A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications.

Abstract

The molecular pathogenesis of pancreatic endocrine tumors is largely unknown. Such tumors are more likely to develop in individuals with the von Hippel-Lindau (VHL) syndrome. We sought to determine whether allelic loss of the recently identified VHL tumor suppressor gene on chromosome 3p25-26 occurs in the more common sporadic forms of these tumors. Allelic loss on chromosome 3p was identified in 33% of 43 patients with endocrine tumors of the pancreas. The smallest common region of allelic loss, however, centered not at the VHL locus, but rather at 3p25, centromeric to VHL . Furthermore, no mutations of the VHL gene were identified in these tumors. Loss of alleles on chromosome 3p was associated with clinically malignant disease, whereas tumors with retained 3p alleles were more likely to be benign. Thus, the VHL gene does not appear to play a pathogenic role in the development of sporadic pancreatic endocrine tumors. Instead, a locus at chromosome 3p25 may harbor a novel pancreatic endocrine tumor suppressor gene, and allelic loss of this chromosomal region may serve as a molecular marker that helps distinguish benign from clinically malignant disease. ( J. Clin. Invest. 1997. 100:404-410.)

Genetic Differences in Endocrine Pancreatic Tumor Subtypes Detected by Comparative Genomic Hybridization

“…18 -20 We found losses of 3p and 6pq and gains of 14q and Xq in association with an advanced disease stage, implying that these chromosomal regions may contain genes playing a role in tumor progression. Indeed, in previous studies 6,17 and the present one, allelic losses at 3p25 were found to be associated with clinically malignant EPTs, which might point to the location of a TSG. Furthermore, losses of 6q (see below) as well as gains of 14q and Xq have been reported to be involved in the progression of various other cancers.…”

“…This locus has been postulated to harbor a novel EPT tumor suppressor gene (TSG). 6,17 Thus, microsatellite and FISH analysis confirmed the CGH data and, moreover, detected tetrasomy for chromosome 3 in one EPT and a microsatellite LOH of 3p25 in two tumors. This LOH was not detected with CGH, probably due to the small size of the chromosomal region lost (Ͻ10 Mb).…”

“…In addition, we found losses of 11p (CRI: 11p13-p14) in 30% of cases, which is in accordance with other data 10 and might point to the Wilms' tumor gene WT1 on 11p13 as a potential candidate TSG. Allelic losses at 3p25 have been found associated with clinically malignant disease in EPTs 6,17 and the present CGH analysis disclosed a statistically significant correlation between chromosome 3p losses and advanced disease. However, 10 of the 13 tumors had actually lost their entire chromosome 3, indicating monosomy, which was confirmed by FISH.…”

Highlights of the biology of endocrine tumours of the gut and pancreas.

“…This finding, however, was not confirmed in CGH and genome-wide allelotype studies (Speel et al 1999, Rigaud et al 2001. Allelic loss at 3p25 centromeric to the locus of the von Hippel-Lindau syndrome gene has been identified by Chung et al (1997) and found to be associated with malignancy. The association of 3p loss and metastatic disease was further supported by a CGH study of 44 tumours of different types (Speel et al 1999) and by a recent large study of 99 pancreatic endocrine tumours (Barghorn et al 2001a) with 3p LOH in 76.7% of metastasizing versus 41.5% of non-metastasizing tumours.…”

Insulinoma Maligno Produzindo Hipoglicemia

“…Alguns estudos têm associado mutações genéticas ao grau de malignidade dos tumores de células beta. A perda de um alelo no cromossomo 3p é descrita em 57% dos tumores com extensão extra-pancreática enquanto a mesma alteração é encontrada em apenas 9% dos insulinomas restritos ao pâncreas (14). A perda de heterozigoze do gene p53 assim como a ativação de genes como o TGF alfa, myc e ras, são processos importantes na progressão do tumor (15).…”