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Genetic Study Provides Clues to Non-Hodgkin Lymphoma

Posted Aug 09 2011 10:13pm

Mobile Phone Use Does Not Raise Cancer Risk in Children and Adolescents

The first-ever study of mobile phone use by children and adolescents carried out in four European countries found no increased risk of brain cancer, according to a report published online July 27 in the Journal of the National Cancer Institute (JNCI).

Investigators in Denmark, Sweden, Norway, and Switzerland conducted a multicenter case-control study involving children and adolescents 7 to 19 years of age who were diagnosed with a brain tumor between 2004 and 2008. The investigators, led by Dr. Denis Aydin of the Swiss Tropical and Public Health Institute in Basel, conducted interviews with 352 brain tumor case patients, 646 healthy control subjects, and their parents.

The children who regularly used mobile phones were not statistically significantly more likely to have been diagnosed with brain tumors than nonusers, the researchers reported. In addition, those who used mobile phones for at least 5 years did not have a statistically significantly higher risk of developing brain tumors. Moreover, the investigators found no increased risk of brain tumors in the parts of the brain that typically receive the highest levels of mobile-phone radiation exposure.

For some of the children, the investigators were also able to obtain data from mobile phone service providers. In these children, brain tumor risk rose with the amount of time since the family began its mobile phone subscription but not with the amount of mobile phone use as recorded by the service providers, the researchers added.

Previous epidemiologic studies among adult users have found no overall increased risk of brain cancer from mobile phone use. This study addressed concerns that the developing brains and nervous systems of children and adolescents might be more vulnerable to the potential adverse health effects of mobile phone use.

“Researchers continue to monitor trends in brain cancer and mobile phone use,” commented Dr. Martha Linet, chief of the Radiation Epidemiology Branch in NCI’s Division of Cancer Epidemiology and Genetics. “Other ongoing research includes a large study of rodents exposed to mobile phone frequencies that is being conducted by the National Toxicology Program; a prospective study recruiting 250,000 mobile phone users in five European countries; and a case-control study comparing 2,000 young people between the ages of 10 and 24 who were diagnosed with brain tumors and an equal number of control subjects from 13 countries.”

Further reading: “ A Conversation with Dr. Martha Linet on Cell Phone Use and Cancer Risk

Computer System for Reading Mammograms Does Not Appear to Improve Cancer Detection

A widely used and expensive computer system created to help radiologists identify suspicious spots on mammograms may not help detect breast cancer , new research suggests. The study , led by Dr. Joshua J. Fenton of the University of California, Davis, appeared online July 27 in the Journal of the National Cancer Institute (JNCI).

In the first large clinical study to assess the performance of computer-aided detection (CAD) in the United States, the technology did not improve the detection of invasive breast cancer . The finding was based on data from approximately 684,000 women and more than 1.6 million mammograms administered at Breast Cancer Surveillance Consortium facilities between 1998 and 2006.

CAD systems are now used to help interpret most screening mammograms in the United States, with annual direct Medicare costs in excess of $30 million, the study authors noted. The Food and Drug Administration approved the technology in 1998 based on limited data, and Medicare began to pay for CAD soon after.

In 2007, the investigators published preliminary results from this population-based observational study . At that time, they found that the use of CAD led to a substantially higher false-positive rate compared with the false-positive rate of radiologists who read mammograms without CAD.

The updated analysis included nearly twice the amount of data that were assessed in the 2007 preliminary study, but the conclusion was essentially the same. As the editors of JNCI summarized, the health benefits of using CAD to interpret screening mammograms “remain unclear, and the data indicate that the associated costs may outweigh the potential benefits.”

CAD technology is popular, in part, because the devices are built into digital mammography systems, which are increasingly common in the United States. Another reason is the financial incentive from Medicare reimbursement, noted Dr. Donald Berry of the University of Texas M. D. Anderson Cancer Center in an accompanying editorial .

Researchers and device companies should work to improve the system, Dr. Berry continued. “But this should happen in an experimental setting and not while exposing millions of women to a technology that may be more harmful than it is beneficial. In the meantime, economic incentives may stoke its continued proliferation.”

