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June 10, 2005

Research Points to New Genetic Method of Diagnosing Cancer

Topics: Medicine

Biotech4Recent work has revealed the existence of a class of small non-coding RNA species, known as microRNAs (miRNAs), which have critical functions across various biological processes.

Researchers used a new, bead-based flow cytometric miRNA expression profiling method to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers.

The miRNA profiles turned out to be surprisingly informative, and reflected the developmental lineage and differentiation state of the tumours studied. They observed a general down-regulation of miRNAs in tumors compared with normal tissues. Furthermore,they were able to successfully classify poorly differentiated tumors using miRNA expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. Their findings highlight the potential of miRNA profiling in cancer diagnosis.

According to Howard Hughes Medical Institute (HHMI) researchers and colleagues, the tiny microRNAs provide a novel genetic route to the initiation of some forms of cancer - a discovery that they believe could open a new chapter in understanding and diagnosing cancer.

Of course the key biological question here is "whether the distinctive miRNA profiles that the researchers have found in cancers represent causation of cancer by miRNAs, or merely an association." However, the researchers believe that what they are seeing is causation rather than association. According to HHMI investigator Todd R. Golub, of the Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, distinctive patterns of activity of microRNAs (miRNAs) in cancer cells can be used to diagnose cancers.

(A speculative model for miRNA involvement in cancers.)

(...) Gregory Hannon, Scott Lowe and colleagues showed that a specific cluster of microRNAs can cause lymphomas in mice, a finding published In a second paper in Nature.

(...) Hannon and Lowe, who recently were appointed as HHMI investigators at Cold Spring Harbor Laboratory, say that given the new findings, they agree with a proposal calling for cancer-causing microRNAs to be dubbed "oncogenic micro RNAs," or "oncomiRs," just as cancer-causing genes are called oncogenes.

(...) These three studies change the landscape of cancer genetics by establishing the specific miRNAs expressed in most common cancers and investigating the effects of miRNAs on cancer development and cancer genes," says Paul Meltzer of the National Human Genome Research Institute in a commentary in the same issue.

(...) MicroRNAs, which are no more than a couple of dozen nucleotides in length, appear to regulate a broad array of physiological and developmental processes.

(...) However, their regulatory roles remain largely mysterious, as the functions of only a few of more than 200 known microRNAs have been established. Unlike the large messenger RNA (mRNA) molecules that code for cellular proteins, the tiny microRNAs regulate gene activity by interfering with mRNAs.

(...) While there had been hints that individual miRNAs were switched on or off in cancers, "there hadn't really been a broad view of miRNA profiles in cancer until this work," says Golub. "The first question was, is there anything interesting to find at all? We suspected microRNAs might be involved in cancer because they play important roles in embryonic development."

(...) While the major focus of cancer research has been on genes that code for proteins, said Hammond, "now we have to -- at the very least -- also consider non-coding genes for miRNAs when we think about the kinds of genetic alterations that can contribute to tumors." Such considerations, he said, likely will influence methods of classifying and diagnosing cancers, as well as treating them.

The Method:
Testing a host of tumor samples on the miRNA-specific beads revealed that the expression patterns of miRNA that not only correlated with the developmental origins of the tumor samples (e.g., epithelial cell, hematopoietic cell, etc.), but also subdivided into specific tumor types based on known genetic alterations. The team also found that miRNA levels are generally lower across tumor types than in the corresponding normal tissue, again supporting the idea that miRNA is critical to reaching and maintaining the differentiated state.

Finally, the researchers tested their discoveries against a panel of tumor samples of histologically uncertain cellular origin (but which had been determined by the anatomical location). Again, the miRNA classification provided amazing accuracy.

Although this is a preliminary study, subsequent validation could have a significant impact on the clinical diagnosis of cancer, resulting in earlier detection and therefore earlier and more effective treatment.

Posted by Hyscience at June 10, 2005 7:48 PM

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