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Original Studies |
Digestive Diseases Branch (S.U.G., F.G., R.T.J., J.S.) and the Metabolic Diseases Branch (C.H., A.L.B., S.J.M., A.M.S.), National Institute of Diabetes and Digestive and Kidney Diseases, and the Laboratory of Pathology, National Cancer Institute (Z.Z., I.A.L.), National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Dr. Robert T. Jensen, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9C-103, 10 Center Drive, MSC 1804, Bethesda, Maryland 20892-1804.
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Introduction |
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Materials and Methods |
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Fifty-one patients who underwent exploratory laparotomy for Zollinger-Ellison syndrome at the NIH between 1990 and 1998 were included in this study. The diagnosis of Zollinger-Ellison syndrome was established as previously reported (19), using measurements of fasting gastrin levels, basal acid output, secretin and calcium-provocative tests, and histological results. Patients with MEN1, diagnosed by family history or laboratory evidence of other endocrinopathies, determined as described previously (20), were excluded from the study. The study protocol was approved by the institutional review board of the NIDDK, and all patients gave informed consent.
To determine correlations of genetic alterations with clinical, laboratory, and tumor characteristics (growth, location, and size), the results from the following investigations performed on all patients were assessed. Measurement of basal acid output (BAO) and maximal acid output were performed as previously described (21). Fasting serum gastrin levels were determined in all patients and analyzed by RIA (Bioscience Laboratories, New York, NY) or Mayo Clinic Laboratories (Rochester, MN). The duration of disease determined in all patients was defined from the time of diagnosis or from the time of disease onset, as previously described (4). Detailed conventional imaging studies (computed tomography with oral and iv contrast, magnetic resonance imaging, ultrasound, selective abdominal angiography with secretin stimulation, and hepatic vein gastrin sampling) and somatostatin receptor scintigraphy were performed as previously reported (5, 22, 23) to locate the primary tumor and evaluate the extent of disease. All patients underwent exploratory laparotomy with an extensive intraoperative evaluation for attempted curative resection (5, 24). The patients were then reassessed within 2 weeks of surgery and 3–6 months postoperatively to determine disease-free status and annually to monitor progression of disease, as previously described (19). Disease-free status was defined by normal fasting gastrin levels (<200 pg/mL), negative results on gastrin provocative testing with secretin (<200 pg/mL increase) and calcium (<395 pg/mL increase), and no evidence of tumor on any imaging study (19, 25). Patients were classified as to whether they were disease free immediately postoperatively and at the last follow-up. In those patients who were not disease free postoperatively, annual detailed imaging studies (computed tomography, magnetic resonance imaging, ultrasound, and somatostatin receptor scintigraphy) provided the basis for assessment of tumor growth. Consistent absence of imagable lesions or lack of increase in size or number of lesions over the follow-up period was defined as a tumor not demonstrating growth. An increase in the size or number of lesions on imaging studies was defined as evidence of tumor growth. The new development of liver metastases during follow-up served as the definition for the liver metastases group.
Mutation analysis
Twenty-four patients had not had the MEN1 status of their gastrinomas previously assessed, and this was determined as described below. In 27 patients the MEN1 mutation status was known and previously reported (15); however, in that study no correlations with tumor phenotype genotype expression were performed. Tumor samples were immediately snap-frozen in liquid nitrogen during surgery and stored at -70 C. Tumor DNA was extracted from 8-µm cryosections of the specimens using a commercial kit (QiAamp blood kit, QIAGEN, Santa Clarita, CA) after analyzing an adjacent slide with hematoxylin and eosin staining to determine that there was no gross contamination with normal tissue. Germline DNA was extracted from leukocytes of these patients using the same kit.
