Regulatory Region Mutations Contribute to Melanoma
Researchers have long believed that mutations in regulatory sequences can cause cancer, but identifying such mutations has been more challenging that finding mutations in protein-coding regions. Now, two separate studies by researchers at the German Cancer Research Center and the Dana-Farber Cancer Institute have used different approaches to identify the first regulatory area that looks to be mutated in the majority of melanomas. The region in question is the promoter for TERT, a part of telomerase. Cancer cells can avoid cell death in part by using telomerase to renew the tips of their chromosomes, or telomeres, which normally shorten with each cell division and provide a form of molecular countdown to senescence. One study used cancer genome sequencing to discover that the TERT promoter was mutated in slightly more than two-thirds of all melanoma samples looked at. Another looked at a melanoma-prone family and discovered that they had a germline mutation in the TERT promoter, and found such mutations in about three-quarters of metastatic melanoma samples of unrelated individuals that they screened. Such mutations also appear to exist in samples from other tumor types, albeit at a lower frequency. The papers were published back to back in the Jan. 24, 2013, advance online edition of Science.
EWAS to Join GWAS?
Researchers from Johns Hopkins University have discovered epigenetic markers that appear to mediate the risk of developing rheumatoid arthritis. Epigenetic changes are at the intersection of genetic and environmental influences on health, and it stands to reason that GWAS-like studies on epigenetic markers could uncover disease associations. But in practice, such associations have been difficult to uncover. The authors reduced confounding factors by correcting for different cell types in their analysis, and by using bioinformatics to filter out epigenetic markers likely to result from rheumatoid arthritis, rather than cause it. The resulting method uncovered 10 sites that were differently methylated in individuals with and without rheumatoid arthritis. The authors said the process they developed "may serve as a guidepost for epigenetic epidemiological studies generally." The paper appeared in the Jan. 20, 2013, issue of Nature Biotechnology.
Gene Therapy Success Unlikely to Be Permanent
Gene therapy for Leber Congenital Amaurosis has been a triumph of gene therapy, leading to significant and long-term improvement in the ability of treated patients to see. Leber Congenital Amaurosis is due to two mechanisms. Photoreceptors in the retina degenerate, and they are also impaired in their function. A team from the University of Pennsylvania has shown that gene therapy works only because of its effects on photoreceptor function. Gene therapy does not reverse or even slow down the retinal degeneration that is part of Leber congenital amaurosis, suggesting that its effects, although they last at least several years, will ultimately not be permanent. The authors concluded that their results "suggest a need for a combinatorial strategy . . . to not only improve function in the short term but also slow retinal degeneration in the long term." They published their findings in the Jan. 20, 2013, issue of the Proceedings of the National Academy of Sciences.
Shocked, Shocked? Location, Location, Location
Researchers from the University of California at San Diego have shown that administering digestive enzyme blockers directly into the intestine improved the long-term survival of animals after shock. Shock itself can arise due to a number of different factors. But a common factor once shock has developed appears to be that the wall of the gut becomes permeable, and digestive enzymes that are meant to break down the protein in food end up leaking out of the gut and destroying the shock victim's organs. The authors modeled three different kinds of shock in their experiments, and used three different kinds of protease inhibitors. Animals that were treated with a protease inhibitor delivered directly to their small intestines an hour after shock-inducing stimuli had less damage to their organs, and significantly improved survival rates after three months, regardless of what the cause of the shock was and which protease inhibitor was used. The authors concluded that "active and concentrated digestive enzymes in the lumen of the intestine play a central role in shock and multiorgan failure, which can be treated with protease inhibitors that are currently available for use in the clinic." Their work, which is being pursued clinically by start-up InflammaGen Inc., appeared in the Jan. 24, 2013, issue of Science Translational Medicine.
Blocking Metastasis Late in the Game
Researchers from Cornell University have used a flow chamber that mimics inflamed tissue to gain new insights into how proinflammatory cytokines contribute to breast cancer metastasis. In order for cancers to metastasize through the bloodstream, they must first circulate, and then adhere to blood vessels to leave the bloodstream and set up camp in a new location. Cancer cells express molecules that can bind to so-called selectins on blood vessel surfaces, but previous experiments had not been able to detect binding of circulating tumor cells. The authors showed that human plasma as well as the proinflammatory cytokines interleukin-6 and TNF-alpha could induce such interactions, enabling tumor cells to bind to blood vessels and aggregate, which would lead to metastases. They concluded that "therapeutic approaches targeting cytokine receptors and adhesion molecules on cancer cells may potentially reduce metastatic load and improve current cancer treatments." Such an approach might be particularly useful because there are usually already tumor cells circulating by the time a cancer is diagnosed. The work appeared in the Jan. 23, 2013, issue of PLoS ONE.
