[Cancer Research 62, 1952-1955, April 1, 2002]
© 2002 American Association for Cancer Research
High Frequency Loss of Heterozygosity in von Hippel-Lindau (VHL)-associated and Sporadic Pancreatic Islet Cell Tumors
Evidence for a Stepwise Mechanism for Malignant Conversion in VHL Tumorigenesis1
Steven T. Lott2,
Dawn S. Chandler2,
Steven A. Curley,
Carolyn J. Foster,
Adel El-Naggar,
Marsha Frazier,
Louise C. Strong,
Mercedes Lovell and
Ann McNeill Killary3
Department of Molecular Genetics [S. T. L., D. S. C., C. J. F., L. C. S., M. L., A. M. K.], Division of Surgery [S. A. C.], Division of Pathology and Laboratory Medicine [A. E-N.], and Division of Cancer Prevention [M. F.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009
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ABSTRACT
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Germ-line mutation of the von Hippel-Lindau (VHL) gene predisposes to the development of multifocal, benign lesions, including retinal and central nervous system hemangioblastomas, pheochromocytomas, and renal and pancreatic cysts. Progression to malignancy in VHL disease is associated primarily with the development of renal cell carcinoma (RCC) and pancreatic islet cell tumors (PICT). Although many reports have documented the multiple functions of the VHL protein, few have investigated the intriguing question related to the tissue-specificity of malignant conversion in VHL disease, a problem not easily explained by strict genotype-phenotype correlations. We investigated a novel VHL kindred with a preponderance of PICTs to determine whether loss of additional genetic loci associated with the sporadic forms of RCC and PICTs might play a role in malignant conversion in this disease. We report the high frequency loss of heterozygosity (LOH) of genetic loci distinct from and mapping proximal to VHL within human chromosome 3p in the VHL kindred under study. Furthermore, chromosome 3p LOH occurs subsequent to VHL mutation and cyst formation, and correlates with malignant progression in VHL-associated PICTs. High frequency LOH was also observed in sporadic PICTs in regions of 3p associated with LOH in sporadic clear cell RCC as well as homozygous deletion in lung cancer. A stepwise model for malignant conversion in VHL disease is herein proposed.
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Introduction
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The VHL4
gene maps to chromosome 3p25 and has been shown to be an RCC tumor suppressor gene with multiple functions including regulation of angiogenesis, ubiquitination, as well as gatekeeper function in G0/G1 (1, 2, 3, 4)
. Despite the variety of tumor types observed clinically in this disease, malignant conversion in VHL involves primarily only two organ sites, the kidney and the pancreas. One hypothesis to explain the selectivity of malignant conversion in VHL disease is that loss or somatic inactivation of additional genetic loci is a requirement for malignant conversion. In support of this hypothesis is clinical data that have shown only a subset of the multiple renal and pancreatic cysts that occur in VHL progress to malignancy (5)
. In addition, although VHL-deficient mice (-/-) die in utero from absence of placental embryonal vasculogenesis (implicating VHL in normal extraembryonic vascular development), VHL heterozygous (+/-) mice fail to develop tumors or develop benign hemangiomas of the liver in tissue-specific knock-out experiments (6
, 7)
. Furthermore, a separate line of experimental evidence is supportive of additional chromosome 3p loci, distinct from VHL, playing a major role in sporadic RCC tumorigenesis. At least three to four separate regions within chromosome 3p (3p25, 3p21.3, 3p14.2, and 3p12) have been documented by high frequency LOH and/or homozygous deletion to harbor important tumor suppressor loci involved in sporadic RCC as well as SCLC tumorigenesis (reviewed in Ref. 8
). In addition, we previously functionally defined an RCC tumor suppressor locus NRC-1 (Nonpapillary Renal Carcinoma-1), distinct from VHL, and mapping within the same chromosome arm (3p12; Refs. 9
, 10
). Microcell-mediated transfer of a normal 3p12 subchromosomal fragment into RCC cell lines with VHL-inactivating mutations resulted in tumor suppression after injection of genetically complemented hybrid cells in vivo (11)
. Thus, the NRC-1 locus is downstream of VHL or in an independent pathway to tumorigenesis in the kidney. These cumulative studies provide ample evidence to suggest that loss or inactivation of additional genetic loci may be involved in malignant conversion in VHL tumorigenesis. Therefore, we hypothesized that loss of the 3p loci proximal to VHL may be a prerequisite for malignant conversion in VHL disease.
