Loss of heterozygosity at 1p36 predicts poor prognosis in gastrointestinalstromal/smooth muscle tumors

Gastrointestinal stromal/smooth muscle tumors are uncommon neoplasms for wh ich current criteria for diagnosing malignancy (size and mitotic index) som etimes fail to predict outcome. Cytogenetic studies reveal frequent chromos ome 1 abnormalities in these tumors, but significant underlying molecular c hanges have not been elucidated, and their significance is unknown. DNA was obtained from the formalin-fixed, paraffin-embedded tissue of 80 gastroint estinal stromal/smooth muscle tumors. Tumors were topographically microdiss ected from surrounding normal tissue; microsatellite markers from tumor and normal tissue were amplified by PCR in the regions of chromosome 1p36 (D1S 199, 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 heteroz ygosity (LOH), tumor size, mitotic index, and survival were investigated us ing correlation analysis, Kaplan-Meier plots, and the Cox model. LOH at 1p3 6 was found in 24 of 80 cases, suggesting the possibility of a tumor suppre ssor gene at 1p36 near the site of a suspected neuroblastoma tumor suppress or gene. Patients whose tumors demonstrated LOH at 1p36 had significantly s horter survival (p = 0.017) than those whose tumors did not. LOH at 1p36 re tained independent prognostic significance in a multivariate model that inc luded KIT mutation status and tumor size; the mitotic index, however, did n ot retain independent significance in such a model. LOH was observed at 1p1 2-1p13 (most frequently at 1p13.3) in 19 of 80 cases, but loss of heterozyg osity at this site did not influence survival. No LOH was observed near 1q3 2. These findings provide strong evidence for a prognostically significant tumor suppressor gene in the region of chromosome 1p36.3.