DNA: from modification to mutation
Our DNA is under continuous attack – by physical or chemical agents produced by or introduced into the body. These agents can modify DNA, forming DNA adducts, which – if not properly repaired – can cause mutations that contribute to deregulated gene expression and cancer.
Linlin Zhao, Ph.D., F. Peter Guengerich, Ph.D., and colleagues (laboratories of Martin Egli, Ph.D., and Carmelo Rizzo, Ph.D.) sought to understand how an unstable DNA adduct (N2,3-ethenoguanine), which is produced by exposure to the occupational carcinogen vinyl chloride, causes mutations. They used a chemical strategy to stabilize the adduct for detailed biochemical, kinetic and structural studies.
The results, reported in the journal Angewandte Chemie, revealed the miscoding tendencies of this DNA lesion and highlighted the diversity of biological effects that can result from DNA adducts. Structural insights suggested that this adduct may be relevant to vinyl chloride-induced tumors, and its presence in unexposed humans (where it is a product of oxidative stress) may be an issue in disease.
This research was supported in part by grants from the National Institute of Environmental Health Sciences (ES010546, ES010375, ES005355, ES007028, ES000267) of the National Institutes of Health.
— Leigh MacMillan
Making order out of ordinal dataStage of disease (mild, moderate, severe) and frequency of drug use (never, yearly, monthly, weekly, daily) are examples of “ordinal” data, a type of data common in medical research. However, statistical methods for analyzing such data are limited.
Chun Li, Ph.D., and Bryan Shepherd, Ph.D., have developed a new approach for analyzing ordinal data. They describe a new “residual” (a measure of how far an observed value is from its expected value) in the June issue of Biometrika. The new approach accounts for the ordered nature of the data without assigning arbitrary scores to categories – and considers categories' relative position to other categories.
In collaboration with the Vanderbilt Institute for Global Health, the researchers then demonstrated the residual’s utility by uncovering a non-linear association between age and the odds of having more severe cervical lesions among HIV-infected women from Zambia.
The authors note that improved statistical methods allow researchers to more easily detect meaningful associations with fewer patients, saving money and increasing the ability to make important discoveries.
The research was supported by grants from the National Human Genome Research Institute (HG004517) and the National Institute of Allergy and Infectious Diseases (AI093234) of the National Institutes of Health.
— Melissa Marino
Roots of childhood brain tumors
Identifying the cellular origins of medulloblastoma – the most common malignant brain tumor in children – may help focus treatment on cell types responsible for tumor initiation. Previous research has linked Sonic hedgehog signaling in neuronal cell precursors within the developing cerebellum to medulloblastoma.
Now, Chin Chiang, Ph.D., and colleagues demonstrate that “turning on” Sonic hedgehog signaling in a different cell type – hindbrain roof plate cells – leads to medulloblastoma. The roof plate cells are a specialized tissue that function as a signaling center regulating neural patterning. Previous studies had suggested that the hindbrain roof plate was restricted in its potential and contributed only to non-neural choroid plexus epithelial cells.
The new studies, reported in April in PLoS ONE, demonstrate that the hindbrain roof plate contributes not only to choroid plexus but also to multiple neuronal and glial cell types in the cerebellum. The findings also show that hindbrain roof plate cells are susceptible to tumorigenic transformation by deregulated Sonic hedgehog signaling.
This research was supported by grants from the National Institute of General Medical Sciences (GM007347), the National Cancer Institute (CA068485) and the National Institute of Neurological Disorders and Stroke (NS042205) of the National Institutes of Health and from the Children’s Brain Tumor Foundation.
— Leigh MacMillan
Gene database to aid disease research
Next generation sequencing (NGS) has dramatically accelerated the discovery of disease-associated genetic variants. Also known as massively parallel sequencing, this technological tour de force can rapidly “read” a sequence of DNA bases (the “letters” in our genomes) in parallel, making genome sequencing feasible in the research lab.
Vanderbilt researchers have developed a “catalog” of human NGS data that they believe will boost the ability of this powerful new technology to uncover the genetic roots of disease and enable the ultimate realization of personalized medicine. In the June issue of Human Mutation, Junfeng Xia, Ph.D., Zhongming Zhao, Ph.D., and colleagues report what they believe to be the first online resource for published NGS studies that focus on human traits and diseases, particularly cancer.
The continually updated database makes important information in the field easily accessible, the researchers explain. Systematically cataloging NGS studies provides an opportunity to examine the potential impact of genetic variants on disease.
The database is available online at http://bioinfo.mc.vanderbilt.edu/NGS/.
The study was supported by the American Association for Cancer Research and by the National Institutes of Health, through a core grant to the Vanderbilt-Ingram Cancer Center (CA068485) from the National Cancer Institute.
— Bill Snyder
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