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Chromosome 9 Allelic Losses and Microsatellite Alterations in Human Bladder Tumors'

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Chromosome 9 Allelic Losses and Microsatellite Alterations in Human Bladder Tumors' [CANCER RESEARCH54, 2848-2851, June 1, 19941 Advances in Brief Chromosome 9 Allelic Losses and Microsatellite Alterations in Human Bladder Tumors' Irene Orlow, Pilar Lianes, Louis Lacombe, Guido Dalbagni, Victor E. Reuter, and Carlos Cordon-Cardo2 Department of Pathology [I. 0., P. L., V. E. R., C. C-C.] and Urology Service [L L., G. D.], Memorial Sloan-Kettering Cancer Center, New York New York 10021 Abstract the inactivation of a tumor suppressor gene (12—14).The inherited basis of these neoplasia appears to be due to an inactivation of DNA Chromosome 9 allelic losses have been reported as a frequent and early damage recognition/repair pathways. However, even in hereditary eventoccurringinbladdercancer.It hasbeenpostulatedthata candidate nonpolyposis colorectal cancers, multiple hits are necessary for the tumor suppressor gene may reside on this chromosome, alterations of which may lead to the development of a subset of superficial bladder transformed cells to acquire the malignant phenotype. The objectives tumors.Morerecently,theinvolvementoftwodifferentregionsharboring of this study were to better define the deleted regions of the chromo suppressor loci, one on each of both chromosome 9 arms, has been some 9 in bladder tumors, to delineate the possible role of the loss of proposed. We undertook the present study with the objectives of better heterozygosity (LOH3) in 9p and 9q arms, and to evaluate the exis defining the deleted regions of chromosome 9 in bladder tumors, as well tence and frequency of microsatellite alterations in urothelial neopla as evaluatingthe frequencyof microsateffitealterationsaffectingcertain sias. We examined genetic alterations occurring on chromosome 9 loci on this chromosome in urothelial neoplasia. Seventy-threeprimary using a well-characterized cohort of patients affected with superficial bladdertumorswereanalyzedusinga setofhighlypolymorphicmarkers, and muscle invasive bladder tumors. We centered our study on the andresultswerecorrelatedwithpathologicalparametersassociatedwith analyses of RFLP, VNTR, and microsatellite markers assigned to both poor Clinical outcome. We observed that, overall, 77% of the tumors arms of chromosome 9. studied showed either loss of heterozygosity for one or more chromosome 9 markers and/or microsteffite abnormalities at chromosome9 loci. De tailed analyses showed that two regions, one on 9p at the interferon Materials and Methods cluster, and the other on 9q associated with the q34.1—2bands, had the Tissues. Seventy-three primary bladder tumors were obtained from rad highest frequencies of allelic losses. Furthermore, T@lesions appeared to ical cystectomy samples (n = 64) and transurethral resection specimens present mainly with 9q abnormalities, while T1 tumors displayed a mix (n 9). Tissues were embedded in tissue TEK OCI' cryopreservative tare of aberrant9p and 9q genotypes.Theseobservationsindicatethat (Miles, Inc., Elkhart, IN) and stored frozen at —70°C.Normaltissue was loss of heterozygosity of 9p may be associated with the development of obtained from the same bladder in an area free of tumor or, in 5 cases, from superficial tumors with a more aggressive biological behavior or, alter other normal tissue (i.e., peripheral blood or prostate). Five-p@msections natively, they may be related to early disease progression. In addition, were used for hematoxylin and eosin staining. The sections were examined microsatellite alterations were documented in over 40% of amplified by a pathologist (V. E. R.) to confirm the presence of tumor, evaluation of cases. Taken together, these data suggest that two different tumor sup tissue morphology, and pathology staging. The 73 cases selected showed at pressor gene loci on chromosome 9 are involved as tumorigenic events in least 50% of tumor cells on the sample and were included in the study. All bladder cancer and that chromosome 9 microsatellite alterations are specimens were graded by WHO classification and staged according to the frequent events occurring in urothelial neoplasia. ThM pathological staging system. Introduction DNAIsolationandSouthernBlotting.Twentyto30consecutive30-g.irn thick sections were cut from each tissue block. The DNA was isolated, Cytogenetic and molecular genetic analyses of bladder cancer have digested, and transferred to nylon membrane as described previously (2, 3). identified abnormalities in a number of chromosomes which appear to The DNA was fixed to the membrane using a UV linker (UV Stratalink 1800; be involved in the development and progression of these tumors Stratagene, La Jolla, CA). (1—4).Loss of heterozygosity of chromosome 9 is a frequent mutation Probes. The following probes with chromosome map positions, loci, and restriction enzymes were obtained from the ATCC (Rockville, MD) and were occurring in both superficial and muscle invasive lesions. Allelic