BONA G.

CADARIO F

DANESINO, CESARE

DELLAVECCHIA C

FIOCCA R

GUALA A

HAINTINK O

LUINETTI O

MINELLI, ANTONELLA

OLIVIERI, CARLA

English

Archivio Istituzionale della Ricerca - Università degli Studi di Pavia

 0165-4608/99/$–see front matterPII S0165-4608(99)00003-5Cancer Genet Cytogenet 113:96–99 (1999)   Elsevier Science Inc., 1999. All rights reserved.655 Avenue of the Americas, New York, NY 10010 Early Onset of Gastric Carcinoma and Constitutional Deletion of 18p Claudia Dellavecchia, Andrea Guala, Carla Olivieri, Oscar Haintink, Francesco Cadario, Ombretta Luinetti, Roberto Fiocca, Antonella Minelli, Cesare Danesino, and Gianni Bona ABSTRACT: We report on the association of a gastric carcinoma and a constitutional deletion of theshort arm of chromosome 18 in a 14-year-old patient. The phenotype of the patient, including micro-cephaly, ptosis, micrognathia, tetralogy of Fallot, and mental retardation, fits well with previouslyreported cases of del(18p); she also showed a positive serology against  Helicobacter pylori . The com-parison of the alleles of polymorphic loci located on the short arm of chromosome 18 between thepatient and her parents showed a maternal origin of the abnormal chromosome. Loss of heterozygosity(LOH) for loci located in the long arm of chromosome 18 is a frequent event in gastric carcinomas; itwas observed in the tumoral mass of our patient and again, the alleles lost were of maternal origin. Wepostulate that the constitutional chromosomal abnormality may have favored the loss of the abnormalchromosome in some cells and that the loss of the deleted chromosome 18 (demonstrated by LOH forthis chromosome in the tumoral mass) has been an early step in the pathogenesis of the gastric carci-noma of our patient with  Helicobacter pylori  infection acting as a cofactor. © Elsevier Science Inc.,1999. All rights reserved. INTRODUCTION Deletion of the short arm of chromosome 18 with break-points at p11,del(18p) is a common cytogenetic abnormal-ity, and at least 136 cases have been described to date. Itsphenotype is well recognizable, and extensive data areavailable on the different malformations and associateddysmorphism [1].To the best of our knowledge, no case of neoplastic dis-ease has been reported in association with constitutionaldel(18p), while the same deletion has been observed as anacquired anomaly in breast cancer, ependymomas, andacute myeloid leukemia [2, 3]. Loss of heterozygosity(LOH) for the short arm of chromosome 18 has been re-ported by Hahn et al. [4] in pancreatic adenocarcinomas,while LOH for loci located in the long arm of chromo-some 18 has been reported in at least 60% of gastric carci-nomas [5].Gastric adenocarcinoma is rare under the age of 20years and only about 20 cases have been described [6]; wereport on the occurrence of gastric adenocarcinoma in a14-year-old patient carrying a constitutional deletion ofthe short arm of chromosome 18. CASE REPORT A female first child of healthy unrelated parents, was bornat term after an uneventful pregnancy, with a birth weightof 1900 g ( , 3rd centile) and a length of 48 cm, ( , 10th cen-tile). In the family history, we recorded a gastric cancer inthe paternal grandfather diagnosed at 64 years, and a sar-coma localized in the lower leg in the maternal grand-mother (at 74 years), but we have been unable to obtainmore detailed information or pathology reports. Physicalexamination at birth revealed microcephaly, ptosis, down-turned corner of the mouth, micrognathia, and widelyspaced nipples. Abdominal ultrasonography demonstrateda situs viscerum inversus.A heart murmur of 4/6 was also recorded; cyanosis waspresent when crying. Further cardiologic investigations From Biologia Generale e Genetica Medica (C. De., C. O., A.M., C. Da.) and the Dipartimento di Patologia Umana ed Eredi-taria, Sezione di Anatomia Patologica (O. L., R. F.), Universitàdi Pavia, Pavia, Italy; Divisione Pediatrica, Ospedale Civile diVigevano (A. G.), Vigevano, Italy; and Clinica Pediatrica diNovara, Università del Piemonte Orientale “A. Avogadro” (O. H.,F. C., G. B.), Novara, Italy.Address reprint