NEW YORK (Reuters Health) - Conventional genomic DNA sequence analysis does not catch all mismatch repair mutations responsible for cases of hereditary nonpolyposis colorectal cancer (HNPCC), investigators report in the February 16th issue of the Journal of the American Medical Association.
Mutations in genes involved in DNA mismatch repair are a frequent cause of colorectal cancer, Dr. Graham Casey at the Cleveland Clinic Lerner College of Medicine in Ohio and colleagues explain in their report. However, DNA sequencing cannot detect certain classes of mutations, particularly large genomic deletions, genomic rearrangements and loss of expression mutations.
That’s important, Dr. Casey told Reuters Health, because “carriers have a lifetime risk of around 80% for developing colorectal cancer or other cancers.”
His group suggests that conversion analysis, in which alleles are separated in hybrids prior to mutation screening, may be more sensitive than conventional DNA sequencing.
They conducted an analysis in which they compared both methods using samples from 89 patients at high risk of carrying mismatch repair germline mutations. Included were 64 patients with hereditary nonpolyposis colorectal cancer (HNPCC), 8 with HPNCC-like disease, and 17 diagnosed prior to age 50 years.
Conventional sequencing identified 28 likely pathogenic coding domain mutations in MLH1, MSH2 or MSH6 genes. Convergence analysis identified all 28 of these, plus 14 others, primarily large genomic deletions or rearrangements.
All told, convergence analysis revealed clinically pertinent information on a total of 63 relevant mutations (56% more than conventional DNA sequencing), including splicing mutations and missense mutations, Dr. Casey told Reuters Health.
Up until now, he said, “we could not define particular families as having HPNCC because we could not find the mutations. With this new technique, we have the ability to define patients with mismatch repair mutations more accurately, so we can provide carriers with more beneficial recommendations on surveillance.”
Source: JAMA 2005;293:799-809. [ Google search on this article ]
MeSH Headings:Colonic Diseases: Colorectal Neoplasms, Hereditary Nonpolyposis: Digestive System Neoplasms: Gastrointestinal Neoplasms: Genetic Techniques: Intestinal Neoplasms: Investigative Techniques: Mutagenicity Tests: Neoplasms: Neoplasms by Site: Neoplastic Syndromes, Hereditary: Colorectal Neoplasms: Gene Deletion: Sequence Analysis: Sequence Analysis, DNA: Germ-Line Mutation: Toxicity Tests: Mutation, Missense: Analytical, Diagnostic and Therapeutic Techniques and Equipment: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