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Materials and Methods
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DNA Isolation.
For the VHL family study, DNA was isolated from peripheral blood lymphocytes and fresh tumor samples obtained from affected individuals using a high salt technique as described previously (11)
. DNA was similarly isolated from frozen PICT tumor samples. DNA isolation from paraffin-embedded archival tissue followed the method of Schubert et al. (12)
.
Microsatellite LOH.
Microsatellite PCR was performed using primers synthesized by Research Genetics (Huntsville, AL). Before amplification, the forward primer was end labeled with 32P by T4 polynucleotide kinase (Promega, Madison, WI). PCR amplification was performed in a 25 µl reaction volume containing: 0.63 µM concentration of forward and reverse primers, 100 ng template DNA, 0.2 mM deoxynucleotide triphosphates, 1.5 mM MgCl2, 0.63 units AmpliTaq polymerase (Perkin-Elmer, Foster City, CA), and HEPES buffer [10 mM HEPES and 50 mM KCl (pH 8.3)]. After initial denaturation and addition of AmpliTaq, reaction products were subjected to 23 cycles of 94°C for 40 s, 55°C for 30 s, and 72°C for 30 s, with a final extension at 72°C for 2 min. Samples were then denatured and loaded on a 6% acrylamide gel with 33% formamide and 6 M urea. Electrophoresis was performed at 60 W for approximately 2–3 h. Subsequently, gels were vacuum dried and exposed to autoradiography film overnight at room temperature.
SSCP Analysis.
SSCP analysis was performed using primers described by Gnarra (#1, #101, #102, #103, #107, and #6; Ref. 13
). Each of the exons was amplified in a reaction mixture consisting of 200 ng template DNA, 1 x PCR buffer [10 mM Tris-HCl (pH 8.3), 50 mM KCl, 2.5 mM MgCl2, and 0.001% gelatin], 200 µM deoxynucleotide triphosphates, 0.5 µM each primer end labeled with 32P, 2.5 units AmpliTaq, and 5% DMSO. Reaction components were denatured for 5 min at 95°C and cycled 35 times at 94°C for 30 s, 68°C for 30 s, and 72°C for 1 min, followed by a final denaturation at 72°C for 10 min. Reaction products were denatured at 95°C for 5 min and loaded on a 6% nondenaturing gel. The gel was exposed to autoradiography film overnight and analyzed.
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Results
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To determine whether chromosome 3p loci, distinct from VHL, were involved in malignant conversion in VHL tumorigenesis, we examined a novel multigenerational VHL kindred (Fig. 1)
in which four siblings developed nonfunctioning PICTs, one of the tumor types that undergo malignant conversion in VHL disease (14)
. Two of the four siblings developed early onset PICT in the third decade of life that metastasized to the liver (Fig. 1, 3J and 3K)
. The third sister was also diagnosed with an islet cell neoplasm (Fig. 1, 3L)
. Mutation screening of the remaining family members led to the detection of the fourth affected sib who developed a complex renal cyst with severe cellular atypia but no invasive malignancy. In addition, two hypervascular pancreatic head tumors (<1 cm) were discovered in this individual (Fig. 1, 3I)
.
An exon 3 missense mutation in codon 238 of the VHL gene was maternally inherited in this family. Interestingly, inheritance of the codon 238 mutation has been suggested to correlate with an increased risk of pheochromocytoma development (15)
; however, the only individual in this three-generation pedigree who developed pheochromocytoma was the mother of the affected sibs who developed late-onset bilateral adrenal pheochromocytomas (14)
. We reasoned that inheritance of the codon 238 mutation in this family may predispose to late onset pheochromocytoma; however, it did not explain the preponderance of early onset malignant PICT, which occurs only rarely in <10% of VHL patients (16)
. To determine whether LOH for 3p loci proximal to VHL correlated with PICT malignant progression, microsatellite analysis using a panel of 10 markers spanning the region 3p25–3p12 was performed on available frozen tissue and paraffin blocks from two malignant PICTs (Fig. 1, 3J and 3K)
as well as the benign PICT and renal cyst of the fourth sibling (Fig. 1, 3I)
.