requests to: Prof. Cesare Danesino, C.P. 217,27100 Pavia, Italy.Received April 16, 1998; accepted January 5, 1999. Gastric Carcinoma in a Patient with del(18p)  97 disclosed a tetralogy of Fallot and patent ductus arterio-sus. The patient underwent cardiac surgery at the age of2.5 years, and subsequent development was uneventful,without any increase in number of infectious disorders.Physical growth has always been at the 3rd centile; de-velopmental milestones were delayed, and mild mentalretardation was soon evident. At the age of 14, she com-plained of abdominal pain and jaundice became apparent.Physical examination confirmed the dysmorphic fea-tures present at birth, with the addition of large, an-teverted prominent ears (Fig. 1), scoliosis, bilateral clino-dactyly of the 5th finger, and numerous dental caries.Weight (29 kg) and height (136 cm) were below the 3rdcentile. An abdominal rock-hard, unpainful, epigastricmass was palpable.Routine laboratory analyses were normal, except for di-rect bilirubin (5.6 mg/dL n.v.  , 1), GOT (370 UI, n.v.  , 40),GPT (459 UI n.v.  , 40), and  g GT (203 n.v.  , 10). Antibodiesagainst  Helicobacter pylori  were 75 U/mL (n.v.  , 2 U/mL).At surgery, a large mass arising in the gastric antrum,extending toward and incorporating the pancreas, biliaryducts, and surrounding tissues was observed. Metastaticdissemination to perigastric nodes and omentum was alsoevident. Partial resection of the mass with gastrojejunos-tomy and colecistojejunostomy was performed. The pa-tient responded poorly to chemotherapy, and died 4months later.  METHODSHistopathology Specimens were fixed in 10% buffered formal saline andparaffin; immunohistochemical studies were performedon representative sections of tumor by means of an immu-noperoxidase technique. The following panel of gastric,intestinal, and pancreatic differentiation markers was ap-plied: BD5 reacting with epithelial cells of normal andneoplastic human intestine, but not with normal gastricmucosa; DU-PAN-2 marking pancreatic ductal epitheliumand related tumors; M1 and Cathepsin E reacting with co-lumnar mucus cells of surface gastric epithelium; Pepsino-gen II (or C) (PGII) expressed by pyloric and oxyntic gastricgland cells [7]. Cytogenetic Chromosome preparations were obtained with routinetechniques from stimulated lymphocytes, and stained forQFQ and GTG bands. Molecular Biology Autoptic material (tumor mass, kidney, normal nodes)from the patient and peripheral blood from the parentswere used for DNA extraction with routine techniques.Genotyping of short tandem repeat polymorphisms (Re-search Genetics) was performed on the patient and herparents by use of standard procedures. Polymerase chainreaction (PCR) amplifications were performed in 8  m l reac-tion mixtures containing 20 ng genomic DNA; 330 nM ofeach primer; 200  m M of dCTP, dGTP, and dTTP; 25  m M ofdATP; 1  m Ci ( a 35 S) dATP; 50 mM KCI; 10 mM TRIS pH 9;1.5 mM MgCI 2 ; 0.1% Triton X-100; 0.01% gelatine, and0.2 U of  Taq  Polymerase. The PCR conditions consisted ofan initial denaturation step followed by 30 cycles of 94 8  Cfor 40 seconds, 57 8  C for 40 seconds, 72 8  C for 40 seconds,and a final extension at 72 8  C for 5 minutes, using a PTC-100 thermal cycler (MJ Research). Four microliters of eachPCR product were resolved by electrophoresis on denatur-ing (7 M urea) 6% polyacrylamide gels for 3–5 hours at 50W. Gels were fixed in 10% methanol, 10% acetic acid,and dried and exposed to x-ray film at room temperature.Informative results were obtained at the following loci:D18S63 and D18S1370 located on the short arm of chro-mosome 18, and D18S363 and GATA06 located in 18q12–21. Three other loci, D1S549 (located on 1q35-qter),D5S820 (5q), and D17S796 (17p13) where chosen to studyregions frequently involved in LOH in gastric cancer [8]. RESULTSHistopathology Routine examination of hematoxylin & eosin (H & E)stained sections allowed a diagnosis of poorly differenti-ated intestinal-type gastric carcinoma according to Lauren[9] which infiltrated the gastric wall transmurally (Fig. 2).M1, PGII, BD5, and DP2 antibodies gave