Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1767-1772
MSH2-deficient murine lymphomas harbor insertion/deletion
mutations in the transforming growth factor beta receptor type 2 gene
and display low not high frequency microsatellite instability
Robert Lowsky,
Anthony Magliocco,
Ryo Ichinohasama,
Armin Reitmair,
Stuart Scott,
Michele Henry,
Marshall E. Kadin, and
John F. DeCoteau
Saskatoon Cancer Centre and Department of Pathology,
Royal University Hospital and University of Saskatchewan, Saskatoon,
Saskatchewan, Canada; Department of Pathology, Tohoku University
Hospital, Aoba-Ku, Sendai 980, Japan; Ontario Cancer Institute and
Department of Pathology, Princess Margaret Hospital and the University
of Toronto, Toronto, Ontario, Canada; Department of Pathology, Beth
Israel Hospital and Harvard Medical School, Boston, MA.
High-frequency microsatellite instability (MSI), defined as more
than 20% unstable loci, is an inconsistent finding in hematologic malignancies; consequently, the significance of deficient DNA mismatch
repair (MMR) to their pathogenesis has been questioned. To further
investigate the relationship between MMR deficiency and genomic
instability in hematologic malignancies, this study evaluated
MSH2
/ murine lymphomas for insertion/deletion (ID) mutations within the transforming growth factor (TGF)-beta receptor type II (T
R-II) gene and MSI at 10 neutral microsatellites.
The lymphomas displayed ID mutations within short mononucleotide runs of TR-II at a high frequency, whereas nonmalignant tissue
from corresponding animals lacked mutations. Loss of
TR-II transcripts and protein was seen in 6 of 7 murine
lymphomas harboring acquired TR-II mutations. In the
analysis of paired nonmalignant and tumor DNA samples, low-frequency
but not high-frequency MSI was found. Low-frequency MSI occurred in 8 of 20 lymphomas and 12 displayed microsatellite stability. MSI was even
less frequent in nonmalignant tissue as only 3 of 20 samples displayed
low-frequency MSI and 17 displayed stability. Evaluation of 20 single
cell clones from the MSH2/ lymphoma 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 TR-II
mutations represent important inactivating events in tumor pathogenesis following MSH2 deficiency. Furthermore, 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-frequency MSI.