Cells Can Recognize Retroviral Genome DNA
Retroviruses integrate into the genome of the cells they infect, but the enzyme that does the integration – reverse transcriptase – makes DNA from viral RNA. Reverse transcriptase, however, is not particularly good at telling the DNA base thymine from the RNA base uracil, and as a result, the reverse transcribed DNA of retroviruses contains quite a bit of uracil, which is not a regular component of DNA. Researchers from Johns Hopkins University have shown that such DNA cannot be integrated into the host genome because it is recognized by a second enzyme, hUNG2, which cuts uracil out of DNA. In cells with high levels of both uracil and hUNG2, DNA copies of the viral genome cannot make their way into the host genome because the freshly reversed transcribed DNA is immediately damaged by hUNG2. The authors said that bumping up levels of both proteins in T cells may protect those cells against becoming stably infected with HIV. Their work appeared in the Jan. 20, 2013, issue of the Proceedings of the National Academy of Sciences.
Cholesterol Drug Treats Frequent ASD Symptom
A team from the Massachusetts Institute of Technology has demonstrated that the cholesterol drug Mevacor (lovastatin, Merck & Co) can prevent the development of epilepsy in mice with Fragile X syndrome. The drug works by correcting excess protein synthesis in the hippocampus. Excess protein synthesis at synapses, or neural connections, appears to be behind many of the symptoms of Fragile X syndrome, an autism spectrum disorder. Epilepsy is especially common in individuals with Fragile X syndrome, but is also frequently seen in individuals across the autism spectrum. The authors tested Mevacor's ability to affect protein synthesis because it inhibits the pathway that is hyperactive in Fragile X. They noted that although their work focused on seizures, many of Fragile X's symptoms result from excessive protein synthesis, and it is reasonable to assume that Mevacor would affect such other symptoms as well. The findings were published in the Jan. 23, 2013, issue of Neuron.
. . . And Recessive Mutations Can Cause ASD
Meanwhile, two separate studies in the same issue of Neuron have used exome sequencing of consanguineous families, that is, families in which the spouses are blood relatives, to identify inherited mutations that contribute to the risk of autism. Studies to date have looked at spontaneous mutations that occur in only one family member. The two new studies looked at so-called multiplex families, where more than one child in a family is affected, to find recessive autism risk genes. The authors, who are at Harvard Medical School, were able to identify both hypomorphic alleles and complete knockouts that contribute to autism risk. The papers appeared back-to-back in the Jan. 23, 2013, issue of Neuron.
Caspase Critical for Innate Immunity
A team from the University of North Carolina at Chapel Hill has discovered a protective role for caspase-11, an enzyme whose activation can trigger a form of cell death called pyroptosis. Caspase-11 plays a role in inflammation; in their studies, the authors showed that the enzyme is part of the innate immune response. Macrophages usually eat invading bacteria after sequestering them in specialized structures called vacuoles, and bacteria try to escape the vacuoles and migrate into the cytoplasm. The authors showed that this escape route triggers caspase-11, which ultimately kills the macrophages, ending the bacterial sanctuary. The mechanism, the authors said, "is critical for surviving exposure to ubiquitous environmental pathogens." They published their findings in the Jan. 25, 2013, issue of Science.
Double Double Helix Forms in Cells
Scientists from the British University of Cambridge have demonstrated that DNA forms quadruple helices as well as the more familiar double helix that is the normal structure of DNA. Such quadruple helices can form in test tubes, and the authors used antibodies to show that it forms in human cells, as well. Quadruple helices are more likely to form in regions of the genome that are rich in guanine. They are also more likely to form in rapidly dividing cells, which makes them a potential target for novel cancer therapies. The work was published in the Jan. 20, 2013, issue of Nature Chemistry.
– Anette Breindl, Science Editor