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Also in the Oct. 28 JNCI

Skewed X Inactivation in BRCA1 Mutation Carriers

One X chromosome is more frequently silenced than the other X chromosome in women who carry mutations in the BRCA1 gene, and the skewed X inactivation is associated with a later onset of breast or ovarian cancer in these women.

Each cell in a woman's body carries two X chromosomes, while those of a man carry only one X chromosome. To compensate for the extra X chromosome, the cells in a woman's body inactivate one of the chromosomes. The inactivation occurs during embryogenesis and usually occurs randomly so that each X chromosome will be inactivated with equal frequency in a blood sample from an adult woman. Previous research suggested that X inactivation may not occur randomly in women with ovarian or breast cancer.

To learn whether X inactivation is skewed in favor of one of the two X chromosomes in women with breast or ovarian cancer, Amanda Spurdle, Ph.D., of the Queensland Institute of Medical Research in Brisbane, Australia, and colleagues tested blood samples from 735 healthy control subjects, 313 ovarian cancer patients, 235 women with familial breast cancer who did not have a BRCA1 or BRCA2 gene mutation, and 323 unaffected and affected women with a BRCA1 or BRCA2 gene mutation.

The investigators found that skewed X inactivation was more common in women with BRCA1 gene mutations, and possibly in women with BRCA2 gene mutations, than in healthy control subjects. The trend was strongest in mutation carriers who did not have breast or ovarian cancer. In addition, skewed X inactivation was associated with an older age at diagnosis of breast or ovarian cancer.

"We propose that skewed X inactivation arises as a mechanism to favor expression of an X-linked allele that protects against cancer and that skewed X inactivation may be exacerbated in BRCA1 mutation carriers due to BRCA1 mutationrelated overexpression of X-linked genes," the authors write.

Contact: Felipe Beltran,, +61 7 3362 0291

Quality of Life Measure for Long-Term Cancer Survivors Refined and Validated

The Impact of Cancer version 2 (IOCv2) questionnaire measures the long-term psychosocial impact of cancer.

The number of long-term cancer survivors is growing rapidly. However, few tools exist to help professional caregivers and researchers evaluate survivors' health-related quality of life. The Impact of Cancer scale was previously developed to measure the unique and multidimensional effects of cancer on long-term survivors.

In the current work, Catherine Crespi, Ph.D., and Patricia Ganz, M.D., of the University of California, Los Angeles and colleagues refined and validated the Impact of Cancer scale using responses from 1,188 disease-free breast cancer survivors, 5-10 years after their initial diagnosis.

The IOCv2 showed consistent results with a more generic health questionnaire as well as a tool developed specifically for breast cancer survivors. Patterns of association between IOCv2 scale scores and demographic, medical, and treatment characteristics indicate that the scale is valuable and well-constructed. The IOCv2 scale covers four areas, including positive impacts, negative impacts, employment concerns, and relationship concerns.

"This instrument is designed to measure impacts of cancer in long-term survivors that are not captured by other instruments and to be suitable for widespread use in investigations of the well-being of this burgeoning population," the authors write.

Contact: Kim Irwin,, (310) 206-2805

Characterization of U.S. Patients With Myelodysplastic Syndromes Yields Insight on Treatment Patterns

Patients with myelodysplastic syndromes (MDS) frequently receive erythropoietin-stimulating agents and a substantial fraction of patients with higher-risk disease are dependent on red blood cell or platelet transfusions.

MDS are a group of diverse bone marrow diseases recently classified as cancers that result in abnormal blood cell production. Although the Surveillance, Epidemiology, and End Results (SEER) database has been tracking the syndrome for 7 years, little is known about the treatment patterns used by physicians in the care of these patients.

In the current study, Mikkael Sekeres, M.D., of the Cleveland Clinic Taussig Cancer Institute in Ohio and colleagues surveyed 101 geographically-representative physicians who treat MDS patients, asking about individual patient characteristics, treatment approaches, transfusion needs, and whether clinical trial participation or bone marrow transplantation were being considered.

With data on 4,514 patients, the investigators found that a high proportion of the patients were dependent on red blood cell or platelet transfusions and more than half of the patients were receiving erythropoiesis-stimulating agents. Moreover, a substantial fraction of the higher-risk patients was being treated with a combination of the erythropoiesis-stimulating agents and other drugs, despite the fact that such combinations are only now being tested in clinical trials. Few patients were being considered for either clinical trials or bone marrow transplantation, which is the only curative therapy available.

"These data may be useful for estimating the resource utility and pharmacoeconomic impact of MDS in the United States," the authors conclude.

Contact: Megan Ferington Pruce,, (216) 445-7452 or (216) 312-3602 (cell)

Gene Variant Is Risk Factor for Smoking Behavior and Lung Carcinogenesis

A gene variant on chromosome 15 increases the risk for both nicotine dependence and lung cancer, but not for other smoking-related cancers or for lung cancer in people who never smoked.

Three research groups have recently identified a region of chromosome 15 that is associated with lung cancer risk. Several genes reside in that chromosomal region, including two that encode subunits of the nicotine receptor. It has not been clear whether the locus increases the risk of lung cancer by increasing the risk of smoking or if it has a direct impact on lung carcinogenesis or if it affects both causal pathways.

To distinguish between those mechanisms, Margaret Spitz, M.D., of the University of Texas M.D. Anderson Cancer Center in Houston and colleagues reanalyzed their genome association data in 3,621 patients and control subjects, looking for association between the previously-identified variant on chromosome 15 and smoking behavior. They also looked for an association between the variant and bladder cancer in 1,092 bladder cancer patients and control subjects and between the variant and kidney cancer in 285 kidney cancer patients and control subjects.

The investigators found a statistically significant association between the variant and some smoking behaviors that are an indication of physiological nicotine dependence, such as the time an individual waits before having their first cigarette in the morning. However, the group also found that the variant had a larger impact on lung cancer risk in individuals who had low smoke exposure compared with those who had a high lifetime exposure, suggesting that the variant has a direct impact on lung cancer development. The variant was not associated with an increased risk of lung cancer in never smokers. They did not find an association between the variant and bladder or kidney cancer risk.

"We conclude that the variants are implicated both in smoking behavior and more directly in lung cancer risk," the authors write.

In an accompanying editorial, Sholom Wacholder, Ph.D., of the National Cancer Institute in Bethesda, Md., and colleagues discuss the difficulties of moving from genome-wide association data to understanding the mechanism by which a gene variant can impact disease risk or development. "For the chromosome 15smokinglung cancer association, interdisciplinary teams will require high-quality information on environmental causes of disease; careful use of perhaps unfamiliar statistical methods; and more gritty, perhaps even hypothesis-based investigation of molecular and behavioral mechanisms," the editorialists write.



Contact: Liz Savage
Journal of the National Cancer Institute

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