MSH2-deficient murine lymphomas harbor insertion/deletion mutations in thetransforming growth factor beta receptor type 2 gene and display low not high frequency microsatellite instability
R. Lowsky et al., MSH2-deficient murine lymphomas harbor insertion/deletion mutations in thetransforming growth factor beta receptor type 2 gene and display low not high frequency microsatellite instability, BLOOD, 95(5), 2000, pp. 1767-1772
High-frequency microsatellite instability (MSI), defined as more than 20% u
nstable loci, is an inconsistent finding in hematologic malignancies; conse
quently, the significance of deficient DNA mismatch repair (MMR) to their p
athogenesis has been questioned, To further investigate the relationship be
tween MMR deficiency and genomic instability in hematologic malignancies, t
his study evaluated MSH2-/- murine lymphomas for insertion/deletion (ID) mu
tations within the transforming growth factor (TGF)-beta receptor type II (
T beta R-II) gene and MSI at 10 neutral microsatellites, The lymphomas disp
layed ID mutations within short mononucleotide runs of T beta R-II at a hig
h frequency, whereas nonmalignant tissue from corresponding animals lacked
mutations, Loss of T beta R-II transcripts and protein was seen in 6 of 7 m
urine lymphomas harboring acquired T beta R-II mutations, In the analysis o
f paired nonmalignant and tumor DNA samples, low-frequency but not high-fre
quency MSI was found. Low-frequency MSI occurred in 8 of 20 lymphomas and 1
2 displayed microsatellite stability, MSI was even less frequent in nonmali
gnant tissue as only 3 of 20 samples displayed low-frequency MSI and 17 dis
played stability. Evaluation of 20 single cell clones from the MSH2-/- lymp
homa cell lines R25 and L15 identified high-frequency MSI in 4 and 2 clones
, respectively, The remaining clones showed low-frequency MSI or stability,
These findings suggest that acquired T beta R-II mutations represent impor
tant inactivating events in tumor pathogenesis following MSH2 deficiency. F
urthermore, for some hematolymphoid malignancies, the evaluation of cancer-
associated genes for ID mutations may represent a more sensitive marker of
MMR deficiency than evaluation of neutral microsatellites for high-frequenc
y MSI, (C) 2000 by The American Society of Hematology.