Further reading: " Mammogram Study Evaluates Computer-Aided Detection "

Higher Breast Density Linked to Increased Cancer Risk and Aggressive Tumors

A study of postmenopausal women has confirmed that higher breast density is associated with a greater risk of breast cancer and revealed that the tumors that do develop are more likely to be aggressive. The findings were published online July 27 in the Journal of the National Cancer Institute.

Dense breast tissue, which has less fat and more glandular and connective tissue, is a known risk factor for breast cancer, and mammograms of dense breast tissue are often more difficult to read and interpret. But whether there are cancer subtypes specific to women with denser breast tissue is unclear.

Researchers from Harvard Medical School analyzed Nurses’ Health Study data from 1,042 women diagnosed with breast cancer between 1989 and 2004 and 1,794 matched healthy control subjects. The women with breast cancer had a higher average breast density than the women in the control group. Those with the highest breast density were more than three times more likely to develop cancer than those with the lowest breast density.

Breast density was associated most strongly with in situ , or noninvasive, tumors. Higher breast density was also associated with larger, higher-grade, and estrogen receptor (ER)-negative tumors, which tend to be more aggressive. The authors pointed out several study limitations. Most important, the findings may apply only to postmenopausal women.

In an accompanying editorial , Dr. Karla Kerlikowske of the University of California, San Francisco, and Dr. Amanda Phipps of the Fred Hutchinson Cancer Research Center suggested that a “masking effect,” in which dense tissue prevents the detection of smaller tumors by mammography, could be responsible for the observed association between dense breast tissue and larger, more aggressive tumors.

They also proposed that tumors may arise more often in dense breast tissue because of interactions with the larger number of epithelial and stromal cells present.

The results “suggest that breast density is an important risk factor for a range of biologically diverse subtypes of breast cancer, including tumors exhibiting characteristics indicative of poorer prognosis,” wrote the editorialists. “Given that the magnitude of the association with breast density is strong across all breast cancer subtypes and particularly for ER-negative disease, breast density should be included in risk prediction models across tumor subtypes,” they concluded.

Further reading: “ Breast Density in Mammography and Cancer Risk

Genetic Study Provides Clues to Non-Hodgkin Lymphoma

Gene mutations that disrupt the normal packaging of DNA in chromatin, the complex of DNA and proteins in chromosomes, are common in some forms of non-Hodgkin lymphoma (NHL) and may play a role in the diseases, new research suggests. The study adds to growing evidence that the proper regulation of DNA packaging—through a process known as chromatin remodeling—may be disrupted in cancer.

Understanding these changes could lead to strategies for treating the disease, Dr. Marco Marra of the BC Cancer Agency in Vancouver and his colleagues reported online in Nature on July 27.

To learn more about the biology of NHL, the researchers sequenced the genomes of 13 patients with diffuse large B-cell lymphoma and one with follicular lymphoma —the two most common forms of NHL. After surveying the genetic changes in another 113 NHL cases, the researchers identified 26 genes with recurrent mutations that could be involved in cancer.

Five of the most commonly mutated genes encode proteins that are involved in the chemical modification of histones, which are chromatin proteins responsible for packaging DNA. When histones are modified, the DNA in chromatin is packaged less tightly and gene expression is facilitated; when histone modifications are removed, the DNA becomes more tightly packaged and gene expression is suppressed. Thus, proteins involved in histone modification can alter the activity of genes across the genome.

Mutations in one of the five genes, MLL2, were identified in 89 percent of the patients with follicular lymphoma, which would make it one of the most commonly mutated genes in NHL. Noting that the gene is mutated in other cancers as well, the study’s authors suggested that the MLL2 protein may normally help suppress tumor formation.

The second mutated gene the authors highlighted, MEF2B, had not previously been linked to cancer, but the pattern of mutations in this gene resembled patterns found in other known cancer-related genes. Based on their findings, the researchers concluded that the mutation of genes involved in histone modification is likely to be a central event in the development of some forms of NHL.

These findings confirm and extend recent reports of mutations in histone-related genes in NHL ( here and here ). Similar genetic alterations have also been found in a form of kidney cancer and the childhood cancer medulloblastoma . Drugs with the potential to reverse epigenetic changes in cells, such as histone modifications, are available, but some researchers caution that the relationship between the recently identified mutations and cancer is unclear.

