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*Lung Cancer
The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 5 1416-1420
Copyright © 1997 by The Endocrine Society

Endocrinological Oncology

Loss of Heterozygosity at 11q13: Analysis of Pituitary Tumors, Lung Carcinoids, Lipomas, and Other Uncommon Tumors in Subjects with Familial Multiple Endocrine Neoplasia Type 1

Qihan Dong1, Larisa V. Debelenko, Settara C. Chandrasekharappa, Michael R. Emmert-Buck, Zhengping Zhuang, Siradanahalli C. Guru, Pachiappan Manickam, Monica Skarulis, Irina A. Lubensky, Lance A. Liotta, Francis S. Collins, Stephen J. Marx and Allen M. Spiegel

Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (Q.D., M.S., S.J.M., A.M.S.); the Laboratory of Pathology, National Cancer Institute (L.V.D., M.R.E., Z.Z., I.A.L., L.A.L.); and the Laboratory of Gene Transfer, National Institute Human Genome Research (S.C.C., S.C.G., P.M., F.S.C.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Allen M. Spiegel, Building 10, Room 9N-222, National Institutes of Health, Bethesda, Maryland 20892. E-mail: allens{at}amb.niddk.nih.gov


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Loss of heterozygosity (LOH) for polymorphic markers flanking the multiple endocrine neoplasia type 1 (MEN-1) gene in parathyroid and pancreatic islet tumors from subjects with familial MEN-1 (FMEN-1) has been well documented and has led to the hypothesis that the MEN-1 gene functions as a tumor suppressor. To assess the role of the MEN-1 gene in the pathogenesis of tumors less commonly associated with MEN-1, we employed a large number of highly informative polymorphic markers closely linked to the MEN-1 gene to study a series of 13 such tumors from subjects with FMEN-1 for LOH at 11q13. We were able to identify LOH for 1 or more 11q13 markers in 2 of 3 pituitary tumors, 3 lung carcinoids, and 1 of 2 lipomas. In every case studied, the allele lost represented the normal allele inherited from the unaffected parent. No LOH was detected in 3 skin angiofibromas, an esophageal leiomyoma, or a renal angiomyolipoma despite the presence of at least 2 informative markers for each tumor. Our results suggest that, like that for parathyroid and pancreatic islet tumors, the pathogenesis of pituitary tumors, lung carcinoids, and lipomas occurring in subjects with FMEN-1 probably involves loss of the normal tumor suppressor function of the MEN-1 gene. Our inability to detect 11q13 LOH in skin angiofibromas, leiomyoma, and angiomyolipoma from subjects with FMEN-1 is consistent with the possibility that these neoplasms arose independently by a mechanism unrelated to the MEN-1 gene, but a role for the MEN-1 gene in the pathogenesis of these tumors cannot be definitively excluded until the gene itself is identified and evaluated for small intragenic deletions or point mutations in such tumors.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MULTIPLE endocrine neoplasia type 1 (MEN-1) is an autosomal, dominantly inherited disorder characterized by the frequent occurrence of parathyroid and pancreatic islet cell tumors and the less frequent occurrence of anterior pituitary tumors (1). Other neoplasms, such as carcinoids and skin lipomas, also occur in kindreds with familial MEN-1 (FMEN-1), but even less frequently than pituitary tumors (1). Recently, we identified multiple facial skin angiofibromas, previously thought to be pathognomonic of tuberous sclerosis (TS), in more than 50% of affected members of several FMEN-1 kindreds (2). In one unique kindred with otherwise typical FMEN-1 features (parathyroid, pancreatic islet, and pituitary tumors), we identified two affected members with additional unusual neoplasms, a renal angiomyolipoma and an esophageal leiomyoma.

