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[Cancer Research 59, 311-315, January 1, 1999]
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[Cancer Research 59, 311-315, January 15, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Deletion of Chromosome 1 Predicts Prognosis in Pancreatic Endocrine Tumors1

Sam A. Ebrahimi, Eric H. Wang, Alan Wu, Rhona R. Schreck, Edward Passaro, Jr. and Mark P. Sawicki2

Department of Surgery West Los Angeles Department of Veterans Affairs Medical Center and the University of California at Los Angeles School of Medicine, Los Angeles, California 90073 [S. A. E., E. H. W., A. W., E. P., M. P. S.] and Department of Pediatrics, Cedars-Sinai Medical Center and the University of California at Los Angeles School of Medicine, Los Angeles, California 90048 [R. R. S.]


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Endocrine tumors, such as parathyroid adenomas and pheochromocytomas, frequently have deletions of chromosome 1, suggesting that inactivation of a tumor suppressor gene from chromosome 1 is important in their tumorigenesis. We hypothesized that deletion of chromosome 1 may contribute to pancreatic endocrine tumor formation. Twenty-nine sporadic and MEN1 pancreatic endocrine tumors were studied for loss of heterozygosity (LOH) with 12 chromosome 1 microsatellite markers. LOH on chromosome 1 was identified in 10 of 29 (34%) tumors studied. Allele loss occurred more frequently in tumors with hepatic metastases (7 of 8) than tumors without metastases (3 of 21) (P = 0.004). Tumors in patients with lymph node involvement and patients with multiple endocrine neoplasia type 1 did not demonstrate LOH for chromosome 1 markers. These data suggest that loss of chromosome 1 is associated specifically with the development of hepatic metastases in patients with sporadic pancreatic endocrine tumors.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
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 Discussion
 REFERENCES
 
Pancreatic endocrine tumors, such as insulinomas, glucagonomas, and vasoactive polypeptideomas, arise within the pancreas, whereas gastrinomas are found within and adjacent to the pancreas, as well as within surrounding lymph nodes (1) . Pancreatic endocrine tumors occur most often sporadically, whereas gastrinomas and insulinomas more frequently occur as part of the autosomal dominant syndrome, MEN13 (2) .

Although the histological characteristics of these tumors are very similar, their malignant potential varies greatly. Glucagonomas, for example, are almost always malignant, whereas about one-third of gastrinomas are malignant, and less than 5% of insulinomas are malignant (2, 3, 4) . Benign and malignant tumors are best distinguished by the presence of hepatic metastases (4 , 5) .

The importance of differentiating between benign and malignant forms of the same tumor is best illustrated by gastrinomas. Gastrinomas are not only the most common tumor, they are frequently (40%) found outside the pancreas contained within lymph nodes (4 , 6, 7, 8) . This has led to considerable controversy both among clinicians and pathologists, some of whom consider such tumors found exclusively within lymph nodes to be evidence of metastatic malignant disease, whereas others find evidence for benignity (9) . Information on the genomic differences between the benign and malignant forms of these tumors would have great clinical relevance and greatly advance our understanding of the molecular events in these and presumably similar tumors.

Chromosome 1 deletions are common in human tumors. LOH analysis reveals deletions of chromosome 1 in common malignancies such as breast cancer, colon cancer, and pancreatic adenocarcinoma (see review in Ref. 10 ). Endocrine tumors, such as parathyroid adenomas (11 , 12) , medullary thyroid carcinomas (13) , and pheochromocytomas (14, 15, 16) also have a high frequency of LOH of chromosome 1. Although there are multiple candidate regions on chromosome 1 proposed as harboring tumor suppressor genes, no candidate genes have been proven to be mutated in these tumors.

While searching for the MEN1 gene, we performed cytogenetic analysis of five primary pancreatic endocrine tumors. The only clonal abnormality identified was one tumor, with a grossly abnormal karyotype including a chromosomal translocation 1p;13cen (p33;q10). Previous analysis of pancreatic endocrine tumors did not identify a significant frequency of chromosome 1 LOH. These studies were performed before microsatellite markers were generally available and therefore were not systematically studied in a large number of tumors (12 , 17) . In this study, we systematically analyzed pancreatic endocrine tumors for LOH on chromosome 1 using a large number of microsatellite markers. We demonstrate a high frequency of LOH, which directly correlates with the prognosis of these patients.


