which type of p53 they have inherited from each of their parents, people may have just the arginine type in their cells, just the proline type or a mixture of both.

Storey and his colleagues decided to investigate whether HPV could trigger the breakdown of both types of p53 equally effectively. He said, “We found that the virus can more easily knock out the arginine form of p53, and that cervical cancers resulting from HPV infection were significantly more likely to occur in women who had only the arginine form.“

In laboratory experiments for the study, the group introduced plasmids expressing either the proline form or the arginine form of p53 into a cell line that does not produce its own p53, as well as a plasmid expressing the E6 protein of HPV 18.

Increasing amounts of E6 caused a dramatic decrease in the amount of the arginine form of p53. However, the proline form of p53 remained undegraded.

The researchers went on to analyze the p53 genotype of cervical tumors using a PCR assay that detected either the proline form or the arginine form of p53. They detected only the arginine form in 76.7 percent of tumors, compared with 36.6 percent of controls matched for ethnic background. The proline/arginine genotype was detected in 16.7 percent of tumors, compared with 58.5 percent of controls.

“On the basis of these findings,“ they wrote in Nature, “with other risk factors being equal, an individual homozygous for p53 arginine would be about seven times more likely to develop HPV-associated cervical cancer than a proline/arginine heterozygote.“

The team's next step is to expand the study to include much larger numbers of samples from a variety of geographical locations, because the frequency of the p53 polymorphism varies.

Storey said testing for p53 status may prove to be another useful tool to help assess a woman's risk of developing cervical cancer.

“It could mean that some women are inherently at higher risk of this type of cancer, which may develop after infection with HPV,“ he observed. “It might be possible to give women who are homozygous for the arginine form of p53 the option of more frequent screening.“ Efforts also are continuing to develop vaccines against HPV. If these are successful, it might be appropriate to target such vaccines to homozygous women.

HPV Linked To Other Cancers

The findings also have implications for certain skin cancers which are linked to HPV infection and exposure to ultraviolet radiation.

Organ transplant recipients, who take immunosuppressive drugs, have a high risk of developing squamous cell carcinoma (SCC). This cancer is linked to ultraviolet radiation and HPV infection and appears five to 10 years after transplant.

The same study showed that patients with the arginine form of p53 were much more likely to develop SCC. Seventy-five percent of transplant patients with SCC had only the arginine form of p53, and 25 percent had the proline/arginine form.

Irene Leigh, head of the Imperial Cancer Research Fund's Skin Tumor Laboratory, said, “SCC in transplant patients is a very big clinical problem. Many of these patients are particularly vulnerable to skin cancer and can develop many tumors, which often require extensive surgery. These findings indicate that those patients who have the arginine form of p53 are at greater risk of developing SCC, and we shall be carrying out further research in this area.“ *

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