Microsatellite instability and allelic imbalance in primary and secondary colorectal cancer.
BACKGROUND
Several studies of colorectal cancer have shown an association between the number and type of genomic defects and the stage of disease. A subset of colorectal tumours are due to inactivation of DNA mismatch repair genes and these tumours exhibit microsatellite instability. The aim of the present study was to compare and contrast the genomic defects present in both the primary and metastatic stages of the disease using microsatellite probes.


METHODS
Modifications of the allelic profiles of 25 microsatellite regions were studied in a total of 85 colorectal tumours using fluorescent polymerase chain reaction (PCR) technology and subsequent direct analysis on an automatic sequencer. This approach was used because it allows the study of microsatellite instability and allelic imbalance. Stepwise logistic regression analysis was used to develop a model to predict whether the tumour was primary or secondary from the percentage of allelic imbalance. Subsequently, a group of 17 patients with primary colorectal tumours was analysed prospectively to test the proposed model.


RESULTS
Six of 39 primary tumours showed microsatellite instability compared to 0 of 29 liver metastases (P = 0.03). Primary tumours showed significantly less allelic imbalance than liver metastases (P < 0.001). Three probes (d18s53, d9s158 and d10s191) were selected for use in a model to classify a tumour as primary or secondary on the basis of the degree of allelic imbalance. When tested prospectively this model had a specificity of 82%.


CONCLUSIONS
The present study demonstrates the potential importance of using microsatellite probes both as a diagnostic tool and as a research technique to investigate the mechanisms of tumour progression. An important clinical finding is that none of the colorectal liver metastases showed microsatellite instability (0 of 29). This analysis also confirmed other work that has shown a direct relationship between the degree of allelic imbalance and the stage of disease.
Schneider
A
A
Department of Molecular Biology, Hôpital de Hautpierre, University of Strasbourg, France.
Rohr
S
S
Kelly
M D
MD
Mitry
R
R
Pignatelli
M
M
Doré
C J
CJ
Gaub
M P
MP
Jaeck
D
D
Meyer
C
C
Oudet
P
P
Habib
N A
NA
D000483:Alleles; D020137:Base Pair Mismatch / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D004260:DNA Repair / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary*; D016015:Logistic Models; D018895:Microsatellite Repeats / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011446:Prospective Studies; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity