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Allelic Deletions on Chromosome 11Q13 in Multiple Endocrine Neoplasia Type 1- Associated and Sporadic Gastrinomas and Pancreatic Endocrine Tumors

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Allelic Deletions on Chromosome 11Q13 in Multiple Endocrine Neoplasia Type 1- Associated and Sporadic Gastrinomas and Pancreatic Endocrine Tumors ICANCERRESEARCH57.2238—2243.June1. 19971 Allelic Deletions on Chromosome 11q13 in Multiple Endocrine Neoplasia Type 1- associated and Sporadic Gastrinomas and Pancreatic Endocrine Tumors Larisa V. Debelenko, Zhengping Zhuang, Michael R. Emmert-Buck, Settara C. Chandrasekharappa, Pachiappan Manickam, Siradanahalli C. Guru, Stephen J. Marx, Monica C. Skarulis, Allen M. Spiegel, Francis S. Collins, Robert T. Jensen, Lance A. Liotta, and Irma A. Lubensky' Laboratory of Pathology, National Cancer institute IL V. D., 1 1, M. R. E-B., L A. L, i. A. LI, National Centerfor Human Genome Research [S. C. C., P. M., S. C. G., F. S. C.], and Branches of Metabolic Diseases (S. J. M., A. M. S.], Diabetes [M. C. S.), and Digestive Diseases [R. T. ii, National Institute of Diabetes and Digestive and Kidney Diseases, N/H. Bethesda, Maryland 20892 ABSTRACT MEN] is a tumor suppressor gene (9—11).MEN1 patients are hypoth esized to inherit a mutation in one copy of the gene, and susceptible Endocrine tumors (ETs) of pancreas and duodenum occur sporadically cells in the target organs are transformed through the inactivation of and as a part of multiple endocrine neoplasia type 1 (MEN1). The MENJ the wild-type copy of the gene, potentially occurring via point muta tumor suppressor gene has been localized to chromosome 11q13 by link age analysis but has not yet isolated. Previous alleic deletion studies in tions, deletions, or gene methylation (6, 7, 10, 11). Sporadic parathy enteropancreatic ETs suggested MENJ gene involvement in tumorigenesis roid and enteropancreatic ETs have also been described to exhibit of familial pancreatic ETs (nongastrinomas) and sporadic gastrinomas. somatic LOH of chromosome 11 loci, including the MEN] region, However, only a few MEN1-associated duodenal gastrinomas and spo suggesting the role of the MEN] gene in the pathogenesis of such radic pancreatic nongastrinomas have been investigated. We used tissue tumors(12—19). microdissection to analyze 95 archival pancreatic and duodenal ETs and Allelic deletions on chromosome 11q13 have been reported in metastases from 50 patients for loss of heterozygosity (LOH) on 11q13 63—100%of MEN1-associated parathyroid tumors and in 25—35%of with 10 polymorphic markers spanning the area of the putative MENI sporadic parathyroid tumors (1 1—13,20). However, previous studies gene. Chromosome 11q13 LOH was detected In 23 of 27 (85%) MEN!- on 11q13 LOH in enteropancreatic ETs have been limited to a small associated pancreatic ETs (nongastrinomas), 14 of 34 (41%) MEN!-asso number of cases in each series (6, 13—19,21—24).Four MEN I- ciated gastrinomas, 3 of 16 (19%) sporadic insulinomas, and 8 of 18(44%) sporadic gastrinomas. Analysis of LOH on !!q!3 showed different dele associated gastrinomas have been reported in the literature to date, and don patterns in ETs from different MEN! patients and in multiple tumors three tumors demonstrated retention of heterozygosity on 11q13 (17, from Individual MEN! patients. The present results suggest that the 19, 24), whereas one gastrmnoma showed a small deletion at marker MENJ gene plays a role in all four tumor types The lower rate of 1!q!3 PYGM (13). Thus, the role of the MEN] gene in enteropancreatic LOH in MEN!-associated and sporadic gastrinomas and sporadic instill endocrine tumorigenesis remains controversial. nomas as compared to MEN! nongastrinomas may reflect alternative We used tissue microdissection to analyze 95 archival duodenal and genetic pathways for the development of these tumors or mechanisms of pancreatic ETs and metastases for LOH on 11q13. The goal was to the MENJ gene inactivation that do not involve large deletions. The investigate the frequency of allelic loss at the MEN] gene locus in isolation of the MENJ gene is necessary to further define its role in tumongenesis of MEN1-associated and sporadic enteropancreatic pathogenesis of pancreatic and duodenal ETs. ETs. In addition, X-chromosome inactivation analysis of six synchro nous primary duodenal microgastrinomas in one FMEN1 female INTRODUCTION patient was performed to investigate clonality of MEN 1-associated gastrinomas, and the results were correlated with the LOH data. ETs2 of pancreas and duodenum may occur sporadically (I) or in association with inherited syndromes such as MEN1 (2). Sporadic duodenal and pancreatic ETs are usually solitary, whereas MEN 1- PATIENTSAND METHODS associated neoplasms are characteristically multiple in the involved organ (3, 4). Insulinomas and nonfunctional ETs (nongastrmnomas) Patient Population. Fifty patientswho underwentexploratorylaparotomy occur exclusively in the pancreas, whereas the most common site for for pancreatic and duodenal ETs at the NIH were included in the study. both sporadic and familial gastrinomas is the duodenum (1—5).Insu Ninety-five formalin-fixed, paraffin-embedded