The MEN-1 gene has been localized to chromosome 11q13 (3) and is thought to be a tumor suppressor gene based on loss of heterozygosity (LOH) for polymorphic markers on 11q13 in typical MEN-1 tumors of pancreatic islet cells (3, 4, 5, 6, 7, 8) and parathyroids (4, 5, 9, 10, 11, 12). Evidence for loss of the wild-type allele in such MEN-1 neoplasms is consistent with the retinoblastoma two-hit model for tumor suppressor genes (13): a germline inactivating mutation is followed by a somatic mutation, often deleting the entire gene and significant portions of flanking regions up to and including the entire chromosome.

Most of the data on 11q13 LOH derive from studies of islet cell and parathyroid tumors. In the present report, we describe our studies of LOH on 11q13 in tumors from a series of 13 affected members of 12 different FMEN-1 kindreds. These included tumors for which there is either little (pituitary, lung carcinoid, and lipoma) or no (angiofibromas, angiomyolipoma, and leiomyoma) previous 11q13 LOH data in subjects with FMEN-1.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and DNA isolation

Clinical and pathological data from the 13 patients affected with FMEN-1 are shown in Table 1Go. All studies were obtained as part of an institutional review board-approved protocol for which informed consent was obtained. Patients were diagnosed as being affected with FMEN-1 on the basis of having at least 2 typical endocrine neoplasms (except for patient 7) as well as at least 2 first degree relatives with MEN-1-related endocrinopathies. Patients 1–11 are unrelated affected members of different FMEN-1 kindreds. Patients 12 and 13 are an affected mother and son, respectively, from a separate FMEN-1 kindred. All tumor specimens were obtained from surgery performed at the NIH. Both fresh-frozen and paraffin-embedded tissues were used in this study. For a fresh-frozen parathyroid tumor (patient 5), the DNA was isolated using TRI Reagent (Molecular Research Center, Cincinnati, OH), as described previously (14). The rest of the parathyroid and other tumors were formalin-fixed and paraffin-embedded. Insofar as possible, tumor cells were microdissected from surrounding normal tissues under direct light microscopic visualization to avoid contamination with DNA from normal cells (15). The endothelial cells in parathyroid tumors were avoided by staining the tissue with CD34 antibody (QBEND 10, Immunotech Inc., Westrock, MA) (16). Procured cells were then suspended in 30 µL DNA extraction solution containing 50 mmol/L Tris-HCl, 1 mmol/L ethylenediamine tetraacetate, 0.5% Tween-20, and 0.2–0.4 mg/mL proteinase K, pH 8.0, and incubated overnight at 37 C, followed by thermal inactivation of proteinase K (95 C for 5 min). Constitutional DNA was derived from peripheral blood or lymph nodes removed at the surgery. Blood DNA was extracted using Qiagen Blood and Cell DNA kit (Chatsworth, CA). Lymph node DNA was extracted in the same way as other paraffin-embedded samples.


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  		Table 1. Clinical and pathological data from 13 patients with FMEN-1

 
Polymorphic markers

DNA was amplified by PCR with primers flanking 10 polymorphic markers spanning the region containing the MEN-1 gene at 11q13. The loci studied were D11S956 (17), D11S480 (17), D11S599 (18), PYGM (17), D11S449 (18), D11S4933 (see below), D11S4908 (15), D11S2072 (PPP1CA) (19), and INT2 (17). The primers for D11S4933 (5'-GTGGCCGCTACCCCCTTGTC-3' and 5'-GTCCCTGGCAGATGTTTGTATTGG-3') amplify a CA dinucleotide repeat with a product of 172 bp. Analysis of D11S4933 with 122 chromosomes from CEPH parents identified 3 alleles with a polymorphism information content value of 0.34. The order of these markers is based on physical mapping and radiation-reduced somatic cell hybrid mapping. Each locus was considered informative when the constitutional DNA showed 2 different alleles (heterozygosity). LOH in the tumor was determined when 1 of the alleles was decreased by 90% compared to constitutional DNA.

