A group of researchers from Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, MIT, and St. Jude’s Children’s Research Hospital in Memphis, has described two important breakthroughs: (1) a surprisingly accurate correlation of the 217 known human microRNAs ( miRNAs – small noncoding RNA molecules that control the levels of proteins made from transcribed genes ) with the development and differentiation of tumors, and (2) the development of a technology that not only enabled this exciting discovery but that could be the basis for an easy and inexpensive diagnostic test.

" This study opened our eyes to how much more there is to learn about genomic approaches to cancer,” said Todd Golub, senior author of the paper. Golub is the Charles A. Dana Investigator in Human Cancer Genetics at Dana-Farber, and director of the Cancer Program at Broad Institute, and a Howard Hughes Medical Institute ( HHMI ) investigator at Harvard Medical School. “ That microRNA profiles have such potential diagnostic utility was a big surprise to us, and one we're keen to validate in future studies."

MiRNAs were first identified in the worm C. elegans and were shown to control development and differentiation of cells. When miRNAs were absent, certain cells went into abnormal rounds of cell division rather than differentiations. " Since the discovery that microRNAs control specific cell divisions in the nematode C. elegans, I have wondered if there might be a relationship between microRNAs and human cancer,” said H. Robert Horvitz, co-author and David H. Koch at MIT and HHMI investigator at Harvard. “ This work establishes a striking correlation between patterns of microRNA expression and cancer and offers the prospect of using microRNA expression patterns to help in the diagnosis and treatment of cancer."

To determine the expression pattern of all the known human miRNAs, the researchers first had to develop an accurate, fast, reproducible and inexpensive method for doing so. Given the small size of miRNA ( approximately 21 nucleotides) as well as their close resemblance to each other, previous attempts to use array-type technologies have been unsuccessful. Instead, the scientists developed an ingenious bead-based miRNA capture method, where each individual bead was marked with fluorescence “tags” that could tell which miRNA was bound as well as its abundance in the sample.

Testing a host of tumor samples on the miRNA-specific beads revealed that the expression patterns of miRNA not only correlated with the developmental origins of the tumor samples ( e.g., epithelial cell, hematopoietic cell, etc. ), but it also subdivided specific tumor types based on known genetic alterations. They 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, especially compared to techniques relying on messenger RNA ( mRNA ) expression patterns.

Although this is a preliminary study, its validation could have significant impact on the clinical diagnosis of cancer.

Source: Dana-Farber Cancer Institute, 2005


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