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Allelic Loss from Chromosome 11 in Parathyroid Tumors

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Allelic Loss from Chromosome 11 in Parathyroid Tumors [CANCER RESEARCH 52, 6804-6809, December 15. 1992] Allelic Loss from Chromosome 11 in Parathyroid Tumors Eitan Friedman, ~ Luiz De Marco, 2 Pablo V. Gejman, Jeffrey A. Norton, Allen E. Bale, Gerald D. Aurbach, 3 Allen M. Spiegel, and Stephen J. Marx Molecular Pathophysiology [E. F., .4. M. S.] and Metabolic Diseases [L.D. M., G. D. A., S. J. M.] Branches, National Institute of Diabetes, Digestive, and Kidney Diseases; the Clinical Neurogenetics Branch [P. V. G.], National Institute of Mental Health; and Surgery Branch [J. A. N.], National Cancer Institute, Bethesda, Maryland 20892, and the Department of Human Genetics [.4. E. B.], Yale University School of Medicine, New Haven, Connecticut 06510 ABSTRACT tion mapping") (17, 18). Since the observed allelic losses in parathyroid tumors in the context of MENI have been shown to Parathyroid tumors may occur in a sporadic fashion or, more rarely, be for the most part chromosome 11 specific, and are often as part of a familial syndrome (such as familial multiple endocrine subchromosomal (8, 10), they may be helpful in the fine map- neoplasia type I). The MENI gene has been mapped by linkage analysis to chromosome 11 at band q11-q13, and presumably acts as a tumor ping of the MENI gene. suppressor gene. In the present study, which is an extension of our Sporadic parathyroid adenomas also display allelic losses previous studies, we examined 41 parathyroid tumors from patients with spanning the MENI gene locus as well as other loci on chro- familial multiple endocrine neoplasia type I and 61 sporadic parathyroid mosome 11 (8, 10, 19). Thus, the MENI gene or other tumor tumors with markers on chromosome 11, to assess the extent of allelic suppressor genes on chromosome 11 (20) may be involved in loss in those tumors. Twenty-four of the MENl-associated tumors the development of sporadic parathyroid tumors. We now show (58%) and 16 of the sporadic parathyroid tumors (26%) displayed allelic the extent of allelic losses from chromosome 11 in our series of loss from chromosome 11. The region of overlap of the allelic losses in 41 parathyroid tumors from 31 patients with MENI and from the MENI-associated tumors enables us to place the MENI gene be- tween PGA centromerically and INT2 telomerically, a region spanning 61 parathyroid tumors from 61 patients with sporadic primary about 7.5 cM. Taken together with locus ordering by linkage analysis, hyperparathyroidism. this clearly localizes the MENI gene telomeric to the PGA locus. Our inability to detect allelic loss on chromosome 11 in some parathyroid MATERIALS AND METHODS tumors suggests the existence of other genes involved in the develop- ment and/or progression of this subgroup of presumably monocional Patients and Specimens. Parathyroid glands surgically excised to tumors; or that localized events involving the 11q tumor suppressor gene correct primary hyperparathyroidism were obtained: 41 parathyroids have occurred in some parathyroid tumors whose detection is beyond the from 31 patients with FMENI. In 8 patients, 2 glands were separately sensitivity of our analysis; or that at least some of the specimens ana- analyzed: in one case, 3 glands were studied, and in one case, 2 regions lyzed were in fact primarily hyperplastic parathyroid tissue. from one large gland were analyzed individually. Thirteen tumors were from cryopreserved tissue and the rest from fresh surgical specimens. INTRODUCTION Sixty-one sporadic parathyroid adenomas were similarly analyzed. The criteria for classifying a parathyroid tumor as sporadic or as part of FMENI 4 is an autosomal dominant disorder characterized by MENI were reported previously (8). The parathyroid tumors reported hyperfunction of the pancreatic islets, the anterior pituitary, in this communication include the subset of parathyroid tumors previ- and multiple parathyroid glands (1, 2). Primary hyperpara- ously reported by us (8). In the previous report, 16 tumors from 14 thyroidism is the most common clinically apparent manifesta- MENI patients and 34 tumors from patients with sporadic hyperpara- tion of MENI, affecting virtually all gene carriers by age 50 (3, thyroidism were tested with 8 chromosome 11 probes (8). In this report, 4). The MENI-susceptibility locus has been mapped by genetic additional tumors (25 in the MENI category and 27 in the sporadic linkage in families to chromosome 11 at bands qll-13: to category) were tested. Variable numbers of 9 additional chromosome 11 restriction fragment length polymorphism markers PYGM (5) polymorphic markers were used to evaluate allelic losses in the entire and INT2 (6). Further linkage analysis localized the gene to group, and we also applied some of the previously used probes to the within a few cM of the PYGM marker (7). Larsson and col- newly reported