Primers for amplification of exons 2–10 of the MEN1 gene were obtained according to the published sequences (http://www.nhgri.nih.gov). PCR was carried out in a final volume of 25 µL with 5–10 ng DNA and 0.5 µU DNA-polymerase (AmpliTaq Gold, Perkin-Elmer Corp., Foster City, CA) according to the manufacturer’s protocol. Dimethylsulfoxide in a final concentration of 5% was added to the PCR reactions for exons 2, 9, and 10. The PCR reaction was run under the following conditions: initial denaturation at 94 C for 10 min; 35 cycles of 94 C for 30 s, 60 C for 30 s, and 72 C for 2 min; and final extension at 72 C for 5 min in a thermal cycler (Perkin-Elmer Corp., 9600 thermocycler). PCR products were then subjected to dideoxyfingerprinting (ddF) as previously reported (26) using previously described primers (http://www.nhgri.nih.gov). The ddF reactions were run in nondenaturing gels (MDE, FMC Bioproducts, Rockland, ME) at 8 watts for 8 h. Subsequently, the gels were dried, and autoradiography was performed overnight. Samples with abnormal ddF patterns were subjected to direct sequencing using the same PCR primers and ddF primers for manual (AmpliCycle, Perkin-Elmer Corp.) and automated (ABI Prism, Perki- Elmer Corp.) sequencing. For those samples in which the mutated sequence could not be unambiguously identified on the sequencing gel, the primary PCR product was cloned in the vector pCR2.1 (TA-Cloning, Invitrogen, Carlsbad, CA) and resequenced.
Statistics
The 
2 test, Fisher’s exact test ,and
Mann-Whitney rank test were used to compare the effects of
MEN1 gene mutations on clinical and laboratory parameters
and tumor characteristics. P < 0.05 was considered
significantly different.
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. This cohort is similar to other
large series (2, 27, 28, 29) with respect to a slight male preponderance
(57%), mean age of the patients (50 yr), and duration of disease, as
defined by the time from onset of continuous symptoms until the surgery
date (9 yr). Mean serum gastrin, preoperative BAO, and maximal acid
output values are not significantly different from those in other large
studies of patients with Zollinger-Ellison syndrome (29). Inhibition of
gastric acid production at the time of surgery was achieved
predominantly with
H+-K+-adenosine
triphosphatase inhibitors (omeprazole 45, lansoprazole 1). In contrast
to older series (1, 2, 30, 31), but similar to other recent studies
(32, 33), half of all identified primary tumors were located in the
duodenum, and only 15% were found in the pancreas. The extent of the
tumor encountered during surgery was comparable to that in other large
surgical series (2), in that one third were confined to the primary
site, another 33% included the primary site and spread to the lymph
nodes, and only 8% had evidence of liver metastases during
surgery.
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, left). No
mutations were found in the corresponding leukocyte DNA. The mutations
consisted of 2 nonsense, 4 missense (all leading to nonconservative
amino acid changes), 9 deletions leading to frame shifts, and one
in-frame deletion of 10 amino acids. Figure 2
shows examples of a single base substitution leading to a nonsense
mutation and a single base deletion leading to a frame shift. In Fig. 2a (top panel), the antisense strand of the mutation R98X
(CGA->TGA) is shown in the gastrinoma tissue. The heterozygous state
is due to amplification of the normal sequence from contaminating
normal tissue, seen in the same patient’s leukocyte DNA (Fig. 2a, top panel). The antisense strand of the mutation 512delC in
a gastrinoma is depicted in Fig. 2b (bottom panel). Figure 3 shows a complex substitution detected by
cloning of the normal and mutated allele (306AGCCCC
T). Three of the
16 mutations detected in our study have been previously found in the
germline of familial MEN1 [R98X (34), 512delC (35), and 483delAT
(36)]. Nine of the 16 mutations were located in exon 2, whereas the
remaining 7 mutations were distributed throughout the other 8 coding
exons (Fig. 1, left). This represents a significant
overrepresentation of mutations per nucleotide (9 of 445 vs.
7 of 1381 nucleotides; P = 0.005) in exon 2.
Furthermore, 11 of 16 (68%) mutations were found in the gene region
encoding amino acids 66–166 (exons 2–3) of the 610-amino acid protein
menin. We encountered several previously recognized polymorphisms
[R171Q, 765–6(CT), 1023–12(AC), D418D, and A541T]. These
polymorphisms include the three most common polymorphisms (35) found in
familial MEN1.
