NCI has awarded $9.8 million in first-year funding for 17 Biomarkers Developmental Laboratories within the Early Detection Research Network (EDRN). Biomarkers are substances found in the blood, other body fluids, or tissues that alone or in combination may signal the presence of cancer or the risk for the disease. These laboratories are now charged with discovering new biomarkers relevant to major cancers and identifying what combinations of biomarkers may best detect cancer or predict cancer risk.

Other EDRN components are Biomarkers Validation Laboratories, which work to validate the biomarker tests; Clinical and Epidemiologic Centers, which conduct the early phases of clinical and epidemiological research on the application of biomarkers; and the Data Management and Coordinating Center, which provides logistical, informatics, and statistical development and support.

These new Biomarkers Developmental Laboratories have one of the biggest challenges in biomarker research: searching through hundreds of samples using a variety of technologies to identify candidate biomarkers. Investigators will examine the human genome (genetic material), proteome (proteins made by genes), epitome (immune response biomarkers via antibody-antigen patterns), and metabolome (metabolic pathways and regulation), looking for potential ways to identify cancer and cancer risk. In a quest to discover cancer at the earliest stage of progression, biomarkers are often used as mileposts of cancer progression; they mark the critical events along the progression pathway from normal, to precancerous, to malignant cell.

More information on EDRN scientific components and projects, including a listing of Biomarkers Validation Laboratories, can be found at http://www3.cancer.gov/prevention/cbrg/edrn/components.html.

BRCA1 Mutation Increases Sensitivity to Chemotherapy

When choosing between chemotherapy agents for patients with breast or ovarian cancer, until now, clinicians have not had available biomarkers to help guide their decisions. But a review published in the November 17 Journal of the National Cancer Institute reveals that BRCA1 gene mutations - biomarkers for breast and ovarian cancer - are associated with sensitivity to DNA-damaging chemotherapy and resistance to spindle poisons.

Researchers at Queen's University Belfast in Northern Ireland (supported by several groups, including the Research and Development Office of Northern Ireland, Breast Cancer Campaign UK, and Cancer Research UK) searched preclinical and clinical papers published between Jan. 1, 1994 and Aug. 31, 2004, finding that BRCA1 is a DNA-damage response gene as well as a regulator of mitosis, possibly through the microtubules that help cells divide. As a result of this dual role, tumors that lack functional BRCA1 may be more sensitive to DNA-damaging chemotherapy agents such as cisplatin, carboplatin, anthracycline, and cyclophosphamide, but may be more resistant to drugs that thwart microtubule assembly and function, such as paclitaxel, docetaxel, vincristine, and vinorelbine, which are known collectively as spindle poisons. Conversely, tumors that overexpress BRCA1, and are therefore resistant to DNA-damaging agents, may be vulnerable to spindle poisons.

Because of conflicting results between preclinical and clinical studies, however, the authors recommend that these associations be tested further, and that patients with BRCA1 mutations have this gene sequenced so that the specific type of mutation they have can be characterized with their response to DNA-damaging chemotherapy and/or spindle poisons. Ultimately, it is hoped that BRCA1 mutation analysis can be used as a predictive marker when choosing chemotherapy options for breast and ovarian cancer patients.

Inverse Association Found Between Selenium and Colorectal Cancer

A study in the November 17 Journal of the National Cancer Institute has found an inverse relationship between selenium blood levels and adenoma recurrence risk. Researchers from the Arizona Cancer Center, in collaboration with other cancer centers and government agencies such as NCI, CDC, and the U.S. Food and Drug Administration (FDA), as well as medical and public health schools across the country, found that higher blood selenium concentrations in study participants were associated with lower risk for developing recurrent adenomas. This study was funded by grants from the U.S. Public Health Service as well as NCI's Specialized Program of Research Excellence (SPORE) in gastrointestinal cancer.

Selenium received attention as a possible cancer preventive agent after initial findings of a trial that examined its effects on nonmelanoma skin cancer. Other epidemiological studies have had mixed results; some have shown selenium to have a protective effect against colorectal cancer, while others have found no association. However, most individual studies analyzed small sample sizes, resulting in greater variability of results. This study pooled data from three separate studies in order to increase the precision of risk estimates.

Selenium concentrations were measured and baseline characteristics were tabulated from a total of 1,763 blood specimens from trial participants. Adenoma recurrence was analyzed for each study, as well as for the pooled population. In the pooled analysis, a linear decrease in the odds of adenoma recurrence was reported with increasing blood selenium levels higher than 100 ng/ml, and a statistically significant inverse relationship was observed between blood selenium levels and adenoma recurrence. Researchers concluded that, based on study results, selenium has a role in reducing the risk of colorectal adenoma recurrence.

Immunosuppressant Drug May Increase Risk of Lymphoma

Methotrexate (MTX) may promote Epstein-Barr virus (EBV)-positive lymphomas in rheumatoid arthritis and polymyositis patients by reactivating latent EBV, according to a study published in the November 17 Journal of the National Cancer Institute. Supported by grants from NCI, U.S. Public Health Service, and National Institutes of Health (NIH), researchers from the University of North Carolina, Chapel Hill, NIH, and the German Research Cancer Centre, also found that withdrawal of MTX therapy can result in regression in some EBV-positive lymphomas in patients.

Patients receiving MTX for rheumatoid arthritis or for polymyositis are at increased risk of developing EBV-associated lymphoproliferative disorders compared with the general population. EBV infection is common, with more than 90 percent of the adult population having a lifelong persistent infection, but normally EBV does not cause B-cell lymphomas. However, in immunosuppressed patients undergoing MTX therapy, an increased level of infectious EBV might overwhelm the capacity of the host immune system to eliminate early EBV-positive tumor cells.

Results from the study indicated that MTX treatment was found to enhance expression of EBV genes in two cell types using the doses expected in the serum of rheumatoid arthritis patients. MXT was also found to induce the release of infectious EBV progeny from the host cells. The authors conclude that "future studies should explore whether MTX treatment of other patients, such as those with malignancies, may increase the risk of EBV reactivation and other EBV-associated tumors."