PCR

PCR was conducted in a total volume of 10 µL that contained 50 ng DNA from fresh-frozen tumors or 1–1.5 µL of the DNA extract from paraffin-embedded tissues, primers (0.1 µmol/L each), deoxy (d)-NTPs (200 µmol/L each), 0.5 U Taq polymerase, and 1 x PCR buffer (Perkin-Elmer/Cetus, Norwalk, CT). The sense primer was end labeled using the fmol kit (Promega, Madison, WI) with [{gamma}-33P]dATP (DuPont-New England Nuclear, Boston, MA). The amplification protocol consisted of denaturation at 94 C for 4 min and 35 cycles of annealing for 45 s, extension at 72 C for 1 min, and denaturation at 94 C for 45 s. The annealing temperatures were 56 C (PYGM), 58 C (S956 and INT2), and 60 C (S480, S599, S449, S4933, S4908, and S2072). A sample substituting H2O for template was included as a control. PCR products were resolved on a 6% polyacrylamide gel. The expected size range of the amplified PCR products was confirmed with an M13 sequence that was internally labeled with [{alpha}-33P]dATP.

X chromosome inactivation analysis

The DNA extracted for LOH studies from an esophageal leiomyoma (patient 12) was also used for study of X chromosome inactivation to assess clonality, as previously described (15).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
For each patient at least two markers were informative (Table 2Go). LOH was seen in all three FMEN-1-associated lung carcinoids (patients 1–3; Table 1Go). The loci showing LOH were S480 and S2072 in patient 1, S4933 in patient 2, and S599 and S4933 in patient 3 (Table 2Go). When the LOH pattern was compared with that of available parathyroid tumors in patients 1 and 3, LOH in the parathyroid tumor of patient 1 was detected only at S2072 (Fig. 1Go). In patient 3, the LOH pattern was identical between parathyroid tumor and lung carcinoid. When the constitutional DNA of an affected first degree relative (mother) of patient 3 was analyzed to differentiate the germline-mutated allele shared by all affected family members from the wild-type allele not shared by all affected family members, it was clear that the allele lost in both parathyroid tumor and lung carcinoid was the wild-type allele (Fig. 1Go).


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  		Table 2. LOH data from 13 patients with FMEN-1

 


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  		Figure 1. Autoradiographs of LOH analysis on lung carcinoid of three FMEN-1 patients with polymorphic markers indicated on the top. N, Patient’s constitutional DNA; PT, parathyroid tumor DNA; C, lung carcinoid DNA; M, constitutional DNA of patient 3’s mother with the FMEN-1 phenotype. Arrows are used to indicate the alleles. Note that the mother of patient 3 is homozygous for markers S599 (lower allele) and S4933 (upper allele) indicating that alleles lost in parathyroid and carcinoid (upper allele for S599, lower allele for S4933) represent wild-type alleles.

 
LOH was seen in one of the two FMEN-1-associated lipomas at loci of S4933 and S2072 (patient 4), but in the parathyroid tumor from this patient, LOH was at S4933 only. Although no LOH was observed in the lipoma of patient 5, LOH was detected in this patient’s parathyroid tumor, and the lost allele was the wild-type allele (Fig. 2Go). There was no LOH detected in all three FMEN-1-associated angiofibromas despite at least three markers being polymorphic in each of the three patients (Table 2Go). In two of the three MEN-1-associated pituitary adenomas, LOH was detected at loci of PYGM and S2072 (patient 9; Fig. 3Go) and S599 and S4908 (patient 10; only S4908 is shown in Fig. 3Go). In patient 11, there was no LOH detected in the pituitary tumor (Table 2Go), but clear LOH was found in his parathyroid tumor (data not shown). No LOH was detected in the leiomyoma and angiomyolipoma from patients 12 and 13, respectively, despite at least four markers being informative (in addition to the markers shown in Table 2Go, retention of heterozygosity was also found at S956 in patient 13 and at S449 and INT2 in patients 12 and 13). X Chromosome inactivation analysis showed that the leiomyoma from patient 12 was a monoclonal tumor (data not shown).