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). No significant
difference between the 2 groups was found regarding gender, age at
surgery, or duration of disease determined from the time of diagnosis
or from the onset of disease. Functional measures of the gastrinoma,
including fasting serum gastrin level, the magnitude of the serum
gastrin increase postsecretin, and the preoperative basal acid output,
were not significantly different in the 2 groups. A similar analysis
was performed to determine whether the presence or absence of a
MEN1 gene mutation in the gastrinoma varied with primary
tumor location or size, tumor extent, curability, or tumor growth
pattern (Table 3). The primary tumor site
was located most often in the duodenum in both groups (43%
vs. 62%; Table 3), and the frequencies of the primary tumor
location did not differ between the 2 groups. Although the resected
tumors with mutations tended to be somewhat smaller in size than the
tumors without a mutation, this difference did not reach statistical
significance [50% vs. 26% (<1 cm); P =
0.08; Table 3]. Similarly, the tumor extent found intraoperatively did
not differ between the 2 groups. Specifically, a similar proportion of
patients had primary tumor only, lymph node metastases, or liver
metastases found at surgical exploration (Table 3). Initially, more
than half of all patients were disease free postresection in both
groups (63% vs. 51%; Table 3). After a mean follow-up of
3.1 ± 0.5 yr, a similar proportion of patients (44%
vs. 46%) remained disease free in both groups. The
postoperative course in the patients with active disease showed a trend
toward a more aggressive form, with evidence of tumor growth or
development of new liver metastases in the group with a MEN1
mutation in the gastrinoma. However, this finding did not reach a
statistically significant level (5 of 9 = 56% vs. 4 of
19 = 21%; P = 0.094).
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), we sought to analyze the tumor
characteristics in those patients with such a mutation compared to
those in patients with mutations at other locations (Table 4). Primary duodenal tumors more
frequently had a nonexon 2 mutation (7 of 10) compared to pancreatic
and lymph node primary tumors (0 of 5; P = 0.011).
Nonexon 2 tumors were more frequently small in size (i.e.
<1 cm; 6 of 7) compared to tumors with an exon 2 mutation (2 of 9;
P = 0.02; Table 4). However, there was no difference in
the rate of disease-free patients or the postoperative tumor growth
pattern in the patients with active disease with or without exon 2
mutations.
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In tumors from patients without a hereditary tumor syndrome (sporadic disease), Knudson’s two-hit model of tumorigenesis postulates a somatic mutation of a tumor suppressor gene and somatic loss of the second allele via chromosomal breakage (40) or some other mechanism. Studies in parathyroid adenomas from patients without MEN1 show a frequency of somatic mutations of the MEN1 gene of 13–21% (41, 42). Sporadic pituitary adenomas only rarely (<5%) are found to harbor MEN1 gene mutations (43, 44). Previous studies of sporadic pancreatic endocrine tumors demonstrate somatic mutations in the MEN1 gene in 27–39% of the tumors (15, 16, 17). In keeping with the published frequency of somatic mutations in pancreatic endocrine tumors, we found 16 mutations in the MEN1 gene in sporadic gastrinomas from 51 patients (31%). Despite a reportedly high rate of loss of heterozygosity (93%) involving the MEN1 gene region in sporadic gastrinomas (15), we found no mutations in 35 gastrinomas. Several reasons can be hypothesized to explain this finding. First, it could be proposed that the screening methodology used lacks sensitivity. We employed ddF as the screening methodology. This technique has a reported sensitivity of more than 90% for detection of germline mutations (35), which is higher than the reported sensitivity of single strand conformation polymorphism to detect single base substitutions (80%) (45) that was used in a previous study (17). Moreover, in one study, direct sequencing of the entire open reading frame, albeit in a small number of sporadic pancreatic endocrine tumors, did not increase the rate of detected mutations in the MEN1 gene (16). Secondly, it is known that PCR-based strategies for mutational analysis can underestimate the rate of large deletions within a gene, i.e. deletion of the entire MEN1 gene, as has been reported in one family with MEN1 (46). A third reason could be the inactivation of gene expression by hypermethylation of the promotor region, as described in several other tumor suppressor genes (47, 48). This alteration would not be detected by the methodology used. Lastly, intron-based mutations may interfere with ribonucleic acid splicing or stability and reduce translational efficiency. However, the rate of detected mutations in this and recent (15, 17) studies confirms that the MEN1 gene probably plays a critical role in the pathogenesis of at least one third of sporadic gastrinomas.
