© The Author 2007. Published by Oxford University Press.
ARTICLE |
Performance of Different Microsatellite Marker Panels for Detection of Mismatch Repair–Deficient Colorectal Tumors
For the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association
Affiliations of authors: Department of Gastroenterology, Germans Trias i Pujol Hospital, Autonomous University of Barcelona, Barcelona, Spain (RMX, XL, EP, AG, MAG); Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi l Sunyer, University of Barcelona, Barcelona, Spain (AC, VP, SCB); Departments of Pathology (CA, AP) and Gastroenterology (RJ), General University Hospital of Alicante, Alicante, Spain; Department of Gastroenterology, Hospital del Mar, Barcelona, Spain (MA, XB); Department of Gastroenterology, San Agustín Hospital, Avilés, Spain (JMD); Department of Gastroenterology, University Hospital of Canarias, Spain (DNP); Department of Gastroenterology, General University Hospital of Guadalajara, Spain (AMG); Department of Gastroenterology, General Hospital of Granollers, Spain (JR)
Correspondence to: Xavier Llor, MD, PhD, Department of Gastroenterology, Germans Trias i Pujol Hospital, Carretera del Canyet s/n, 08916 Badalona, Barcelona, Spain (e-mail: xllor{at}comb.es).
BACKGROUND: Colorectal tumors caused by failure of the DNA mismatch repair system commonly show microsatellite instability. Our goals were to compare the performance of two panels of markers (a panel previously recommended by the National Cancer Institute [NCI] and a pentaplex of mononucleotide repeats) and to devise the simplest diagnostic strategy for identification of patients with colorectal cancer characterized by defects in mismatch repair.
METHODS: We recruited 1058 patients who were newly diagnosed with colorectal cancer. DNA from fresh-frozen and paraffin-embedded tumors was tested for microsatellite instability, using the NCI-recommended panel of microsatellite markers and the pentaplex panel of mononucleotide repeats, respectively, as templates for polymerase chain reactions (PCRs). Microsatellite instability in fresh-frozen tumors was also assessed using the pentaplex panel of mononucleotides in a crossover analysis. The expression of mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) in the tumors was determined immunohistochemically. The sensitivity and specificity with which the marker panels identified tumors with deficiencies in the expression of mismatch repair proteins were calculated. All statistical tests were two-sided.
RESULTS: The sensitivity and positive predictive value of the NCI panel were 76.5% (95% confidence interval [CI] = 61% to 92%) and 65.0% (95% CI = 49% to 81%), respectively; corresponding values for the mononucleotide pentaplex panel were 95.8% (95% CI = 89% to 103%) and 88.5% (95% CI = 79% to 98%), respectively. A panel consisting of the mononucleotide repeat markers BAT26 and NR24 alone had the same predictive value as the pentaplex panel of mononucleotide repeats.
CONCLUSIONS: The pentaplex panel of mononucleotide repeats performs better than the NCI panel for the detection of mismatch repair–deficient tumors. Simultaneous assessment of the instability of BAT26 and NR24 is as effective as use of the pentaplex panel for diagnosing mismatch repair deficiency.
| CONTEXT AND CAVEATS Prior knowledge There is a need to identify colorectal cancers that are due to defects in DNA mismatch repair because the presence of these defects helps to define two important types of colorectal cancers. One of these is an inherited condition called Lynch syndrome. However, there are also sporadic colorectal cancers with similar defects, and patients with this form of colorectal cancer have a unique prognosis and respond differently to particular drug therapies. Study design Tumor samples from a multicenter cohort of colorectal cancer patients were analyzed for concordance between microsatellite instability, as detected by different tests, and mismatch repair protein expression. Contribution The authors have improved the accuracy of a testing method that identifies those patients whose colorectal cancer is caused by defects in mismatch repair. The test is based on sequencing stretches of the patient's DNA called microsatellite sequences to identify characteristic changes (mutations). Implications The improved test could result in more patients being assigned to proper treatment based on their disease profile. Limitations The ultimate effect of a test for the presence of defects in mismatch repair in sporadic colorectal cancers on patient outcomes remains to be determined.
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