Hereditary nonpolyposis colorectal cancer (HNPCC) has historically been diagnosed based on family history, according to background information in the article. Approximately 70 percent of HNPCC cases and a proportion of cases that do not fit these criteria can be accounted for by mutations in any one of several genes involved in DNA mismatch repair (a mechanism that corrects errors made during DNA replication). Identification of a mutation may prompt genetic counseling, screening, and surveillance of relatives to reduce illness and risk of death. It has been proposed that screening of all patients with colorectal cancer for mismatch repair gene mutations may be both feasible and desirable.

"The accurate identification and interpretation of mismatch repair mutation carriers is essential for clinical management of colorectal cancer patients and for scientific studies in which the mutation status of participants is an important variable. Currently, most genetic testing is performed by genomic DNA sequence analysis, but certain classes of gene mutations are not detected using this approach, " the authors write.

There is evidence that large genomic mutations may account for a substantial proportion of colorectal cancer cases. Recent studies have suggested that conversion analysis, in which human chromosomes are separated in hybrids prior to mutation screening, represents a more sensitive mutation detection method than conventional DNA sequencing for identifying such mutations. There have been no studies comparing the relative accuracy and specificity of conversion analysis with other mutation testing methods in a rigorous way, which is essential if the method is to be widely used clinically and in research.

Graham Casey, Ph.D., of the Cleveland Clinic Lerner College of Medicine, Cleveland, and colleagues performed a blinded comparison of conventional DNA sequencing and conversion analysis to identify certain genetic mutations in 89 colorectal cancer cases. The study included patients who participate in the Colon Cancer Family Registry. Mutation analyses were performed in participant samples determined to have a high probability of carrying certain mutations. Samples from a total of 64 hereditary nonpolyposis colorectal cancer cases, 8 hereditary nonpolyposis colorectal cancer-like cases, and 17 cases diagnosed prior to age 50 years were analyzed from June 2002 to June 2003.

The researchers found that conversion analysis identified all mutations detected by genomic DNA sequencing, plus other mutations, particularly large genomic deletions, yielding an increase of 33 percent (14 of 42) in diagnostic yield of deleterious mutations. Conversion analysis also provided additional information on the deleterious consequence of other sequence changes for an increase of 56 percent (35 of 63) in the diagnostic yield of genetic testing compared with genomic DNA sequencing alone.

"These results have important implications for genetic testing of individuals for both clinical and research purposes. Testing strategies, whether conversion analysis, as validated herein, or a combination of other approaches, must take into account the highly heterogeneous nature of mismatch repair mutations in colorectal cancer," the authors conclude.

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