BioWorld International Correspondent
LONDON Tests to predict which people are more likely to develop certain cancers and which people with cancer are likely to do well following treatment are likely to be available soon. Researchers in the UK already have shown that a small genetic difference in a key gene is more likely to be present in someone with malignant melanoma, and are preparing to publish a string of papers linking genetic differences with the risk of developing a range of cancers.
Ian Hutchinson, professor of immunology at the University of Manchester, and his collaborators have examined the genes encoding several growth factors for variations, known as polymorphisms, that affect how much growth factor someone manufactures. They published a paper in the Feb. 2, 2002, issue of The Lancet showing that people with malignant melanoma were more likely to have a particular polymorphism in the gene encoding epidermal growth factor (EGF) than controls who did not have malignant melanoma. They also have shown that the polymorphism in question is associated with higher production of EGF than other variants of the gene.
Hutchinson told BioWorld International, “Much work has already shown that expression of EGF receptors by cancer cells is very important in their growth, so if there is less EGF in the circulation or the EGF molecule can be prevented from binding to and activating its receptor, then you may be able to retard or eliminate the growth of the tumor.”
Several pharmaceutical companies are working on producing inhibitors of tyrosine kinases, the enzyme through which the EGF receptor signals. Hutchinson said pilot studies of an inhibitor specific to the tyrosine kinase used by the EGF receptor had shown that it could inhibit the growth of breast cancer. “The type of study we have done could help predict who is going to respond better to this kind of treatment, which will be very useful because these drugs are very expensive,” he said. “You would expect that people who are high producers of EGF have greater signaling through the EGF receptor and that you would be more likely to have an effect in these people by inhibiting this receptor.”
The team is looking for partners to help develop the work further. They already identified genotypes that are associated with high and low production of a range of different growth factors. As well as that reported in The Lancet, they have data on functional polymorphisms in the genes encoding vascular endothelial growth factor, insulin-like growth factor 1, transforming growth factor beta and others. They have looked for correlations with several different cancers, including breast, prostate, cervix and bladder.
“These data are at present unpublished,” Hutchinson said, “but in all these cancers we have found an association between the EGF genotype and either the risk of having the disease or how quickly the disease progresses. It appears that it does have an effect on the growth of solid tumors. Some of the other growth factors also play a role, but EGF is the most important one.”
In The Lancet paper, Hutchinson, together with colleagues at the University of Manchester and collaborators at Keele University and North Staffordshire Hospital, both in Stoke-on-Trent, and at Leicester Royal Infirmary in Leicester, report their discovery of a single nucleotide substitution, of guanine to adenine, at position -61 in the EGF gene.
They studied 135 white European patients with malignant melanoma and 99 healthy white European controls. People who had two copies of adenine at position -61 in the EGF gene (A/A) produced significantly less EGF than those who had two copies of guanine (G/G). Patients with malignant melanoma were significantly more likely to be G/G than controls. Those people who were G/G who had malignant melanoma also were more likely to have thick lesions, which correlate with poor prognosis.
Hutchinson predicted that determining patients’ genotypes for growth factors will help dictate their future treatment and follow-up. “For example,” he said, “after organ transplantation there is a 10-fold increase in susceptibility to cancer, including skin cancers. The genotyping work we have done allows us to distinguish between those who need to be examined within the two years after transplantation and those we needn’t bother to see for 10 years. So these differences can be quite clear cut.”
His next target is to write up all the papers relating to the other growth factors and other cancers on which the team has data.