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Archive - Feb 19, 2010


Novel Method of Transcription Regulation Seen in Malaria Parasite

In trying to understand how the human malaria parasite (Plasmodium falciparum) multiplies in red blood cells, a research team has discovered that a kind of "histone crash" takes place--a massive breakdown of the chromatin architecture that explains how the parasite can extensively and rapidly replicate its DNA and coding genes. "If this mechanism can be stopped," said Dr. Karine Le Roch, an assistant professor of cell biology and neuroscience at the University of California-Riverside, and senior author of the report, "Plasmodium replication would cease or be severely inhibited, thus controlling the spread of malaria." "Dr. Le Roch's findings document a global mechanism mediating significant changes in gene expression as the parasites transition through developmental stages in the human hosts," said Dr. Anthony A. James, a distinguished professor of microbiology & molecular genetics and molecular biology & biochemistry at the University of California-Irvine, who was not involved in the research. "As well as being a major basic discovery, this provides a basis for probing the mechanisms for novel drug development." The current study was spurred, in part, by an earlier observation that, in Plasmodium falciparum, specific transcription factors are apparently under-represented relative to the size of the parasite’s genome, and by the fact that mechanisms underlying transcriptional regulation in Plasmodium have remained controversial. “Our results demonstrate that the processes driving gene expression in Plasmodium challenge the classical eukaryotic model of transcriptional regulation occurring mostly at the transcription initiation level. We found in our experiments that histones are massively evicted everywhere in the Plasmodium genome, resulting in most of the Plasmodium genes to be transcribed at once," said Dr. La Roch.

Many Copy Number Variations Universal Among Diverse Tumors

An international team of researchers has created a genome-scale map of 26 different cancers, revealing more than 100 genomic sites where DNA from tumors is either missing or abnormally duplicated compared to normal tissues. The study, the largest of its kind, finds that most of these genetic abnormalities are not unique to one form of cancer, but are shared across multiple cancers. "Our findings show that many genome alterations are universal across different cancers. Although this has been known for some types of changes, the degree to which so many alterations are shared was pretty surprising to us," said senior author Dr. Matthew Meyerson, a professor of pathology at the Dana-Farber Cancer Institute and senior associate member of the Broad Institute of Harvard and MIT. "It suggests that, in the future, a driving force behind cancer treatment will be common genomic alterations, rather than tumors' tissue of origin." In 2004, a scientific team led by researchers at the Dana-Farber Cancer Institute and the Broad Institute launched a project to systematically map genetic changes across different cancers. They focused on a particular type of DNA change in which segments of a tumor's genome are present in abnormal numbers of copies. Instead of the usual two copies, tumors often carry several copies of one piece of DNA (an "amplification") or may lack it altogether (a "deletion"). These genetic abnormalities are known as somatic copy-number alterations or SCNAs. As the foundation for their analysis, the scientists collected over 2,500 cancer specimens representing more than two dozen cancer types, including lung, prostate, breast, ovarian, colon, esophageal, liver, brain, and blood cancers.

Study Distinguishes Between “Driver” and “Passenger” Cancer Mutations

A new study of mutations in cancer genomes suggests how researchers can begin to distinguish the “driver” mutations that push cells towards cancer from the “passenger” mutations that are by-products of cancer cell development. The study also shows that at least one in nine genes, on average, can be removed from human cancer cells without killing the cells. This is in sharp contrast to the corresponding figure for genes in normal human cells [X chromosome (1 in 100 genes); normal human genome (1 in 50 genes)]. Thus, cancer cells seem to be more tolerant to gene loss than the cells of healthy people and can lose a much greater proportion of their genes without losing the ability to live and grow. Many cancer genomes are riddled with mutations. The vast majority of these are likely to be passengers—i.e., mutations that don't contribute to the development of cancer, but have occurred during the growth of the cancer--while a small minority are the critical drivers of cancer growth and proliferation. The challenge of efficiently picking out the guilty drivers in the huge set of mutations found in a cancer genome has yet to be fully met. "It is essential that we can distinguish the drivers from the passengers because knowing the driver mutations, and hence the critical genes they are in, leads to understanding of the cellular processes that have been subverted in cancers, and hence to new drugs," explained the Wellcome Trust Sanger Institute’s Dr. Michael Stratton, senior author of the report. "Our study provides one example of how researchers can sift through the large numbers of a particular type of mutation present in cancer genomes in order to distinguish drivers from passengers."