A comparison of type and location of mutations in the MEN1 gene detected in sporadic gastrinomas in the present study and in other recent studies (15, 17) reveals a difference in the spectrum of mutations in the sporadic disease from that found in the MEN1 syndrome. Combining our data with results taken from the literature of other cases of sporadic gastrinomas (17), 40% of the 28 mutations described (8 missense and 3 in-frame deletions) are predicted to alter the amino acid sequence of menin. All amino acid substitutions were nonconservative. Seventeen mutations in sporadic gastrinomas are predicted to result in a truncated protein (60% of the total). The majority of mutations in fMEN1 lead to a truncated menin protein [103 of 141 (73%) germline mutations] (34, 35, 39) and probably loss of a functional protein. None of the observed missense mutations involves either of the two nuclear localization signals at the carboxyl-terminal end of the protein (47). Menin has been shown to interact with the transcription factor Jun-D (49). All missense mutations and in-frame deletions except two (1733del30 and S543L) are located in the putative menin binding region to Jun-D (0–323 amino acids) as found on deletion analysis (49) and conceivably could alter the interaction between these 2 proteins. The majority of all mutations in sporadic gastrinomas were located in the 5'-end of the coding region. In the nucleotide stretch from 300–610 (exons 2–3), corresponding to amino acids 66–166, we found 64% of the mutations compared to 36% in the remaining 1516 nucleotides. In contrast, the mutations in patients with fMEN1 are distributed rather evenly throughout the open reading frame regardless of the presence or absence of gastrinoma (35). It is conceivable that mutations involving the 3'-end of the coding region could lead to an abnormal protein that retains some wild-type function and may be less likely to promote tumorigenesis in sporadic gastrinomas. In fact, 6 of the 11 mutations leading to an intact protein with an altered amino acid sequence are within this region, possibly interfering with binding properties to potential interaction partners. Whether the clustering of mutations in this region is relevant for functional impairment of the menin protein in sporadic gastrinomas awaits further analysis of protein function.
Gastrinomas are not a homogeneous group of tumors. Not only do they differ in the primary location (duodenal, pancreas, and other sites), but also in clinical behavior, biological behavior, and growth pattern (25% pursue an aggressive course) (2, 3, 4, 50). Even in patients with liver metastases from progressive gastrinomas, the growth patterns are highly variable (50, 51), with 30% demonstrating no or minimal tumor growth, 30% having slow growth, and 40% having aggressive growth. The factors contributing to these different phenotypes are largely unknown. Genotype/phenotype correlations in hereditary tumor syndromes and a few sporadic tumors have at times suggested a relationship between the type or location of the mutation and the severity of the clinical disease or clinical expression of the disease. Examples of such associations in hereditary tumor syndromes have been described for MEN2 and neurofibromatosis type 2 (NF2) (18, 52). Specifically, mutations in the RET protooncogene are responsible for several different inherited tumor syndromes. Familial MEN2A and familial medullary thyroid cancer are usually caused by a mutation of one of five different codons coding for cysteine residues in exon 10 or 11 (18). Among these mutations, a mutation of codon 634 confers a higher risk of developing pheochromocytomas and hyperparathyroidism (18, 53). Furthermore, in patients with MEN2B, which is most frequently caused by the specific mutation M918T in exon 16 (54), a clinically more aggressive form of medullary thyroid cancer occurs than in MEN2A or familial medullary thyroid cancer. Thus, evidence of such a mutation in a patient with an inherited form of medullary thyroid cancer confers a higher risk of an aggressive course of the disease. Similarly, in NF2, truncating mutations of the NF2 gene are associated with a more severe disease phenotype (earlier onset and multiple tumors) compared to nontruncating mutations (52, 55). In other hereditary cancer syndromes (breast cancer and hereditary nonpolyposis colon cancer), no correlation between genotype and disease severity has been established (56, 57). In fMEN1, to date, no correlation between the location of the mutation or the type of mutation and clinical phenotype or severity of disease has been found (34, 35, 39). Our data suggest that there may be at least one genotype/phenotype correlation in sporadic gastrinomas. Comparison of the primary tumor site to location of the mutation revealed that nonduodenal primary tumors harbored only exon 2 mutations, whereas only 30% of the duodenal tumors did. This conclusion is based on relatively small numbers of gastrinomas (i.e. n = 16) and will need to be confirmed by larger studies in the future. This result is corroborated by the finding that 75% of the larger (>1-cm) primary tumors had an exon 2 mutation. As duodenal tumors are commonly small (<1 cm), and nonduodenal primary tumors are usually larger than 1 cm (2, 4, 5, 9), these results together suggest a relationship between the site of the MEN1 gene mutation and the location of the sporadic primary tumor.