tumors. Gland volume was assessed from the gland dimensions recorded at surgery and the formula for an ellipsoid (21). leagues (5) showed that 2 malignant insulinomas had lost chro- Estimated volume was converted to mass by assuming density equal to mosome 11 alleles inherited from the unaffected parent. Sub- that of water (1 g/cm3). sequently, parathyroid tumors from patients with MENI have Statistical Analysis. Data on gland size were analyzed after logarith- been shown frequently to display allelic loss with markers from mic (base 10) transformation. Group means were compared by the chromosome 11 (8-11). These allelic losses in parathyroids Scheffe test (22). were for the most part confined to chromosome 11 (8, 10). DNA Extraction, Southern Blotting, and Probe Hybridization. High The observation of allelic loss in tumors was first outlined in molecular weight DNA was isolated from tumor specimens and peri- familial retinoblastoma (12), and helped confirm the 2-hit hy- pheral blood leukocytes according to standard protocols (8). In tumor pothesis of tumorigenesis (13). Genes that can underlie this tissue processed immediately after surgery, adjacent, clearly distinct, mechanism have been called tumor suppressor genes (14-16). non-tumor tissue (e.g., fat, fibrous tissue) was manually dissected out. By comparing normal and tumor tissue from the same individ- No attempt was made to quantify the tumor cell fractions in histological slides from tumor tissues. DNA samples (5-10 #g) were digested to ual with multiple probes, a region of allelic loss overlapping in completion with restriction endonucleases (Boehringer Mannheim), different tumors can sometimes be delineated (so-called "dele- electrophoresed on 0.8% agarose gels, transferred to nylon filters (GeneScreen Plus; New England Nuclear), and hybridized to radiola- Received 8/14/92; accepted 9/30/92. beled probes as described (8). The chromosome 11 probes used were: The costs of publicationof this article were defrayed in part by the payment of PTH (pPTHm122), INS (pHINS310), CAT (pINT800), H-ras page charges. This article must thereforebe hereby marked advertisement in accord- ance with 18 U.S.C. Section 1734 solely to indicate this fact. (pTBB2), DI 1S147 (HBI18P1), D11S29 (L7), DI 1S144 (MCT128.1), To whom requests for reprints should be addressed, at Department of Clinical D11S288 (p3C7), DllS149 (pTHH26), PGA (phpepl4-21), PYGM Genetics, Karolinska Hospital, P.O. Box 60500, S-104 01, Stockholm, Sweden. (pMCMP1), DllS146 (pHBI59), INT2 (SS6), and DllS84 (p2-7- 2 Supported by CNPq and FAPEMIG, Brazil. 3 Deceased. I D6). In addition, dinucleotide markers (also called microsatellite 4 The abbreviation used is: FMENI, familial multiple endocrine neoplasia probes) D11S35, CD3D, and DllS420 were used (see below). The type I. nomenclature, chromosomal localization, and linear ordering of the 6804 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1992 American Association for Cancer Research. ALLELIC LOSS FROM CHROMOSOME I1 IN I'ARATHYROID TUMORS probes is based on a prior analysis (23, 24) and is shown in Fig. 1C. The RESULTS criteria for scoring a signal as allelic loss were described previously (8). PCR for Microsatellite Markers. Two hundred ng each from paired Allelic Loss in Parathyroid Tumors in MENI. Constitu- tumor and peripheral blood DNA samples were used as a template. The tional and tumor samples were compared at 17 loci on chro- PCR was carried out in a final volume of 15 ul in a microtiter plate, mosome 11 for 41 tumors from 31 patients. In 31 tumors, more using the Techne MW2 thermocycler (Cambridge, England). The re- than 10 probes per tumor were tested; in 5 tumors between 5 action included 1.5-ul 10x buffer (50 mM KC1; 10 mMTris HCI, pH 8.3, 0.01% gelatin, and 1.5 mM MgCl2), 0.25 UM spermidine, 8 pmol of each and 9 markers were tested, and in 5 tumors between 1 and 4 oligonucleotide primer, 200 uM each of dATP, dTTP, dGTP, 2.5 UM of markers were tested. All patients were heterozygous (i.e., infor- dCTP, 0.3/~Ci of [a-32p]dCTP (3000 Ci/mmol), and 0.5 unit of Taq mative) with at least one probe. Seventeen tumors (42%) from DNA polymerase (Perkin Elmer, Norwalk, CT). To quantitate the ef- 14 patients did not display allelic loss with any of the chromo- ficiency of the amplification and the correct amount of DNA in each some 11 markers examined (tumors 6, 8B, llA, llB, 13, 14, reaction, a set of primers from a different chromosome (D 19S75 from 16, 16A, 17, 19A-C, 22, 25B, 26B, 27B, and 30). Twenty-four chromosome 19) that amplifies a region with a different size range was of 41 tumors (58%) showed allelic loss with at least one marker also included in the same reaction mixture (multiplexing). Samples were overlaid with 20 ul light mineral oil to prevent evaporation. After from chromosome 11 (Figs. 1 and 2). The extent of these losses an initial denaturation step at 92~ for 5 min, 20 cycles consisting of is presented in ideograms (Fig.
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