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Loss of Heterozygosity of Chromosome 1q in Gastrinomas

Occurrence and Prognostic Significance

Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892-1804 [Y-J. C., R. T. J.], and Molecular Pathogenesis Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland 20892-2540 [A. V., Z. Z., S. H.]

A proportion of gastrinomas demonstrates aggressive growth, and most deaths occur in this group. Little is known about the molecular pathogenesis of growth of this tumor, and there are no predictive factors that are useful in an individual patient. Chromosome 1 (Chr 1) loss of heterozygosity (LOH) is frequent in a number of nonendocrine tumors and in a few endocrine tumors, and its presence can correlate with tumor aggressiveness and survival. In gastrointestinal endocrine tumors including gastrinomas, little data are available on Chr 1 LOH, and the limited results are contradictory. In the present study we determine whether Chr 1 LOH occurs in gastrinomas and is associated with aggressive growth by performing Chr 1 allelotyping with microsatellite markers in microdissected tumor tissue from 27 human gastrinomas and the leukocyte DNA of the patients. Detailed clinical pathological correlations were possible, because tumor growth in all of the patients was prospectively assessed with yearly imaging studies. Twelve gastrinomas (44%) had Chr 1 LOH, and in all of the cases 1q LOH occurred. 1q LOH was associated with aggressive growth (P = 0.0004), presence of liver metastases (P = 0.019), and postoperative development of hepatic metastases (P = 0.017). Eight (75%) of the 12 tumors with 1q LOH had 1q31–32 LOH over a 17.3 cM region, whereas LOH in 6 tumors (50%) occurred at 1q21–23 over a 12.3 cM area. The presence of 1q31–32 LOH and 1q21–23 LOH correlated with aggressive tumor growth (P = 0.0056 and P = 0.0031, respectively), and with postoperative development of liver metastases (P = 0.0114 and P = 0.011, respectively). These data suggest that 1q LOH is not infrequent in gastrinomas and could be a molecular/genetic prognostic factor for aggressive growth that could be useful clinically. The high frequent allelic loss at 1q31–32 as well as 1q21–23, which was associated with tumor aggressive growth, suggests these two regions harbor putative tumor suppressor gene(s) that are important for aggressive growth of this tumor.

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