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Genomics In The Journals: May 10, 2012

NEW YORK (GenomeWeb News) – In Nature Genetics, two large research teams report on the relationships between cancer, aging, and the clonal mosaicism.

In the first study, a US National Cancer Institute-led team used data from genome-wide association studies done at NCI's cancer epidemiology and genetic division and core genotyping facility, along with data from a Spanish bladder cancer study. The researchers tested 31,717 cancer cases and 26,136 cancer-free controls for evidence of mosaic abnormalities. They found mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity in .89 percent of individuals. In cancer-free individuals, the frequency of mosaic abnormalities increased with age from .23 percent in those under 50 years old to 1.91 percent in individuals between the ages of 75 and 79.

In a subset of 14.050 people with cancer for whom it was possible to determine that DNA had been collected before or at the time of diagnosis (and pre-treatment), the researchers observed a stronger association between mosaic abnormalities and diagnosis with non-hematological cancer. Associations for lung and kidney cancers also increased in significance, they reported.

For a second study, another group led by the University of Washington brought together information from 15 studies done through the Gene-Environment Association Studies, or GENEVA, consortium to assess the link between clonal mosaicism, cancer, and aging. As with the other study, the detection of mosaic abnormalities increased with age.

The researchers used SNP microarray data from more than 50,000 subjects recruited for the Geneva GWAS. In total, they observed 514 mosaic anomalies in 404 of the subjects from the GWAS. In subjects less than 50 years of age the number of such anomalies was less than .5 percent, rising to 2.7 percent in subjects over 80 years old.

They also found that many of the mosaic anomalies are characteristic of those found in hematologic cancers. For example, the researchers said that 222 of 669 recurrent duplications and deletions found in hematological cancers have a greater than 80 percent overlap with at least one mosaic CNV in Geneva subjects. However, the proportion of subjects with one or more mosaic abnormalities who had a record of hematological cancer before DNA sampling was low (2.8 percent).

"These results suggest that the clonal mosaicism observed in elderly subjects may be an asymptomatic condition with a predisposition to hematological cancer that is often not realized," the study authors wrote.


A trio of US researchers conducted a study, published this week in PLoS One, comparing DNA samples from modern and prehistoric gray whales and determined that the population of Pacific gray whales was much higher pre-whaling than previously thought. The researchers, led by Elizabeth Alter of the City University of New York, isolated DNA from whale bones taken from archaeological sites, dated 150 years to 3,500 years before present. They compared these samples to DNA from 120 eastern Pacific and 45 western Pacific gray whales.

While previous estimates suggested there were 15,000 to 35,000 eastern Pacific gray whales before large-scale commercial whaling in the 19th and early 29th centuries, estimates from the researchers' genetic analysis suggests that number was much higher — around 78,000 to 116,000. However, this discrepancy could be explained by a pre-whaling decrease in population, they said.

"Overall, the genetic evidence presented here supports the hypothesis that gray whales experienced a major population decline, and that this reduction occurred recently," the study authors wrote.


An international team found recurrent mutations in the PTEN regulatory gene PREX2 in metastatic melanoma — work that they describe online in Nature.

The group sequenced 25 metastatic melanomas, along with matched normal tissue, looking at the nature and frequency of mutations in relationship to the primary tumor site. Not surprisingly, the rate of point mutations was highest in individuals who were known to have a good deal of sun exposure and lowest in those whose primary tumors occurred in parts of the body not normally exposed to the sun, consistent with a role for UV light in melanoma-related mutagenesis. Metastases from primary tumors on the trunk fell in the middle of the point mutation rate spectrum.

Among the recurrently mutated genes, meanwhile, researchers found known melanoma players such as BRAF, NRAS, KIT, and ETV1, along with mutations in new genes, including PREX2. The latter gene was mutated in around 14 percent of the 107 additional melanoma tumors that they tested by targeted PREX2 sequencing.

"Although its precise mechanism(s) of action remains to be elucidated in melanoma, PREX2 appears to acquire oncogenic activity through mutations that perturb or inactivate one or more of its cellular functions," the study authors wrote. "This pattern of mutations may exemplify a category of cancer genes that is distinct from 'classic' oncogenes … and tumor suppresors."


Rapid growth in human populations has spurred a jump in rare alleles in the human genome, according to a Science study conducted by a pair of researchers from Cornell University.

"Rapid recent growth increases the load of rare variants and is likely to play a role in the individual genetic burden of complex disease risk," co-authors Alon Keinan and Andrew Clark wrote. "Hence, the extreme recent human population growth needs to be taken into consideration in studying the genetics of complex diseases and traits."

The researchers point to disease-gene association studies migrating to exome and whole-genome sequencing, which means that the models of the genetics of complex traits need to accommodate the recent, rapid growth in human population. "The medical implications of an excess of rare genetic variation and increased individual mutational load are of particular interest in light of the limited success of genome-wide association studies at explaining the genetic basis of complex human diseases," they wrote.


Genomics In The Journals is a weekly feature pointing readers to select, recently published articles involving genomics and related research.