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Loss of Heterozygosity Associated with Uniparental Disomy in Breast Carcinoma Sabita K

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Loss of Heterozygosity Associated with Uniparental Disomy in Breast Carcinoma Sabita K Loss of Heterozygosity Associated with Uniparental Disomy in Breast Carcinoma Sabita K. Murthy, Ph.D., Lisa M. DiFrancesco, M.D., R. Travis Ogilvie, M.D., Douglas J. Demetrick, Ph.D., M.D. Departments of Pathology and Laboratory Medicine (SKM, LMD, RTO, DJD), Oncology (LMD, RTO, DJD), and Biochemistry and Molecular Biology (DJD), The University of Calgary; and Calgary Laboratory Services (LMD, RTO, DJD), Calgary, Alberta, Canada presence of both copies of the tumor suppressor Loss of heterozygosity is commonly assumed to be gene in the cases with loss of heterozygosity of span- due to deletion of the appropriate genomic region ning markers and internal markers for that tumor in one chromosome within a neoplastic cell but may suppressor gene could be explained by somatic re- be due to other mechanisms such as mitotic non- combination resulting in uniparental disomy, but disjunction or somatic recombination leading to not mitotic nondisjunction or deletion. As the uniparental heterodisomy. We chose to study the mechanism for physical deletion of a chromosome genomic regions surrounding the p53 and RB1 tu- may be different from those mediating somatic re- mor suppressor genes in breast carcinoma to eval- combination, study of this phenomenon may iden- uate the different mechanisms that could mediate tify different pathways of genomic instability that loss of heterozygosity. A microsatellite analysis of may be of diagnostic or treatment significance in polymorphic markers in 50 breast cancer samples breast or other cancers, particularly in those treat- showed loss of heterozygosity for at least 1 of the 10 ments based upon DNA-altering agents. markers analyzed in 50% of the tumors studied, and an overall 8.47% of the informative loci showed loss KEY WORDS: Breast cancer, FISH, Loss of heterozy- of heterozygosity. All of the cases with loss of het- gosity, Microsatellite, Somatic recombination. erozygosity were further analyzed for gene copy Mod Pathol 2002;15(12):1241–1250 number of the tumor suppressor genes RB1 and p53 by fluorescence in situ hybridization of either tu- The cumulative activation of oncogenes and inac- mor touch preparations or microdissected tumor tivation of tumor suppressor genes causes disrup- nuclei with specific genomic probes. Surprisingly, tion of critical events in cell division and differen- all samples showed the presence of both copies of tiation, leading to neoplastic clones (1, 2). The tumor suppressor genes, including 4/50 cases show- paradigm of ordered alterations in the tumor sup- ing loss of heterozygosity of tumor suppressor gene- pressor gene is first a mutation of one allele and spanning markers. One of the 4 cases showed loss of then the loss of the other allele, thus, allelic losses heterozygosity of markers spanning a distance of 6 are regarded as hallmarks of chromosomal regions cM over the RB1 gene, with normal copy numbers harboring tumor suppressor genes (1, 3–6). Reduc- of the gene. Three other cases showed loss of het- tion to homozygosity of the tumor suppressor gene erozygosity of markers within the tumor suppressor can be detected as loss of heterozygosity of infor- gene (RBI or p53) and at least one other spanning mative polymorphic markers in the region of the marker. No cases showed a simultaneous reduction tumor suppressor gene. In conventional models of to homozygosity of markers both near the tumor tumor suppressor gene inactivation, an initial mu- suppressor gene and distal loci. We suggest that the tational event sets the stage for cancer, however, it is the second event of mutation that is thought to Copyright © 2002 by The United States and Canadian Academy of initiate the cancer (3, 4). Pathology, Inc. By comparing the constitutional and tumor ge- VOL. 15, NO. 12, P. 1241, 2002 Printed in the U.S.A. Date of acceptance: July 20, 2002. notypes, it was possible to determine whether loss The Canadian Institutes of Health Research and Calgary Laboratory Ser- vices provided salary support to DJD. This work was supported by an of heterozygosity occurred for the whole chromo- Alberta Cancer Board Pilot Project grant. some, or a part of the chromosome. As gene dele- Address reprint requests to: Douglas J. Demetrick, Ph.D., M.D., Room 302, HMRB, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2L 1X9; e-mail: tion is usually accepted to be the second hit, loss of [email protected]; fax: 403-283-8727. heterozygosity at chromosomal sites of known tu- DOI: 10.1097/01.MP.0000032535.62750.D1 mor suppressor genes is considered indicative of 1241 mutations in the remaining copy of the gene and ered by comparing normal and neoplastic alleles of loss of tumor