consistentlynegative results, while Cathepsin E antiserum markedabout 80% of cancer cells (data not shown). Cytogenetic Chromosome analysis on peripheral blood lymphocytesfrom the patient demonstrated a deletion of the wholeshort arm of chromosome 18 in all 30 mitoses examined(Fig. 3d) with a karyotype 46,XX,del(18)p11). The parents’karyotypes were normal.Figure 1 The patient at 14 years of age. 98  C. Dellavecchia et al. Molecular Biology The comparison of STR polymorphisms between the childand her parents at loci D18S63 and D18S1370, both lo-cated in short arm of chromosome 18, showed the pres-ence of the paternal allele and the absence of the maternalone, both in normal tissues (kidney and normal nodes)and in the tumor mass of the patient, thus demonstratingthat the deletion occurred on the maternal chromosome(Figs. 3a, 3b)We also analyzed two other loci, D18S363 andGATA06, located in 18q12 z q21 (a region known to be fre-quently involved in LOH in gastric cancer) comparing tu-mor mass and normal tissues, and an asymmetric patternof the alleles was observed in the tumor mass, but not inthe normal tissues of the proposita or in the samples fromher parents (Fig. 3c). This finding is interpreted as evi-dence of LOH for the loci tested, limited to the tumor mass.No evidence of LOH was observed at D1S549, D5S820and D17S796, but microsatellite instability was observedat D5S820 in the tumor mass (data not shown). DISCUSSION The phenotype of the patient fits well with previously re-ported cases of del(18p); in our patient we recorded 14 ofthe 34 clinical signs which occur in more than 10% of the136 cases included in Schinzel’s Human Cytogenetic Data-base [1].Histopathology (Fig. 2) could be easily interpreted asadenocarcinoma, and the finding of 80% positive cellswith Cathepsin E antibodies, coupled with a negative stainfor DP2, is consistent with a gastric origin of the tumor [10].The parental origin of the deleted chromosome hasbeen studied in only two cases of del(18p) in which a pa-ternal origin was demonstrated [11]; in our patient the ori-gin of the anomaly was demonstrated to be in the maternalchromosome by molecular analyses (Figs. 3a, 3b), however,the number of observations is too limited to propose a ran-dom parental origin and to exclude a preferential paternalorigin of the anomaly as observed for terminal deletions [11].Gastric cancer is rarely observed in patients below 20years; a recent correlation with  Helicobacter pylori  (HP)infection has been established [12] and confirmed also forearly-onset gastric cancer by Craanen et al. [13]. In our pa-tient, the presence of the infection from HP was demon-strated on the basis of an increased titer of antibodies.The simultaneous presence of a chromosomal anomalyand a neoplastic disorder in the same patient may, ofcourse, be a random event. However, as both the type ofchromosomal anomaly and the type of tumor are quiterare, the alternative hypothesis of a causal relationshipshould also be taken into account.Loss of heterozygosity on the long arm of chromosome18 is frequent in gastric carcinomas and is considered anearly event with involvement of the  DCC  gene [5]; in ourcase, LOH was indeed observed in the tumor mass for lociof the long arm of chromosome 18 (Fig. 3c), and the allelelost was from the maternal chromosome.The loss of a structurally abnormal chromosome, even-tually followed by duplication of the normal chromosome,has been described in somatic cells [14], and will result inLOH. As in our case, the constitutionally abnormal chro-mosome is of maternal origin, and the alleles lost in tu-moral mass are again of maternal origin; we postulate thatthe presence of a constitutional structural anomaly (thedeleted maternal chromosome 18) has favored the loss ofthe abnormal chromosome in some gastric cell, and mayhave been an early step in the pathogenesis of the gastriccancer, with HP infection acting as a cofactor.Figure 2 Histopathological aspects of gastric neoplasia: cancer cells arranged in irregular, poorIy-differentiatedgland structures, and in small clusters (H & E 36.3). Gastric Carcinoma