   Materials and Methods
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 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Tumor DNA Samples.
Sporadic and MEN1-associated pancreatic endocrine tumors were obtained after operation and immediately snap frozen in liquid nitrogen as previously described (6) . Frozen section analysis confirmed that the tumors contained minimal adjacent normal tissue. Constitutional DNAs were obtained from peripheral blood leukocytes of each respective patient. DNAs from tumor and normal tissues were isolated by phenol:chloroform extraction as previously described and stored at 4°C until PCR amplification (6) .

Cytogenetic Analysis.
Chromosome preparations were obtained from fresh tissue by a direct methodology. Fresh tumor tissue was cut in small sections (<1 mm2) and incubated overnight at 37°C in Velban (Sigma Chemical Co.) (0.5 µg/ml). The following day, the tissue was minced in a collagenase (0.63 mg/ml) solution to obtain a single cell suspension. Cells were then exposed to hypotonic solution (0.75 M KCl) and fixative (3:1 methanol:acetic acid). Microscopic slides were prepared and analyzed by quinacrine and Giemsa banding.

Microsatellite DNA Markers and PCR.
Primer pairs for 12 tri- and tetranucleotide repeat markers spanning both arms of chromosome 1 were based upon the human mapping from the Cooperative Human Linkage Center. Primer sequences are available on-line (http://www.resgen.com) or upon written request from the authors. The PCR primers were commercially prepared and conjugated with 5' fluorescent dye (Research Genetics). The template sequence DNA was amplified by PCR in a PE9600 (Perkin-Elmer) thermocycler. Each reaction contained 25–50 ng of target DNA, 2.5 µl of 10x Taq polymerase buffer containing 1.5 mM MgCl2, plus 20 pmol of each primer, 250 µM each of dATP, dCTP, dGTP, and dTTP. Finally 2.5 units of Taq Polymerase (Perkin-Elmer) mixed with an equimolar amount of Taq Start Antibody (Clontech) was added. DNA amplification was performed in a 25 µl reaction, with initial denaturation at 94°C for 5 min, annealing at primer-specific temperature (58–63°C) for 30 s, and extension at 72°C for 30 s for total of 40 cycles.

PCR Fragment Analysis.
The PCR products were analyzed on 6% polyacrylamide (29:1 acrylamide:bis) denaturing gels in 0.6x TBE buffer in an automated laser-activated fluorescent DNA sequencer (Amersham Pharmacia Biotech). Five µl of PCR product were diluted with stop solution (95% formamide, 10 mM EDTA, 0.1% xylene cyanol, and 0.1% bromphenol blue) to yield a 1:10 to 1:20 dilution. The mixture was then denatured at 95°C for 10 min, cooled on a dry ice-isopropanol bath and loaded on a preheated gel at 45°C. The samples were electrophoresed at 45 W, 38 mA, 1500 V for 2–3 h. The fluorescent peak data was collected and area under curve calculated using Fragment Manager (Amersham Pharmacia Biotech). Fluorescent-labeled 50-bp ladder was simultaneously run to determine allele size. The quantitation of data was measured in terms of peak size, area, and height. Allele loss was defined as signal reduction of 40% equivalent to an allele peak ratio of less than 0.6. The allele peak ratio was obtained by dividing tumor DNA peak by the allele peak of the paired normal DNA.

Statistical Analysis.
We compared the proportion of malignant tumors with and without chromosome 1 loss of heterozygosity via an exact permutational {chi}2 test (Statxact, Cytel Corp.). Malignant tumors were defined as those pancreatic endocrine tumors with multiple hepatic metastases. Tumors within lymph nodes were not considered malignant.


   Results
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Discussion
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Five tumors underwent cytogenetic analysis, and only one tumor revealed a clonal abnormality. This tumor, 12T, had a grossly abnormal karyotype: 40, X, -X, der(1)t(1;13)(p33;q10), der(11)t(11;?)(p15;?),-13,-14,-17,-19,-20,-21, +mar1, +mar2. This tumor was a metastatic nonfunctional pancreatic endocrine tumor (Fig. 1)Citation . The chromosome 1 rearrangement resulted in loss of the terminal portion of 1p, which is common in many tumor types.



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  		Fig. 1. Karyotype of tumor 12T with Q-banding at about the 400 band level of resolution.