primary pancreatic and duode nal ETs and metastases were obtained from the file of the Laboratory of linomas usually follow a benign clinical course, whereas gastrinomas Pathology, National Cancer Institute, NIH. Clinical and family histories were have high malignant potential, with regional lymph node or liver reviewed in each case. Sixteen patients (9 males and 7 females; mean age, 45; metastases developing in up to 90% of the cases. age range, 23—74years)were diagnosed with MENI, and 34 patients (18 males The putative MENJ tumor suppressor gene has been linked to and 16 females; mean age, 42; age range, 15—67years)had sporadic ET. chromosome 1 1q13 (6, 7). FMENI is an autosomal dominant syn Fourteen of 16 MEN! patients were categorized as having FMEN1 because in drome in which the affected individuals develop multiple tumors in addition to two typical endocrine neoplasms, they had at least two first-degree the parathyroid glands (90—97%), pancreas (30—82%), duodenum relatives with MEN1-related endocrinopathies. The diagnosis of gastrinoma (25—60%),and anterior pituitary (35—60%;Refs. 2, 3, and 8). Loss of (Zollinger-Ellison syndrome), insulinoma (hyperinsulinemic hypoglycemia), the wild-type allele at the MEN] locus in tumors arising in affected or nonfunctional tumor was made on clinical grounds and confirmed by individuals is commonly observed, supporting the conclusion that pathological examination of the tumor. Seven MEN1 patients had pancreatic nongastrinomas, I 1 MEN1 patients had gastrinomas, and 16 and 18 patients had sporadic insulinomas and gastrinomas, respectively (Tables 1—4).Among Received 1I/l 1/96; accepted 4/4/97. The costs of publication of this article were defrayed in part by the payment of page the 16 MEN! patients, 10 had gastrinomas only, 4 had pancreatic nongastri charges. This article must therefore be hereby marked advertisement in accordance with nomas only, and 2 (patients 3 and 4) had both gastrinomas and nongastrinomas 18 U.S.C. Section 1734 solely to indicate this fact. available for the study. Nine MEN1 patients had multiple tumors evaluated I To whom requests for reprints should be addressed, at Laboratory of Pathology, (Tables 1 and 2). National Cancer Institute, NIH, Building 10, Room 2N212. 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 496-0549; Fax: (301)480-9488. Microdissection. Tumor and normal cells were selected from routine 2 The abbreviations used are: ET, endocrine tumor; MENI, multiple endocrine nan 5-@tm-thickH&E-stained histological slides and microdissected under direct plasia type I ; FMENI. familial MENI ; LOH, loss of heterozygosity. light microscope visualization as described previously (Fig. 1; Refs. 20 and 2238 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1997 American Association for Cancer Research. GENETIC ALTERATIONS IN ENDOCRINE TUMORS MEN!pancreaticendocrinetumors(nongastrinomas)3a4Table 1LOHon!1q13in27 InNFb@4f@NFNFNFNFNFNFNFNFNFNFNFNFNFNFNFNF123456123478591011121314151617181920216In12 InInIn13 NFNFInc14 @4}@1516 D11S1256― .. I I DllS956 I I • 0 I 0 I I II DllS48O I I I 0 I I I 0 D11S599 I I I 0 I 0 I I PYGM I I 0 I I I I I I I I I I I I I I I I — D11S4908 0 PPP1CA I I I 0 I 0 I I I I I I I I I • I I — D11S534 INT-2 I I • 0 I I • I — a Patientno. b Tumor type and tumor no. NF, nonfunctional; In, insulinoma; I, LOH; 0, retention of heterozygosity; —,not informative; blank, not done. C Liver metastasis. d Chromosome I 1q13 markers are listed in order from centromeric (top) to telomeric (bottom). 25). Normal duodenal epithelium, exocrine pancreas, or lymph node tissue was (D11S457,PYGM, and PPPJCA).Labeled amplifiedDNA was mixed with an used as a control. equal volumeof fonnamide loadingdye (95% formamide,20 mxiEDTA, 0.05% DNA Extraction. Procuredcells were resuspendedin 30 @lofsolution bromphenol blue, and 0.05% xylene cyanol). The samples were denatured for 5 containing Tris-HCI (pH 8.0), 0.1 MEDTA (pH 8.0), 1% Tween 20, and 0.1 mm at 95°Candresolved on a 6% polyacrylamidegel. Autoradiographywas mg/mI proteinase K and incubated overnight at 37°C.Following thermal performed with Kodak X-Omat film (Eastman Kodak, Rochester, NY). inactivation ofproteinase K (95°Cfor5 mm), 1—1.5piofthe DNA extract was The case was considered to be informative for a polymorphic marker on used for PCR analysis. Ilql3 if normal tissue DNA showed two alleles (heterozygosity). Complete or PCR Markers. Ten polymorphicDNA markerswere used in this study: near complete (90% decreased intensity) absence of an allele in tumor samples D11S1256 (26), D11S956, D11S480 (27), D11S599 (28), D11S457 (29), was interpreted as LOH (Fig. 2). Each experiment was repeated two or three PYGM (CA)(GA) (27), D1]S4908 (20), PPP]CA (30), D]1S534 (31), and times, and the data were reproducible. INT2 (27). Labeling of PCR product was achieved by incorporating Combined tumor and family study in a FMEN1 patient 8 with multiple [a-32P]dCTP. PCR was conducted in a total volume of 10 .d that contained gastrmnomaswas performed with the informative marker D11S956 using nor 1—1.5,.tlof DNA extract, 200 @MeachdNTP, 0.1—0.5 @Meachprimer, 0.1 mal and tumor DNA from the patient and her brother (Fig.
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