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Comparative Study
. 2001 Jun;158(6):1903-11.
doi: 10.1016/S0002-9440(10)64658-5.

Putative tumor suppressor loci at 6q22 and 6q23-q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors

A Barghorn  1 , E J Speel, B Farspour, P Saremaslani, S Schmid, A Perren, J Roth, P U Heitz, P Komminoth
Affiliations
Comparative Study

Putative tumor suppressor loci at 6q22 and 6q23-q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors

A Barghorn et al. Am J Pathol. 2001 Jun.

Abstract

Our previous comparative genomic hybridization study on sporadic endocrine pancreatic tumors (EPTs) revealed frequent losses on chromosomes 11q, 3p, and 6q. The aim of this study was to evaluate the importance of 6q losses in the oncogenesis of sporadic EPTs and to narrow down the smallest regions of allelic deletion. A multimodal approach combining polymerase chain reaction-based allelotyping, double-target fluorescence in situ hybridization, and comparative genomic hybridization was used in a collection of 109 sporadic EPTs from 93 patients. Nine polymorphic microsatellite markers (6q13 to 6q25-q27) were investigated, demonstrating a loss of heterozygosity (LOH) in 62.2% of the patients. A LOH was significantly more common in tumors >2 cm in diameter than below this threshold as well as in malignant than in benign tumors. We were able to narrow down the smallest regions of allelic deletion at 6q22.1 (D6S262) and 6q23-q24 (D6S310-UTRN) with LOH-frequencies of 50.0% and 41.2 to 56.3%, respectively. Several promising tumor suppressor candidates are located in these regions. Additional fluorescence in situ hybridization analysis on 46 EPTs using three locus-specific probes (6q21, 6q22, and 6q27) as well as a centromere 6-specific probe revealed complete loss of chromosome 6 especially in metastatic disease. We conclude that the two hot spots found on 6q may harbor putative tumor suppressor genes involved not only in the oncogenesis but maybe also in the malignant and metastatic progression of sporadic EPTs.

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Figures

Figure 1.
Figure 1.
Patient 16 (69-year-old male; malignant insulinoma, 3.5 cm in diameter). a: Allelotyping, LOH for two of five markers (D6S268 and D6S310, red arrowheads; ARG1 is not informative; UTRN and IGF2R-II show retention of heterozygosity). b: CGH-analysis on chromosome 6: digital image (left) and fluorescent ratio profile (right). The red bar on the left of the chromosome ideogram (center) indicates region of loss. c: FISH analysis, loss of one of the 6q-specific green spots in two of three probes (6q21 and 6q22) in DAPI-stained tumor nuclei. At 6q27 both centromere and 6q-specific probes are detected. The FISH analysis confirms the allelotyping results.
Figure 2.
Figure 2.
Examples of benign EPTs with isolated allelic losses. a: Patient 1, LOH at IGF2R-II. b: Patient 91, LOH at D6S310.
Figure 3.
Figure 3.
a: Patient 43, additional LOH with tumor progression. LOH only in the metastasis (M) but not in the primary tumor (T). b: Patient 33. FISH-analysis at 6q22 demonstrates monosomy. c: Patient 1. FISH analysis at 6q22 demonstrates trisomy (upper nucleus) and tetrasomy (lower nucleus). Tetrasomy was an exceptional finding and not representative for the FISH analysis in this patient.
See this image and copyright information in PMC

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