 
Because deletions of chromosome 1 are common in many types of malignancies, we determined the frequency of LOH in a large group of pancreatic endocrine tumors. Twenty-nine pancreatic endocrine tumors were examined for loss of heterozygosity at 12 loci on chromosome 1 (Table 1)Citation . Tumor phenotypes included 18 gastrinomas, 2 insulinomas, 2 VIPomas, and 7 nonfunctional tumors. Both benign and malignant tumors were studied. All patients were explored, their tumors were staged, and resection or biopsy was performed. In some instances, the primary tumor was available for study, and in others, only the hepatic metastases were biopsied. In some instances of gastrinoma the only tumor identified was found within lymph nodes.


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  		Table 1 LOH examination

 
LOH was identified in 10 of 28 pancreatic endocrine tumors (Fig. 2)Citation . In 7 of 8 tumors with hepatic metastases (28% of all tumors tested), LOH at one or more chromosome 1 microsatellite markers was observed (Fig. 3)Citation . In contrast, only 3 of 21 tumors without hepatic metastases (Fig. 4)Citation demonstrated LOH for chromosome 1 markers (P = 0.004). Three of the eight tumors with hepatic metastases demonstrated LOH at all informative loci tested. The remainder had smaller regions of LOH. In one malignant tumor, 83T, two LOH regions are separated by a large area that retained heterozygosity. Two malignant tumors, 12T and 120T, revealed localized LOH at the distal short arm. The LOH results for tumor 12T are concordant with the karyotype data. Tumor 4T demonstrated LOH within the mid long arm. The smallest regions of overlap for LOH on the short arm lies between D1S1597 and pter, defined by tumor 120T. There is a second region of LOH located on the long arm where the consensus region lies between D1S534 and D1S549 defined by tumors 83T and 4T respectively. Only one tumor with hepatic metastases failed to reveal LOH (28T). This was a metastatic nonfunctional tumor, and it was informative for the majority of loci examined (10 of 12).



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  		Fig. 2. LOH analysis of pancreatic endocrine tumors. Shown are representative traces from tumors with LOH. N, normal DNA; T, tumor DNA. Arrow, lost allele.

 


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  		Fig. 3. LOH for chromosome 1 DNA markers is shown for tumors with hepatic metastases. The nomenclature is identical to Table 1Citation . Tumor 12T had a translocation 1p;13p(p33;q10) in the majority of metaphase spreads from a primary tumor culture. L, LOH; H, retention of heterozygosity; N, noninformative. Regions that have LOH and are bounded by heterozygous alleles are shaded.

 


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  		Fig. 4. LOH for chromosome 1 DNA markers is shown for tumors without hepatic metastases. L, LOH; H, retention of heterozygosity; N, noninformative.

 
Very few of the tumors without hepatic metastases demonstrated LOH for chromosome 1. Three independent regions of LOH separated by two or more markers retaining heterozygosity were present in a benign insulinoma, 22T. Two of these regions overlapped the regions of LOH in malignant tumors 12T and 4T. Tumor 26T had LOH at D1S2134, which does not overlap with the other common LOH regions. Tumor 65T revealed LOH for all informative markers but was not metastatic. None of the gastrinomas with lymph node involvement (n = 6) or MEN1 (n = 3) had LOH of chromosome 1.


   Discussion
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
The goal of this study was to determine whether chromosome 1 contains a tumor suppressor gene region necessary for pancreatic endocrine tumor development. We identified LOH for chromosome 1 DNA markers in 7 of 8 pancreatic endocrine tumors with hepatic metastases and 3 of 21 tumors without metastases (P = 0.004). Remarkably, six gastrinomas with lymph node involvement, but no hepatic metastases, did not reveal LOH for chromosome 1. Likewise, gastrinomas from patients with the MEN1 syndrome did not demonstrate LOH. These data suggest the presence of a tumor suppressor gene(s) located on chromosome 1 important for the development of these tumors, and in particular their metastatic potential.

LOH on chromosome 1 is a strong predictor of prognosis in pancreatic endocrine tumors. This putative tumor suppressor gene(s) is highly associated with hepatic metastases in these tumors. Tumors with involvement of lymph nodes only or association with MEN1 do not have LOH. Previous studies have not identified LOH for chromosome 1 in these tumors, but a recent study suggests LOH for chromosome 3p21–26 DNA markers is also associated with a poor prognosis (18) . There are several parallel findings between the chromosome 3 analysis and our findings on chromosome 1. Most of the tumors with hepatic metastases had LOH for chromosome 3 markers. The few tumors with lymph node involvement that had not metastasized to the liver did not have LOH for chromosome 3. Similarly, the MEN1-associated pancreatic endocrine tumors had a low frequency of LOH for chromosome 3. These two studies show a marked distinction between clinically benign and malignant pancreatic endocrine tumors at the molecular level.