Results indicate loss of all informative markers in the two individuals with malignant PICT (Fig. 2, A and B)
in the tumor tissue as compared with peripheral blood lymphocytes. Subsequent analyses using a total of 20 microsatellite markers on tumor and normal samples from the proband confirmed these results and again indicated that 100% of informative markers were lost spanning the region 3p26–3q13 (Fig. 3A)
. These findings are consistent with loss of most or all of the entire short arm of chromosome 3p, a common event documented in VHL. However, microsatellite analysis using 10 microsatellite markers failed to show any evidence of 3p LOH proximal to VHL in the hypervascular pancreatic head tumors from individual 3I with benign disease (Fig. 2A, 3I
; Fig. 2C
). In addition, although little DNA was recovered from the necrotic, cystic lesion of the kidney of individual 3I, microsatellite analyses using markers D3S1578 (3p21) and D3S1295 (3p14; Fig. 2C
) failed to document LOH for any marker tested. A subsequent microsatellite analysis was performed on microdissected samples from the benign PICTs of individual 3I. All of the informative markers (D3S1283, D3S1478, and D3S2372) were retained in the sample tested (data not shown). Additional confirmation of these results was obtained from the analysis of a second microdissected benign PICT (<1 cm) derived from a different VHL kindred in which retention of the microsatellite markers D3S1283, D3S1478, and D3S2372 was observed (data not shown). These studies document that within a single sibship, LOH of proximal 3p loci correlated with malignant conversion, whereas no 3p LOH occurred in either the kidney or the pancreatic lesions subsequent to VHL germ-line mutation and tumor formation in the fourth sib with benign disease. In addition, a second VHL-benign PICT failed to show evidence of 3p LOH proximal to VHL. If 3p LOH in familial PICT correlates with malignant conversion, then we next asked whether 3p regions of high frequency LOH observed in sporadic RCC coincide with regions of loss in sporadic PICT.
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Fig. 2. Microsatellite analysis of chromosome 3p loci in VHL kindred. A, LOH analyses performed at 10 chromosome 3p microsatellite repeat loci using normal and tumor DNA from two affected siblings with malignant PICTs (3J and 3K), and one sib with benign PICTs and renal cysts (3I). B, representative LOH in proband with malignant PICTs (3J). C, representative microsatellite analysis documenting retention of markers in pancreatic and renal lesions from individual 3I with benign disease.
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Fig. 3. Analysis of chromosome 3p LOH and VHL-SSCP in sporadic PICTs. A, LOH analysis on PICT frozen tumor samples. Matched tumor and normal DNA samples from proband 3J (sample 1) and five individuals with sporadic PICTs (samples 3–7) were examined for LOH at 20 microsatellite loci spanning chromosome 3 p25–26-3q13. B, LOH performed on DNA from paraffin-embedded PICT tumor samples (samples 9, 10, 11, 12, 14, 15, 16, 17, and 20) using 14 microsatellite repeat loci in regions identified from initial analysis. C, SSCP analysis of the VHL gene was performed on DNA from tumors of five patients (samples 3–7) affected with sporadic PICTs.  , Loss of heterozygosity;  , noninformative;  , no loss of heterozygosity.
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To test the role of chromosome 3p proximal loci in sporadic PICTs, we performed a retrospective analysis of a collection of frozen, sporadic PICTs, all of which were malignant. Initial LOH studies were conducted with 20 microsatellite markers spanning the region 3p26–3q13. Four of five tumors (80%) showed 3p LOH (Fig. 3A)
. In two of four tumors, losses were restricted to single markers within the 3p21.3 region, one at D3S1227, and the other at D3S1235. Both markers map within the well-characterized 3p21.3 homozygous deletion regions in SCLC (17)
. In the remaining two sporadic PICT tumors that showed LOH, terminal as well as interstitial losses were observed in distinct regions shown to be important in RCC tumor formation (3p24-p21.3, 3p14.1–21.2, as well as 3p12; Ref. 8
). Two of five tumors that contained interstitial losses demonstrated distinct boundaries for LOH within 3p12 at D3S1577 and D3S2372 that map within the previously well-characterized homozygous deletions observed in SCLC cell lines as well as within the functionally defined region containing NRC-1 identified in our previous studies (18)
.