used for RFLP analysis in this study: p08782 (9q34—qter; Assgl; HindIII); losses in 9p (5—7)and 9q (3, 8, 9) have been reported, estimating the pabl K2 (9q34; v-nb!; TaqI); pMCOA12 (9q; D9S28; MspI); p04580 (9q34.3; area of deletions between 9p22 and 9q34.1. The involvement of two D9SJO; TaqI) VNTR; pEFD126.3 (9q34; D9S7; TaqI) VN'FR; DR6 different regions containing suppressor loci in bladder tumors has (9p21 —ter;D9S3; Hind!!!) (provided by Jane Fountain, Massachusetts Insti been recently proposed (10). In addition, somatic instability at mic tate of Technology-Center for Cancer Research, Cambridge, MA); pINIF A3 rosatellite repeats, detected in low stage bladder tumors, has been (9p22; interferon a-2; MspI) (provided by Dr.P.M. Pitha Rove, The John reported as an early alteration associated with tumorigenic events in Hopkins University-Oncology Center, Baltimore, MD). such neoplasias (11). The microsatellite instability observed in the Primers. The following primers were used for the present study: IFNA hereditary nonpolyposis colorectal cancers (Lynch syndrome) sug cluster (5'-TGCGCGTFAAGTTAA11XIG1T-3' and 5'-AGTGGGGGlTf C- gested that these tumors may arise through a mechanism different than CACCITAC-3', provided by Dr. Manuel Diaz, Loyola University School of Medicine, Chicago, IL); D9S54 (ATCC); ABL 1 (9q34.1) (ATCC); and Ass (9q34.1) (ATCC). Received 2/28/94; accepted 4/21/94. Thecostsof publicationofthisarticleweredefrayedinpartby thepaymentofpage Hybridization, PCR Amplification, and Autoradiography. The probes charges. This article must therefore be hereby marked advertisement in accordance with were labeled to a high specific activity with [a-32P]dCTP by the random 18 U.S.C. Section 1734 solely to indicate this fact. oligolabeling technique using the Primed DNA Labeling kit (Boehringer I This work was in part supported by NCI Grant CA-47538 (to C. C. C.). P. L is the Mannheim, Indianapolis, IN), and membranes were pretreated and hybridized recipient of a Postdoctoral Fellowship from the Spanish Government (P155 93/5052) and an NCI/EORTC Award. L L is the recipient of a Fellowship Award from the Kidney Foundation of Canada. 3 The abbreviations used are: LOH, loss of heterozygosity; RFLP, restriction fragment 2 To whom requests for reprints should be addressed, at Department of Pathology, length polymorphism; VNTR, variable number of tandem repeats; ATCC, American Type Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Culture Collection; PCR, polymerase chain reaction. 2848 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1994 American Association for Cancer Research. CHROMOSOME9MUI@ATIONSINBLADDERCANCER parameters,@a,FNAaABLeASS―D9S10'@&ageT@Table 1 AssociationbetweenLOH, microsatellite aiterations, andpathological Ta @3 GO 1/2 0/0 1/3 1/1 1/2 1/2 1/3 T1 Wll 0/1 7/8 0/4 2111 0/3 2/6 3/12 3/lI 2W45Total11/613/1626/405/3913/655/2013/4113/6525/61o@1T2@W2 11/45Gil 3/141/1 17/29Q'l 5/341/2 9/491/2 3/140/1 lW320/2 9/491/2 2 1/9 Gfl 5/5 @5 3/10 1/4 1/6 5/Il 3/9 17/45Total11/603/1526f405/3812/634/1713/4113/6322/60N31/6 9f45WI 3/132/4 19/311/3 4/303/7 6/46WI 3/123/5 9/3046 4/46216 and MSt*usNo 3/10TotallG'532/1422/344/351N@,M'1W43 Wl01/10 1/417/27 5/72/26 2/99/45 2/145/15 tWl48/26 5/109/45 2/1318/43 1/595/2913/361 1/5821/53 @ a of allelic losses/number of informative cases. b Number of alterations/number of amplified cases. as described previously (15). The dinuclcotide repeat polymorphism was presented LOH. There was no statistical significant correlation be anal@ by PCR amplification according to the Gene Amp kit protocol tween allelic losses at the IFNA and D9S3 loci and pathological (Perkin-Ehner Cetus, Norwalk, Cl) with the following modifications. The parameters. Only one case showed LOH for all the markers tested on final reaction volume was reduced to 20 p1; 2 g@Ci[a-32P]dCTPwere added 9p, indicating loss of the short arm without areas of retention. per reaction; and annealing temperatures ranged from 55 to 60°C,depending Chromosome 9q Allelic Losses. The 9q34.l—34.3region was en the set of primers used. This was followed by polyaciylamide gel electro informed in terms of LOH at ASS, ABL, D9SJO, and/or D957 loci. phoresis on 8% acrylamide gels. For samples in which the normal tissue showed heterozygosity for a given probe or set of primers, the presence of the Seventy-one of 73 cases evaluated for this region were informative for alleles in the normal and the tumor tissues was assessed by densitometry using at least one of the probesused, obtainingan overall LOHrateof 45%. an Ultrascan XL Laser Densitoumter (Phannmia LKB Biotechnology, Pisca Allelic losses were distributed as follows: 2 of 2 Tis, 3 of 4 Ta, 6 of tawny, NJ). The relative decrease or the absence of the allele was established, 12 T1, and 21 of 53 T2@lesions. Data from each of the individual loci as reportedpreviously,comparingthenondeletedallelesin thenonnaland may be briefly summarized as follows. Thirteen of 65 informative tumor tissue counterpart (2, 3). cases showed LOH at the D9S7 locus. There was an association Statistical Methods.
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