In a few instances specific mutations of a gene thought to be involved in tumorigenesis of sporadic tumors correlate with the severity of the clinical disease (58, 59, 60, 61, 62). Hence, detection of such a mutation may serve as a prognostic marker and modify therapeutic strategies. In our study the presence of a mutation in the MEN1 gene in sporadic gastrinomas did not influence the rate patients were rendered disease free after surgery or the rate of tumor growth, although a trend toward a more aggressive course in the patients with active disease was observed (P = 0.09). Future studies involving a large number of patients and a long duration of follow-up may provide confirmation of this trend. Moreover, the type of mutation (data not shown) or location of the MEN1 gene mutation did not correlate with the rate of tumor growth. Therefore, no prediction about tumor extent or the postoperative growth behavior of the tumor could be made from MEN1 gene mutational analysis of the resected tumor. In contrast, analysis of the RET protooncogene in sporadic medullary thyroid carcinoma shows the mutation M918T to be present in 20–45% of the tumors and to be associated with a poor prognosis (58, 59, 60). Amplification of the N-myc gene in sporadic neuroblastomas appears to be a power-ful predictor of poor prognosis (61). In sporadic vestibular schwannomas, mutations of the NF2 gene are demonstrated in a similar frequency as MEN1 gene mutations in gastrinomas (38%) (62). Furthermore, the spectrum of mutations with regard to location or type of mutation is somewhat different from the reported germline mutations in NF2, analogous to our observations in the MEN1 gene. When the researchers attempted to correlate the presence of a mutation, location, or type of mutation to growth characteristics of the tumors, as measured by a calculated growth index or proliferating cell nuclear antigen immunostaining, no strong evidence for a correlation was found (62).
The reasons for the lack of correlation between the presence or site of a MEN1 gene mutation and the severity of disease in sporadic gastrinomas may be severalfold; sporadic gastrinomas, albeit clinically a biochemically homogenous syndrome, display a variable clinical course (2, 3, 9, 50) and thus may represent the common clinically apparent end point of diseases of various etiologies. This is underscored by the recently proposed concept of different embryonal origins of gastrinomas from different locations (8). Hence, different molecular alterations in the various cells of origin may lead to the common end point, a tumor secreting gastrin, and thereby differentially influence tumor growth patterns. Secondly, tumorigenesis has been proposed to be a multistep process, as exemplified in the colon cancer model (63), involving several successive molecular alterations that lead to the development of a tumor. Analogous to the colon cancer model, the frequency of mutations in the MEN1 gene in sporadic gastrinomas would suggest a possible role early in tumor development, but probably requires other genetic hits to explain the progression from the to date unknown progenitor cell to a gastrinoma. As an extension to this idea, a mutation of the MEN1 gene may promote the development of a sporadic gastrinoma, but factors further downstream in the evolution of the tumor may be responsible for the phenotypic expression of the disease, i.e. extent or metastases.
In summary, we find that the MEN1 gene is mutated in one third of sporadic gastrinomas. These mutations are clustered between nucleotides 300–610, in contrast to the finding in fMEN1, where they are more evenly distributed throughout the exons. The presence of a MEN1 gene mutation does not correlate with clinical characteristics, tumor extent, or growth behavior of the gastrinoma; however, there was a statistically significant correlation between the location of the MEN1 gene mutation and the primary gastrinoma location. Therefore, although the study confirms the importance of MEN1 gene mutations in sporadic gastrinomas, we could not establish a predictive value in the detection of a mutation regarding tumor growth patterns, which is one of the most important correlations that would directly affect clinical management (2, 4, 7, 50, 64, 65). Such predictive factors may arise from further understanding of the molecular steps involved in the pathogenesis of these tumors.
Received June 16, 1999.
Revised August 30, 1999.
Accepted September 1, 1999.
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