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SUMMARY: Gastrointestinal
stromal/smooth muscle tumors are uncommon neoplasms for which current criteria
for diagnosing malignancy (size and mitotic index) sometimes fail to predict
outcome. Cytogenetic studies reveal frequent chromosome 1 abnormalities
in these tumors, but significant underlying molecular changes have not been
elucidated, and their significance is unknown. DNA was obtained from the
formalin-fixed, paraffin-embedded tissue of 80 gastrointestinal stromal/smooth
muscle tumors. Tumors were topographically microdissected from surrounding
normal tissue; microsatellite markers from tumor and normal tissue were
amplified by PCR in the regions of chromosome 1p36 (D1S199, D1S228, D1S450,
D1S214, D1S243), 1p12 (D1S418), 1p13 (D1S252, D1S514), and 1q32 (D1S103).
The presence or absence of heterozygosity for each case was mapped at each
informative marker. Relationships among loss of heterozygosity (LOH), tumor
size, mitotic index, and survival were investigated using correlation analysis,
Kaplan-Meier plots, and the Cox model. LOH at 1p36 was found in 24 of 80
cases, suggesting the possibility of a tumor suppressor gene at 1p36 near
the site of a suspected neuroblastoma tumor suppressor gene. Patients whose
tumors demonstrated LOH at 1p36 had significantly shorter survival (p
= 0.017) than those whose tumors did not. LOH at 1p36 retained independent
prognostic significance in a multivariate model that included KIT mutation
status and tumor size; the mitotic index, however, did not retain independent
significance in such a model. LOH was observed at 1p12-1p13 (most frequently
at 1p13.3) in 19 of 80 cases, but loss of heterozygosity at this site did
not influence survival. No LOH was observed near 1q32. These findings provide
strong evidence for a prognostically significant tumor suppressor gene in
the region of chromosome 1p36.3. |