Sporadic PICT derived from paraffin-embedded tissue blocks were also analyzed for LOH in the regions implicated from the initial study. In nine malignant PICT and adjacent normal tissue samples, LOH was observed in 100% of samples. In addition, 100% of informative tumors showed LOH for D3S1038 within 3p25 as well as for three markers within 3p12 (D3S1284, three of three; D3S1511, five of five; and D3S2372, three of three). In six of eight informative tumors, losses, as in initial studies, centered in the 3p21.3 region around D3S1478.
Our results document LOH in sporadic PICTs that correlates with regions of high frequency LOH and homozygous deletion in sporadic RCC and SCLC, respectively. To determine whether the sporadic, malignant PICTs under investigation carried VHL mutations as have been reported in sporadic RCC, SSCP analysis was performed on PICT tumors 2–7 (Fig. 3, A and C)
. SSCP analysis failed to indicate the presence of mutations in the VHL coding region in five of five PICT tumors.
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Discussion
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To date, very few studies have been undertaken to elucidate the genetic mechanisms underlying the development of PICTs. This may be attributable in part to the rare occurrence and difficulty in culturing these tumors. In a study by Chung et al. (19)
, five polymorphic markers flanking the VHL gene as well as two markers within 3p21 were used to screen a series of benign and malignant endocrine tumors of the pancreas. Results indicated 31% of 43 tumors examined showed LOH for one or more 3p25 loci and only 26% (9 of 34) showed 3p21 LOH. No tumors with 3p LOH exhibited VHL mutations, as also documented in this report. On the basis of this analysis, the authors suggested the existence of a novel pancreatic tumor suppressor locus proximal to VHL within 3p25. In a similar study on benign and malignant PICTs, Nikiforova et al. (20)
found PICT LOH in 53% of benign tumors (8 of 15) and 83% of malignant tumors (five of six) for the region 3p14.2–3p21. Our study on sporadic, malignant PICTs indicated multiple regions of high frequency LOH within 3p. In addition, the regions of highest frequency LOH directly coincide with regions of homozygous deletion or high frequency LOH in RCC and SCLC. Thus, data presented herein suggest that LOH for particular 3p regions may be an important event in common in these cancers in the sporadic form of the disease and a prerequisite for malignant conversion in PICTs associated with VHL disease. Mutation analysis of sporadic PICTs indicated an absence of VHL mutation. Thus, unlike RCC, which shows high frequency of VHL mutation, PICTs appear to progress to malignancy independently of loss of the VHL tumor suppressor gene. Additional studies to examine VHL methylation as well as protein function will be required, however, before an accurate determination of the role of the VHL gene in sporadic PICTs can be made.
Therefore, these data indicate an involvement of chromosome 3p loci in sporadic pancreatic islet cell tumorigenesis and predict a model of stepwise progression to malignancy in VHL tumorigenesis in which genetic alterations of 3p loci proximal to the VHL gene play an important role in malignant conversion in those VHL-PICT tumors that progress to malignancy. Given the wide spectrum of primarily benign tumors that develop in affected individuals, one must consider the possible interactions of other genes that might influence the progression of VHL-associated malignancies. Studies on VHL-associated RCC have documented by both cytogenetic and LOH analyses that losses occur commonly along the whole 3p arm. Our study in VHL-associated PICTs indicates that in two affected individuals with malignant PICTs, LOH was observed for all of the informative markers on the 3p arm. These data, in combination with observations in VHL-associated RCC, would suggest a mechanism whereby either: (a) loss of the entire short arm of 3p is a requirement only for the loss of the remaining wild-type copy of the VHL gene; or that (b) chromosome 3p losses in addition to VHL germ-line mutation and LOH are a requirement for malignant conversion in tumors associated with VHL. LOH studies, presented herein, support the latter hypothesis in that 3p LOH proximal to VHL within 3p correlated with malignant progression and were subsequent to benign tumor formation.