“This study opens quite a few new avenues for researchers by introducing a list of genes that no one had thought would be involved in these diseases,” said the first author, Ryan Morin of the BC Cancer Agency. And because certain mutations were found in only some subtypes of NHL, the alterations, if confirmed, could help doctors diagnose the disease and select the most appropriate therapies, he added. 

Studies Reveal the Genetic Complexity of Head and Neck Squamous Cell Cancers

Two independent, multi-institution research teams have identified a large number of previously unknown genetic defects associated with head and neck squamous cell carcinoma (HNSCC), the most common form of head and neck cancer . The researchers sequenced the entire protein-coding regions, or exomes, of the DNA in dozens of patient tissue samples, and the findings were published online July 28 in two papers in Science ( here and here ).
 
The studies were led by researchers from the Broad Institute of MIT and Harvard, the University of Pittsburgh Cancer Institute, the Johns Hopkins Kimmel Cancer Center, and the University of Texas M. D. Anderson Cancer Center.

Tobacco use, excessive alcohol consumption, and human papillomavirus (HPV) infection are known risk factors for HNSCC, which includes cancers arising in the mouth and throat. The 5-year survival rate for many types of HNSCC has improved little over the past 40 years.

To search for gene defects, or mutations, that may play a role in HNSCC, the researchers compared whole-exome sequences of tumor tissue with those of matched normal tissue from the same patients. Both research teams confirmed genetic abnormalities that were previously implicated in HNSCC, including mutations in the TP53 tumor suppressor gene , which were by far the most common.

The two teams also identified a large number of unexpected gene mutations in HNSCC, most notably in the NOTCH1 gene and other genes involved in squamous cell differentiation—the process by which less mature, rapidly dividing cells develop into more specialized squamous cells that divide more slowly.

“The degree of differentiation—that is, tumor cell grade —has never consistently been shown to be a clinical prognostic factor” in HNSCC, said Dr. Jennifer Grandis of the University of Pittsburgh, a senior author of one of the studies. “So it was surprising to find mutations in a series of genes that…appear to contribute to differentiation.”

Both studies found far fewer mutated genes in HPV-positive tumors than in HPV-negative tumors, supporting the idea that HPV-positive HNSCC, which has a better prognosis, is a distinct disease and thus merits different treatment.

The results of multidisciplinary collaborations such as these “will allow us for the first time to understand the complex biology of head and neck cancer,” Dr. Grandis said. “It’s clearly not one disease. It’s many diseases, despite appearing identical under the microscope.

“It’s right to be cautiously pessimistic,” Dr. Grandis said. But she believes that delving into the biological complexity of cancers such as HNSCC will ultimately reveal new therapeutic targets.

“We’re still in just the baby steps of these genetic findings,” she continued. The most important next step, she explained, is to identify the subset of mutations that drive tumor formation and figure out how to target them. “These are the patients’ tumors—they are speaking to us. Whether we understand what they say is a different question.”

Also in the Journals: Key Genetic Mutations Found in One Type of Brain Cancer

Researchers have identified mutations in two genes that may play a critical role in the development of oligodendroglioma , the second-most-common type of brain cancer in adults.

In the study , published online August 4 in Science, Dr. Chettan Bettegowda and his colleagues at the Johns Hopkins University Kimmel Cancer Center sequenced the exomes, or protein-coding portions of DNA, in seven oligodendroglioma tumors and found that two genes, CIC and FUBP1, were frequently mutated. The researchers then performed exome sequencing on 27 additional oligodendroglioma samples and again found that both genes were frequently mutated. The genes had a mutational pattern that is consistent with those commonly seen in tumor suppressor genes , the researchers reported.

“Whenever we find genes mutated in a majority of tumors, it is likely that the pathway regulated by that gene is critical for the development and biology of the tumor,” said study co-author Dr. Nickolas Papadopoulos in a news release.

According to Dr. Bettegowda, further research is needed to determine whether the genes’ mutational status can be used to guide prognosis and whether the genes can be targets for therapy.

    

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