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Seeing Missing Letters
Genetic test promises more accurate diagnoses

Context: There are many ways that a gene can go wrong. A single DNA “letter,” or nucleotide, in a sequence of letters may be replaced with another. Or a long string of letters may get deleted, reversed, or duplicated. With certain diseases, patients are likely to have mutated versions of the same gene but unlikely to have the same mutation. Current genetic tests overlook certain kinds of mutations; they are a bit like a word-processing program that can find misspelled words but not missing words or sentences. They usually sequence a gene’s DNA in separate chunks, examining each chunk for mutations. But people have two copies of almost every gene, and if a chunk is entirely missing from one copy, current tests will detect the intact chunk from the other copy. To find out how many mutations conventional tests miss and so determine how useful new genetic tests could be, Graham Casey of the Cleveland Clinic and colleagues separated copies of genes to look at each individually.

Methods and Results: The researchers studied cells from 89 colon cancer patients, each of whom appeared to have a mutation in one of three genes. They examined the cells’ DNA using both traditional sequencing and another technique called “conversion analysis.” In conversion analysis, researchers create new cells, each of which contains only one copy of the gene being studied; they then compare the RNA messages coming from both copies.

Sequencing analysis found 28 mutations deemed likely to have ill effects; conversion analysis found all these and 14 more. Sequencing also found 42 mutations that could not be classified as either harmful or harmless; conversion analysis identified 21 of these as harmful (and the rest as innocuous). Thus, traditional sequencing identified 28 harmful mutations, while conversion analysis found 63.

Why it Matters: Genetic deletions likely contribute to breast cancer, neurofibromatosis, Duchenne’s disease, and Parkinson’s. Researchers and physicians know that traditional tests do not detect large genetic deletions. As a result, doctors often advise preventive procedures to at-risk patients, no matter what the genetic tests say. Not only may patients be unnecessarily worried, but they may also undergo expensive and painful procedures, like colonoscopies, that are unlikely to benefit them. Even healthy patients cannot know how likely they are to pass genetic mutations to their children. Casey and colleagues have, for the first time, rigorously examined how frequently such mutations are missed and shown that, for some diseases, the more difficult genetic tests might be worth the investment.

Source: Casey, G., et al. 2005. Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. Journal of the American Medical Association 293:799–809.

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Tagged: Biomedicine

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