Recent studies indicate that the VHL protein is a part of a protein complex (pVHL/Elongin C/Cul2) that functions in ubiquitination of hypoxia-inducible genes, including hypoxia inducible factor-1 (3
, 21)
. Hypoxia inducible factor-1 is activated during hypoxic conditions and stimulates transcription of a series of hypoxia-responsive genes, including vascular endothelial growth factor, an important protein in tumor angiogenesis. Cells that are VHL (-/-) constitutively express vascular endothelial growth factor and activate angiogenesis. Thus, two functions have been clearly determined for VHL. VHL must function in the onset of hyperplasia and transformation, via gatekeeper function, as well as angiogenesis, via a ubiquitination pathway. In a transgenic mouse model for PICT formation, induction of angiogenesis occurred during the transition from hyperplasia to neoplasia in activated islet cells (22)
. Transgenic mice, which exhibited cell-type-specific expression of the SV40 large T antigen under the control of the rat insulin promoter, showed a progression from hyperplasia to angiogenesis and tumor formation. These results suggested that additional genetic events subsequent to expression of SV40 large T antigen were required for angiogenesis and tumor formation, and implicated mouse chromosome 9 and 16 by LOH analysis (23)
. Considerable homology between human chromosome 3 and mouse chromosomes 9 and 16 has been well documented in a number of studies with an 11 cM syntenic region on mouse chromosome 9 and human chromosome 3p21-p22 (Jackson Laboratory, Bar Harbor, ME).5
In fact, previous allelotyping studies of Nikiforova et al., which documented LOH within 3p14-p21 were undertaken initially to determine whether LOH in syntenic regions identified between the mouse transgenic model system and human PICT could be found (20)
. Given the high frequency of LOH presented in this report in two homozygous deletion intervals within 3p, it seems likely that genes involved in the progression of PICT will be identified in these regions. Candidate RCC tumor suppressor genes have been identified in the 3p21.3 region, including the Ras association family 1 gene, isoform RASSF1A, which is hypermethylated in RCC cell lines and tumor samples (both with and without VHL mutation; Ref. 24
). The Dutt1/Robo1 gene within chromosome 3p12 encodes a neural-cell adhesion molecule, which on introduction into the mouse germ line in deleted form, resulted in lung hyperplasia (25)
. The role of Dutt1/Robo1 in RCC has not been described, suggesting that additional gene(s) for RCC and PICT within 3p12 may yet to be elucidated.
We conclude that the most likely mechanism for malignant conversion in VHL-associated tumorigenesis involves not only inheritance of a gatekeeper gene such as the VHL gene, which may predispose to the hyperplastic state and to the initiation of angiogenesis, but also the loss of additional genes within 3p critical to malignant progression in RCC and PICTs.
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ACKNOWLEDGMENTS
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We thank James Luca for excellent technical assistance. We also gratefully acknowledge support from the MDACC core history laboratory.
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FOOTNOTES
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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 Supported in part by NIH CA 62027 (to A. M. K.) and NCI 5T32 CA09299 (to S. T. L. and D. S. C.). 
2 These authors contributed equally to this work.
3 To whom requests for reprints should be addressed, at Department of Molecular Genetics, Box 11, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4095. Phone: (713)-792–7833; Fax: (713) 792-8382; E-mail: akillary{at}mdanderson.org
4 The abbreviations used are: VHL, von Hippel-Lindau; RCC, renal cell carcinoma; PICT, pancreatic islet cell tumor; LOH, loss of heterozygosity; SCLC, small cell lung carcinoma; NRC-1, nonpapillary renal carcinoma-1; SSCP, single-strand conformation polymorphism.
5 Internet address: http://www.informatics.jax.org.
Received 9/28/01.
Accepted 2/ 6/02.
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Top
ABSTRACT
Introduction
, central nervous system hemangioblastomas; 
, PICTs; 
, pheochromocytomas; and 
, renal cysts.