Genetic Markers May Predict Risk for Lung, Prostate, Colorectal, and Cervical Cancers

Recent advances in research focused on identifying genetic and other markers that can predict cancer risk were reported at the annual meeting of the American Association for Cancer Research (AACR). Included in the presentations were reports of markers for prostate, colon, and cervical cancers and an enzyme that appears to predict lung cancer risk in African-Americans.

Predicting Lung Cancer Risk in African-Americans

Jean G. Ford, MD, and colleagues at Columbia University’s Harlem Lung Center conducted a case-control study to determine the role of glutathione S-transferase M1 (GSTM1) in the development of lung cancer in African-Americans. Because the body converts external poisons into benign substances through chemical reactions that are enhanced by an enzyme produced by GSMT1, it was thought that deleting GSTM1 may impede the body’s ability to detoxify some carcinogens, thereby causing cancer.

For the study, DNA was obtained from 117 African-American lung cancer patients and 120 African-American controls to assess the presence of the GSTM1 deletion. Dr. Ford and his colleagues found that 31.6% of the lung cancer patients were deficient in GSTM1, compared with 20% of controls. Furthermore, smokers with the GSTM1 deletion were 8.2 times more likely than nonsmokers without the GSTM1 deletion to develop lung cancer, and the risk increased proportionately with the number of cigarettes smoked. Heavy smokers (30 pack-years) who lacked GSTM1 had four times the risk of those who did not lack GSTM1.

"After controlling for smoking, age, and gender, we found that African-Americans with lung cancer were more than twice as likely to have the GSTM1 deletion than were those without lung cancer," said Dr. Ford. "Our data provide clear evidence that GSTM1 deletion may act in conjunction with smoking to increase the risk for lung cancer," he added.

New Prostate Cancer Risk Factor Identified

A new marker of risk for prostate cancer--high circulating levels of insulin-like growth factor-1 (IGF-1)--was the subject of another study presented at the meeting. This study suggested that testing for IGF-1, which is similar in structure to insulin, may be complimentary to the prostate-specific antigen (PSA) test.

Michael N. Pollak, MD, Riesman Clinician-Scientist at Jewish General Hospital and professor of medicine and oncology at McGill University in Quebec, along with June Chan, PhD, and colleagues at Harvard University, conducted a case-control study to investigate the association between blood levels of IGF-1 and risk for prostate cancer, independent of PSA levels. Using blood samples from the US Physician’s Health Study, they compared IGF-1 levels in 152 prostate cancer patients and 152 controls.

They observed a significant relationship between IGF-1 levels and the incidence of prostate cancer. Men in the highest quartile of IGF-1 levels were four times more likely to have prostate cancer than were men in the lowest quartile.

"Unlike the PSA test, measuring IGF-1 appears to identify men at high risk for cancer before they develop the disease. This study suggests that IGF-1 levels can predict prostate cancer risk and, possibly, cancer progression. We are interested in the possibility that the IGF-1 test may be useful in identifying high-risk men for closer monitoring, and we are also investigating new treatments for prostate cancer that target IGF-1 bioactivity," said Dr. Pollak.

IGF-1 Levels and Premenopausal Breast Cancer

Susan Hankinson, PhD, in collaboration with Dr. Pollak and colleagues at Harvard, obtained additional data suggesting that IGF-1 levels may also be related to risk for premenopausal breast cancer. These data raise the possibility that IGF-1 physiology differs among normal individuals and may influence susceptibility to both prostate cancer and breast cancer.

"While the risk associated with high IGF-1 levels is much less than that associated with mutations in cancer-causing genes, such as BRCA1, the burden of cancer related to high IGF-1 levels may be considerable. The reason is that high IGF-1 levels are much more common than mutations in BRCA1 or other similar genes," said Dr. Pollak.

PSA Not an Ideal Marker for Response to Some Drugs

In another study on prostate cancer markers, William D. Figg, PharmD, senior investigator, Medicine Branch, National Cancer Institute, and colleagues found that TNP-470, an experimental angiogenesis inhibitor, increased PSA levels. Previous studies have shown that some chemotherapeutic drugs can alter PSA levels without affecting tumor growth, thereby providing misleading information about the patient’s prognosis.

Dr. Figg and colleagues studied this phenomenon in the laboratory using a human prostate cancer cell line treated with TNP-470. They found that the drug decreased the number of tumor cells by 40% but increased PSA levels by as much as 52%. The researchers attributed the increase in PSA levels to the direct effect of TNP-470 on PSA formation. However, this was independent of the drug’s effect on the tumor.

According to Dr. Figg, "TNP-470 appears to inhibit angiogenesis and prevent the growth of the tumor while at the same time increasing the levels of the marker used to measure treatment progress. This makes PSA a poor surrogate marker for measuring the effect of treatment with TNP-470 and perhaps with other similar chemotherapeutic drugs."

Marker Predicts Survival in Colorectal Cancer Patients

In other research presented at the meeting, scientists reported the identification of a marker--soluble urokinase receptor (suPAR)--that independently predicts survival in patients with colorectal cancer. This receptor is part of the urokinase plasminogen activation system. It was first isolated and cloned at the Finsen Laboratory in Copenhagen, Denmark.

To determine whether blood levels of the urokinase receptor correspond with a tumor’s ability to spread and eventually kill the patient, Nils Brünner, MD, DMSC, associate professor of medicine, and Ross W. Stephens, PhD, of the Finsen Laboratory and their colleagues analyzed blood levels of suPAR in 591 patients with colorectal cancer who were scheduled to undergo surgery. They found that, after an average of 5 years of follow-up, the cancer patients with high blood levels of suPAR had a much poorer survival rate than did patients with low blood suPAR levels.

"Even more importantly," Dr. Brünner said, "by using suPAR measurements, we could identify high-risk patients with even early-stage colorectal cancer. These patients should be offered adjuvant therapy, which they do not receive today. On the other hand, patients with low suPAR blood levels had a survival indistinguishable from that of a similarly aged section of the general population. Those patients should, therefore, be spared adjuvant treatment, which is often toxic."

Cellular Protein May Be a Marker for Cervical Dysplasia

Susan K. Keesee, PhD, manager of cell biology at Matritech, Inc., reported on a new marker that may allow physicians to detect precancerous cervical irregularities before cervical cancer develops.

Dr. Keesee and colleagues followed a two-step process. First, they identified a unique cellular protein that appears to be associated with cervical cancer and tested for it in the tumors of 20 patients with cervical carcinoma and in normal cervical tissue from 10 hysterectomy patients. The nuclear matrix protein, known as NMP-179 (CvC-3), was found in all of the cervical tumors but in none of the normal tissue samples.

Dr. Keesee then developed a method to test the NMP-179 marker on a large scale, using a monoclonal antibody that binds to the NMP-179 protein. She evaluated 322 cervical/vaginal tissue samples and found that the antibody could detect both low- and high-grade cervical dysplasia with great accuracy.

"We believe that NMP-179 could be a valuable marker for early screening of cervical dysplasia," said Dr. Keesee. "If we can detect dysplasia before it progresses to cancer, we may be able to offer the patient a more conservative treatment, such as surgical removal of the cancerous tissue vs total hysterectomy for invasive cancer, and a better prognosis," she added.