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  		Figure 2. LOH analysis on skin lipoma of two FMEN-1 patients with polymorphic markers indicated on the top. N, Patient’s constitutional DNA; PT, parathyroid tumor DNA; L, skin lipoma DNA; F, constitutional DNA from patient 5’s father with the FMEN-1 phenotype. Arrows are used to indicate the alleles. Note that the father is homozygous for the upper allele of S4933, indicating that the lower allele lost in parathyroid tumor is wild-type allele.

 


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  		Figure 3. LOH analysis on pituitary tumors of two FMEN-1 patients with polymorphic markers indicated on the top. Arrows are used to indicate the alleles. N, Patient’s constitutional DNA; T, pituitary tumor DNA.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, employing a large number of highly informative polymorphic markers spanning the MEN-1 gene region on 11q13, we identified LOH in several tumor types that are less frequently observed clinically in subjects with MEN-1 than the more typical parathyroid and pancreatic islet cell tumors. LOH was detected in carcinoid tumors from three FMEN-1 subjects, lipomas from one of two subjects with FMEN-1, and pituitary tumors from two of three FMEN-1 subjects. In contrast, we were unable to detect 11q13 LOH in angiofibromas from three FMEN-1 subjects or in a leiomyoma or angiomyolipoma from a mother and son, respectively, with FMEN-1.

Carcinoids in MEN-1, unlike the sporadic variety, are primarily of the foregut type and occur with an estimated frequency of 7% (1). Skin lipomas, often multiple, have been estimated to occur in 20% of individuals with MEN-1 (1). The incidence of pituitary tumors in MEN-1 subjects varies widely (from 0–100%) in different studies, most likely reflecting the diligence of screening for these relatively occult tumors (1, 20). Some studies suggest, however, that there may be true differences in the occurrence of pituitary tumors such as prolactinomas in certain FMEN I kindreds, perhaps reflecting allelic heterogeneity or other genetic factors (21, 22).

In the few previous studies of 11q13 LOH in carcinoid tumors from subjects with MEN-1, LOH was detected in a single gastric carcinoid (23) and not in another gastric carcinoid (12), lung carcinoid (7), or two thymic carcinoids (24). Our ability to detect LOH in a higher proportion of MEN-1 carcinoid tumors presumably reflects the use of a larger number of informative markers within the MEN-1 gene region. More careful dissection of tumors from stromal tissue before DNA extraction may also have contributed to our greater ability to detect LOH. A recent study of sporadic (non-MEN-1-associated) carcinoid tumors detected LOH at 11q13 in the majority of tumors examined, a result consistent with the possibility that the MEN-1 gene is involved in the pathogenesis of many non-MEN-1-associated carcinoid tumors as well (25). LOH at the D11S146 locus on 11q13 was previously reported in a pharyngeal lipoma from a patient with MEN-1 (26). LOH at 11q13 has been studied in relatively few MEN-1 pituitary tumors because they are rarely treated surgically. LOH on chromosome 11 was not detected in a GH-secreting adenoma (4), but was found in another GH-secreting tumor (27), a GH and PRL-secreting tumor (28), and a prolactinoma (12). Detection of 11q13 LOH in carcinoids, lipomas, and pituitary tumors is consistent with these lesions being integral features of the MEN-1 phenotype and with their having a common tumor suppressor gene pathogenesis involving germline mutation of one MEN-1 gene allele and somatic loss of function mutation of the wild-type allele. This hypothesis is further supported by evidence that the LOH specifically involves the wild-type allele.

The extent of chromosome 11q13 loss detected by LOH varied in different tumors from the same patient, as we (15) and others (12) have previously observed. This is consistent with tumorigenesis reflecting independent somatic events in separate lesions from the same patient. In all cases where it could be studied, however, loss occurs from the chromosome bearing the wild-type allele. Our ability to detect LOH at 11q13 in carcinoid tumors and lipomas from patients with FMEN-1 suggests that in addition to parathyroid and pancreatic islet tumors, these tumors can be used in deletion mapping studies to define the MEN-1 gene interval. The present studies (patients 2 and 4) are consistent with previous observations defining PYGM as the proximal boundary of the MEN-1 gene interval (15).

