Genetic Test for BRCA 1 and 2 Benefits High-Risk African American Women

African American women at high risk for breast cancer because of their family history will benefit from genetic testing, report researchers from the University of Chicago Medical Center. One of the first major studies to examine the value of testing across different ethnic groups for the BRCA1 and BRCA2 gene mutations, its findings were published in the October 19 Journal of the American Medical Association.

The researchers found, after DNA sampling, that significantly more non-Hispanic, non-Jewish whites had one of the nearly 50 known BRCA1/2 mutations (46.2 percent), but also found mutations in 27.9 percent of African American women. Yet African Americans were nearly four times as likely to have a variant in these genes that is not known to - but could - be a breast cancer susceptibility mutation. Dr. Rita Nanda and colleagues write that "unfortunately, there is a paucity of data about…the functional consequences of these variants."

The BRCAPRO risk assessment tool worked in predicting which African American women were likely to have a BRCA1/2 mutation (which would be discovered by subsequent genetic testing) as well as it did for white women, Ashkenazi Jewish women, and the overall study population of 155 families that were identified by the statistical model.

Among all women in the study, early age at diagnosis of breast cancer was associated with an increased likelihood of carrying a BRCA1/2 mutation. A woman's chance of having a mutation increased relative to how many of her close relatives had been diagnosed with breast or ovarian cancer.

CD19-Targeted Monoclonal Antibody Looks Good in Animal Model

A new monoclonal antibody that targets B cells could prove to be as effective as rituximab (Rituxan) for treating non-Hodgkin lymphoma (NHL), as well as other lymphomas and leukemias, Duke University researchers are reporting. Many lymphomas and leukemias are of B cell origin.

In a study published October 10 in the early online edition of the Proceedings of the National Academy of Sciences, Dr. Thomas Tedder and colleagues report that, in mouse models, use of monoclonal antibodies (mAbs) that target a protein on the surface of B cells called CD19 was highly effective at eliminating B cells - both mature cells as well as precursor and immature B cells. Rituximab, which targets the CD20 protein on B cells, only aids in the depletion of mature B cells. It is effective in approximately half of NHL patients.

In addition, use of the CD19-targeted mAbs in 10 mice with malignant B cell lymphomas eliminated the presence of tumor cells in the circulation and tissue for up to 7 weeks, the study found.

While some earlier efforts were made to target CD19, they were limited by various shortcomings. Since those experiments, the mechanism by which antibodies to proteins such as CD20 and CD19 aid the immune system in killing cells is better understood. "Now we know the mechanism, we know how to choose the patients better, we know how to choose better antibodies, and we've done the pharmacokinetics and dosing," says Dr. Tedder.

Planning is underway to test the CD19-targeted mAbs in early clinical trials through a company Dr. Tedder founded, and which was recently purchased by the biotechnology company MedImmune.

ADHD Symptoms Linked to Likelihood of Smoking in Young Adults

Researchers from Duke University examining the relationship between reported attention-deficit hyperactivity disorder (ADHD) symptoms in young adults and smoking behaviors found a significant relationship between the number of reported ADHD symptoms and lifetime regular cigarette smoking, according to study results published in the October issue of Archives of General Psychiatry.

The analysis included 15,197 participants from wave III of the National Longitudinal Study of Adolescent Health, a nationally representative sample of adolescents followed from 1995 to 2002, which is primarily funded by the National Institute of Child Health and Human Development. Controlling for demographic and conduct disorder symptoms, each retrospectively reported symptom of ADHD inattention and hyperactivity/impulsivity significantly increased the likelihood of ever regularly smoking. However, hyperactivity/impulsivity symptoms were found to be a better predictor of lifetime regular smoking than inattention symptoms, even in individuals reporting subclinical ADHD symptoms.

The findings suggest that self-reported ADHD symptoms are associated with the age of onset of regular smoking and support other studies associating ADHD with increased risk of smoking.

Suppression of Type I Collagen Synthesis Limits Angiogenesis

Angiogenesis - the formation of new blood vessels - is required for the growth and repair of normal tissue. This process can be used by cancer cells, allowing tumors to commandeer oxygen and nutrients needed for growth. Scientists are searching for the molecular pathways responsible for the angiogenic switch - the point at which a tumor begins creating its own network of blood vessels.

A new study by NCI researchers implicates loss of thrombospondin-1 (TSP1), an angiogenesis modulator, and subsequent upregulation of type I collagen as important components of new blood-vessel formation.

Investigators established an ex vivo model of endogenous TSP1 loss using tissue explants from transgenic mice lacking the molecule. Upregulated type I collagen expression was found to be dependent on the lack of endogenous TSP1, and treatment with exogenous TSP1 suppressed collagen Iα1 and Iα2 levels. In turn, this suppression of type I collagen inhibited angiogenesis in the explants. Blocking mRNA expression for collagen Iα1or Iα2 also inhibited blood-vessel growth. These results suggest blocking type I collagen expression may be an effective anti-angiogenic therapy.

"Several labs have previously identified type I collagen gene products as markers of tumor blood-vessel growth and tumor metastasis in human and mouse cancers," said Dr. David D. Roberts, of the Laboratory of Pathology in NCI's Center for Cancer Research, whose lab performed the research published in the October 10 early online edition of Oncogene. "The fact that these genes that encode a major structural component of cartilage are also key players in tumor angiogenesis and metastasis was not previously understood."

Ireland's National Smoke-Free Law Proves Effective and Popular

In March 2004, the Republic of Ireland became the first nation in the world to implement a comprehensive smoke-free law covering all the nation's workplaces, including restaurants and bars. Now, two studies, funded in part by NCI, demonstrate the success of Ireland's landmark legislation.

A study in the October 17 Tobacco Control documents that the new law has led to a dramatic decline in smoking in all workplaces in Ireland and an increase in the proportion of Irish homes that are smoke-free. But the new law has had other positive effects, according to lead author, Dr. Geoffrey T. Fong, of the University of Waterloo in Canada. The study found widespread acceptance and support for the new law among Irish smokers; overall, 83 percent rated the smoke-free law a "good" or "very good" thing. Nearly half of Irish smokers said the new law had made them more likely to quit, and of those smokers who had quit after the new law went into effect, 80 percent reported that the law had helped them in the process.

"This study demonstrates that Ireland's comprehensive smoke-free workplace law is achieving its public health goals while also achieving a high level of acceptance among smokers," said Dr. Fong. "These findings support enactment of smoke-free workplace policies in countries around the world, as fears of a smoker backlash or lack of compliance are simply unfounded."

A related study in the October 17 British Medical Journal documents that Ireland's smoke-free law protects nonsmoking bar workers from exposure to the harmful effects of second-hand smoke (SHS). Compared with bar workers in Northern Ireland, which has no smoke-free law, bar workers in the Republic of Ireland had significantly less exposure to SHS and significantly improved respiratory health, study author Dr. Shane Allwright and colleagues reported.

"Comprehensive smoke-free laws effectively reduce SHS exposure and are widely accepted by the public, including many smokers," said Dr. Robert T. Croyle, director of NCI's Division of Cancer Control and Population Sciences, which funded the research. "This research is an excellent example of how empirical evidence can inform public health policy."