LOH for chromosome 1 DNA markers has been reported for a variety of tumor types, including neuroblastoma, colorectal carcinoma, breast cancer, hepatocellular carcinoma, and melanoma (see review in Ref. 10 ). Pancreatic endocrine tumors have not previously been reported to have a high frequency of LOH for chromosome 1, but other endocrine tumors, such as pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenomas, have a high frequency of LOH on chromosome 1 (11, 12, 13, 14, 15, 16 ). The majority of these have allele losses on the short arm of chromosome 1. The most frequently involved region is 1p36. Although limited regions of LOH have been defined, no candidate genes from these regions are mutated in these tumors. The recent mapping of p73 to chromosome 1p36 suggests that it is an ideal candidate (19) . This gene has significant homology to p53, which is clearly established as a tumor suppressor. Analysis of neuroblastoma cell lines with 1p deletions did not reveal p73 mutation. Because the majority of these cell lines did have absent or mono-allelic expression, it has been argued that imprinting is involved with transcriptional inactivation of this gene in these tumors. This hypothesis remains unproven.

Two regions of LOH on chromosome 1 are associated with malignant pancreatic endocrine tumors. A limited region of 1p between D1S1597 and pter is lost in six malignant tumors. This overlaps the region 1p36 frequently lost in other types of tumors. Interestingly, loss of this region is also associated with poor prognosis in neuroblastomas (20) . The second region lost is located within the mid long arm between markers D1S534 and D1S549. Six tumors have LOH overlaping this region. It is impossible to know whether the LOH of the entire chromosome is unmasking either one or both tumor suppressor loci. In addition, it is difficult to determine the contribution of these regions to the aggressive tumor phenotype. A candidate gene for the region of the long arm may be the hereditary hyperparathyroidism-jaw tumor syndrome locus, which is linked to 1q21-32 (21) . LOH on 1q occurs in renal hamartomas in these patients, suggesting that this gene functions as a tumor suppressor gene.

Previous reports of chromosome surveys in pancreatic endocrine tumors did not identify frequent LOH on this chromosome (12 , 17) . There are several reasons that explain this discrepancy. First, there is a preponderance of these changes in tumors with hepatic metastases. These tumors are rarely operated on and account for a smaller percentage of tumors studied. Second, the earlier studies did not extensively utilize microsatellite markers, which significantly enhance the sensitivity of this type of analysis. Finally, the number of loci examined per chromosome is small and thereby limits the chances of finding LOH.

The most useful criteria to distinguish benign and malignant pancreatic endocrine tumors is the presence of hepatic metastases. Our findings suggest that LOH for chromosome 1 DNA markers is an excellent predictor of prognosis. Moreover, these data show a clear distinction between tumors with lymph node involvement and those with hepatic metastases. This finding correlates with clinical studies that suggest that in the particular case of gastrinomas, lymph node involvement has a relatively good prognosis (3, 4, 5 , 22) . The long-term goal of these studies is to identify genes which may be useful in distinguishing benign from malignant tumors. This LOH analysis is critical for identifying such genes. Further LOH analysis will be necessary to isolate these genes by positional cloning.


   ACKNOWLEDGMENTS
 
We are thankful for the support of Dr. Edward H. Livingston for his strong support of this research and Dr. Stephen Pandol for his encouragement. We also thank the following surgeons for contributing tumors for analysis: Drs. Nicola Basso (Universita Degli Studi Di Roma), Christopher Ellison (Ohio State University), Armando Guilliano (University of California at Los Angeles), Kennith Ramming (University of California at Los Angeles), Howard Reber (University of California at Los Angeles), Ronald K. Tompkins (University of California at Los Angeles), Charles F. Brunicardi (University of Texas, Baylor), Bruce Stabile (University of California at Los Angeles-Harbor Medical Center), Sean Mulvihill (University of California at San Francisco), and Haile T. Debas (University of California at San Francisco).


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by the Department of Surgery, West Los Angeles Department of Veterans Affairs Medical Center. Back

2 To whom requests for reprints should be addressed, at Department of Surgery (112), 11301 Wilshire Boulevard, Los Angeles, CA 90073. Phone: (310) 268-3298; Fax: (310) 268-4967; E-mail: msawicki{at}ucla.edu Back

3 The abbreviations used are: MEN, multiple endocrine neoplasia; LOH, loss of heterozygosity. Back

Received 10/23/98. Accepted 11/30/98.


   REFERENCES
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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