We recently found a high incidence of multiple skin angiofibromas in affected members of typical FMEN-1 kindreds (2). These lesions have previously been considered pathognomonic of TS. A mother and daughter have been described in whom, in addition to typical TS lesions, tumors typical of MEN-1, including hyperplasia of all four parathyroids in both and pancreatic islet cell and pituitary tumors in the daughter, also occurred (29). In two members of a kindred with otherwise typical FMEN-1, we detected unusual tumors, an esophageal leiomyoma and a renal angiomyolipoma, the latter a lesion characteristic of TS. Although these observations involve a very limited number of subjects and could merely reflect coincidence, they raise the question of some overlap between MEN-1 and TS.

If the angiofibromas, leiomyoma, and angiomyolipoma observed in our FMEN-1 patients arise by the same mechanism as typical MEN-1-associated tumors, one would expect to find evidence for LOH at 11q13. We were unable, however, to detect LOH in these lesions despite testing several informative markers on 11q13. There are several possible explanations. These lesions could arise through a completely independent mechanism not involving the MEN-1 gene on 11q13, and their occurrence in subjects with FMEN-1 could be coincidental. Alternatively, their pathogenesis might involve loss of the MEN-1 gene, but a variety of factors could preclude detection of 11q13 LOH. We have previously found that microdissection of even relatively homogeneous tumors of the parathyroids is helpful in detecting LOH by reducing contamination with normal cell DNA (15). Certain lesions, such as angiofibromas, could represent an admixture of normal and neoplastic cells, and as microdissection is not readily performed in such lesions, contamination with normal cell DNA may preclude detection of LOH. X Chromosome inactivation analysis of the esophageal leiomyoma (patient 12), however, indicated that it is a monoclonal tumor, a result that effectively excludes significant normal cell DNA contamination of this tumor. Another possibility is that in certain tumors, somatic loss of the wild-type allele occurs only by small intragenic deletions or point mutations not detectable by conventional LOH analysis of flanking markers. In a recent study of neurofibromatosis type 1-associated neurofibromas, for example, LOH was demonstrable in some tumors only when intragenic markers were used (30). Indeed, the somatic mutation in one neurofibromatosis type 1-associated neurofibroma was shown to be a 4-bp deletion in the NF1 gene (31).

In TS, LOH for markers at 9q34 and 16p31 has been detected in some, but not all, typical lesions. LOH for loci at 9q34 and 16p13 was demonstrated in 32 of 49 renal angiomyolipomas from TS1 and TS2 patients, but in only 4% of brain lesions and in neither of 2 skin angiofibromas studied (32). Thus, our inability to detect LOH at 11q13 in skin angiofibromas and even in the leiomyoma and angiomyolipoma from our subjects with FMEN-1 does not exclude tumorigenesis involving loss of function of the MEN-1 gene on 11q13. Our data suggest that in subjects with FMEN-1, loss of the MEN-1 gene is important not only in pathogenesis of parathyroid and islet cell tumors, but also in less common tumors, such as pituitary, lipomas, and carcinoids. For even more unusual tumors, such as skin angiofibromas and angiomyolipomas, cloning of the MEN-1 gene will be necessary to define its role in their pathogenesis.


   Acknowledgments
 
The tumors studied in cases 2 and 10 are from patients cared for by the Digestive Diseases Branch, NIDDK, and the Developmental Endocrinology Branch, NICHD, respectively. Angiofibromas were studied in collaboration with Thomas Darling and Maria Turner, Dermatology Branch, NCI. We are grateful to Mary Beth Kester for assistance with the DNA extraction, and to Craig Lotterman for assistance with the LOH analysis.


   Footnotes
 
1 Present address: Department of Medicine, University of Sydney, Sydney, Australia. Back

Received December 30, 1996.

Revised February 4, 1997.

Accepted February 12, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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