in a Patient with del(18p)  99 In addition, the short arm of chromosome 18 may har-bor gene(s) relevant in the control of cell proliferation, assuggested by the involvement of this region in breast andpancreatic cancers, ependymomas, and in myeloid leuke-mia [2–4] and confirmed by the recent identification of arepressor of  c-myc  on 18p [15]. It is thus worthwhile to ac-quire more data on the incidence of cancer in patientswith deletions of the short arm of chromosome 18, to ver-ify if they are in fact at increased risk to developing malig-nancies. We thank Prof. Marco Fraccaro for critical reading of the manu-script. The financial support of Telethon to project C.18 (DNAand Cell Bank) is also gratefully acknowledged. REFERENCES 1. Schinzel A (1994): Human Cytogenetics Database. OxfordUniversity Press, Oxford.2. Mitelman F (1991): Catalogue of Chromosome Aberration inCancer. John Wiley & Sons, Inc., New York.3. Mitelman F, Mertens F, Johansson B (1997): A breakpointmap of recurrent chromosomal rearrangements in humanneoplasia. Nature Genet 15:417–474.4. Hahn SA, Seymour AB, Hoque AT, Schutte M, da Costa LT,Redston MS, Caldas C, Weinstein CL, Fisher A, Yeo CJ (1995):Allelotype of pancreatic adenocarcinoma using xenograftenrichment. Cancer Res 55:4670–4675.5. Uchino S, Tsuda H, Noguki M, Yokota J, Terada M, Saito T,Kobayashi M, Sugimura T, Hirohashi S (1992): Frequent lossof heterozygosity at the DCC locus in gastric cancer. CancerRes 52:3099–3102.6. McGill TW, Downey EC, Westbrook J, Wade D, de Ia Garza J(1993): Gastric carcinoma in children. J Pediatr Surg28:1620–1621.7. Fiocca R, Villani L, Tenti P, Solcia F, Cornaggia M, FrigerioM, Capella C (1987): Characterization of four main cell typesin gastric cancer: foveolar, mucopeptic, intestinal, columnarand goblet cells. An histopathologic, histochemical andultrastructural study of “early” and advanced tumors. PatholRes Pract 182:308–325.8. Sano T, Tsujino T, Yoshida K, Nakayama H, Haruma K, Ito H,Nakamura Y, Kajiama G, Tahara F (1991): Frequent loss ofheterozygosity on chromosomes 1q, 5q, and 17p in humangastric carcinomas. Cancer Res 51:2926–2931.9. Lauren P (1965): The two histological main types of gastriccarcinoma: diffuse and so-called intestinal-type carcinoma.Acta Pathol Microbiol Scand 64:31–49.10. Fiocca R, Villani L, Tenti P, Cornaggia M, Finzi G, Riva C,Capella C, Bara J, Samloff IM, Solcia E (1990): The foveolarcell component of gastric cancer. Hum Pathol 21:260–270.11. Cody JD, Pierce JF, Brkanac Z, Plaetke R, Ghidoni PD, KayeCJ, Leach RJ (1997): Preferential loss of the paternal alleles inthe 18q 2  syndrome. Am J Med Genet 69:280–286.12. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogel-man JH, Orentreich N, Sibley RK (1991): Helicobacter pyloriinfection and the risk of gastric carcinoma. N Engl J Med325:1127–1131.13. Craanen ME, Blok P, Dekker W, Tytgat GNJ (1994): Helico-bacter pylori and early gastric cancer. Gut 35:1372–1374.14. Petersen MB, Bartsch O, Adelsberger PA, Mikkelsen M,Schwinger E, Antonarakis S (1992): Uniparental isodisomydue to duplication of chromosome 21 occurring in somaticcells monosomic for chromosome 21. Genomics 13:269–274.15. Sobek-Klocke I, Disque-Kochem C, Ronsiek M, Klocke R,Jockusch H, Breuning A, Ponstingl H, Rojas K, Overhauser J,Eichenlaub-Ritter U (1997): The human gene ZFP161 on18p11.21-pter encodes a putative c-myc repressor and ishomologous to murine Zfp161 (chr 17) and Zfp161-rs1 (Xchr).Genomics 43:156–164.Figure 3 (a, b) The two central lanes refer to normal (left) andtumoral (right) tissue from the patient; for both loci studied, onlythe paternal alleles are present. (c) LOH at locus D18S363 limitedto the tumoral mass (right central lane) of the patient; the alleleshowing reduced intensity is the maternal one. (d) Partial karyo-type of the patient with normal (left) and deleted (right) chromo-some 18.

Early onset of gastric carcinoma and constitutional deletion of 18p.

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Early onset of gastric carcinoma and constitutional deletion of 18p.

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