suppressor function of the gene prod- polymorphic markers surrounding or within a gene, uct. The loss-of-heterozygosity event, however, with a quantitative evaluation of neoplastic cell may theoretically arise by several mechanisms, in- gene copy number (Fig. 1). Although deletion of a cluding deletion, mitotic nondisjunction, or so- gene may lead to a loss of heterozygosity pattern matic recombination resulting in uniparental dis- (Fig. 1: Options 2b, 2c, 3d), the presence of a normal omy (Fig. 1; 7–12). The net result of any of these gene copy number in the context of loss of het- mechanisms may be loss of the normal allele of a erozygosity is evidence for a different mechanism of tumor suppressor gene, with subsequent selection allelic loss (Fig. 1: Options 2d, 3a, 3b, 3c, 3d). Sur- of clones bearing only mutant alleles. Using the prisingly few of these evaluations have been per- typical example of a tumor suppressor gene, ge- formed. One study of breast cancer by fluorescence netic analysis of retinoblastomas showed often that in situ hybridization (FISH) with an RB1 genomic somatic recombination rather than deletion events probe identified a discordance between FISH- resulted in the phenotypic expression of the mu- observed RB1 copy number and that expected from tated tumor suppressor gene (10, 13). loss of heterozygosity analysis (17). These investi- Uniparental disomy has been occasionally docu- gators suggested that somatic recombination or du- mented in pediatric cancers associated with inher- plication of chromosome 13 containing mutant RB1 ited syndromes such as Beckwith-Wiedemann syn- could explain their findings. The authors also com- drome (14–16). In these pediatric tumors, mented, however, that their evaluation of p53 did uniparental disomy was confirmed using DNA from not yield similar findings, and these observations both parents. It is more difficult, however, to dem- were subsequently published (18). Another study of onstrate uniparental disomy by conventional strat- breast cancer examined loci within chromosome 3p egies in adult cancer types, such as breast cancer, (19). This investigation found that the dominant where parental DNA samples are usually not avail- alteration within 3p in breast cancer was a physical able. Fortunately, many of these cases will have deletion, demonstrated by concordance between normal tissue within the specimen that can be dis- loss of heterozygosity, as assessed by restriction sected free of tumor and can serve as a source of fragment length polymorphisms, and FISH copy normal patient DNA. From such specimens, indi- number. The other cases, however, showed discor- rect evidence for uniparental disomy may be gath- dance between FISH or loss of heterozygosity da- FIGURE 1. Mechanisms leading to loss of heterozygosity due to uniparental disomy. Strategies for possible recombination events leading to loss of heterozygosity and their detectable sequelae. Informative microsatellite alleles are A and B and are in the region of the tumor suppressor gene. White and grey markers distinguish specific alleles of the tumor suppressor gene. Solid black signals indicate the FISH interphase appearance with a specific tumor suppressor gene probe that cannot distinguish alleles. The asterisk (*) is a distal FISH chromosomal marker (or a centromeric probe). Note that several mechanisms can give rise to an loss of heterozygosity, but only 2b, 2c, and 3di and 3dii are associated with a copy number deletion. Cells with any of these events may be selected during clonal outgrowth. 1242 Modern Pathology ta—either with normal copy number in the pres- laser capture microdissection (Pix Cell II, Arcturus ence of loss of heterozygosity or allelic gain. The Engineering Inc.). Cases with Ͼ80% tumor cellular- authors suggest that different mechanisms of tumor ity were used without laser capture microdissection suppressor gene inactivation may be specific for for tumor specimens, and their corresponding nor- certain chromosomal locations. Another study also mal tissue margin blocks were used for normal identified discordance between FISH and loss of tissue specimens. For the cases in which laser cap- heterozygosity in specimens of Wilms’ tumor ture microdissection was performed, approximately (20)—a pediatric tumor that has been shown to 2000–5000 cells were collected on the laser capture illustrate uniparental disomy for the WT1 locus. In microdissection cap. Normal cells were collected this study, 4/18 cases showed loss of heterozygosity from the same slide on another cap or from a sep- with a normal copy number at DS16S422 by FISH. A arate normal tissue section. DNA was extracted recent, extensive study of colon carcinoma cell lines from cap samples by incubating the cells in 50 ␮Lof passaged in nude mice identified a variety of struc- laser capture microdissection DNA digestion buffer tural alterations
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