Loss of Heterozygosity of the Putative Prostate Cancer Susceptibility Gene HPC2/ ELAC2 Is Uncommon in Sporadic and Familial Prostate Cancer1

[CANCER RESEARCH 61, 8651–8653, December 15, 2001] Advances in Brief

Yu-Qun Wu, Hong Chen, Mark A. Rubin, Kirk J. Wojno, and Kathleen A. Cooney2 Departments of Internal Medicine [Y-Q. W., H. C., K. A. C.], Urology [M. A. R., K. A. C.], and Pathology [M. A. R.], University of Michigan Medical School, Ann Arbor, Michigan 48109-0946, and St. John Hospital and Medical Center, Detroit, Michigan 48236 [K. J. W.]

Abstract setting of LOH, the remaining allele is presumed to be nonfunctional, either because of a preexisting inherited mutation or because of a sec- The recognition that prostate cancer clusters within families has led to the ondary sporadic mutation. If the newly identified hereditary prostate search for prostate cancer susceptibility genes. Recently, the HPC2/ELAC2 cancer gene HPC2/ELAC2 functions as a tumor suppressor gene in gene on chromosome 17p has been identified as a potential prostate cancer predisposition gene using both family based as well as case-control studies. prostate cancer, we hypothesized that deletion of 17p may be observed in Many cancer susceptibility genes act as tumor suppressor genes in which some familial prostate cancer cases. Furthermore, tumor suppressor genes inactivation of one allele in the tumor can be detected via loss of heterozy- important in the pathogenesis of hereditary cancers are sometimes ob- gosity (LOH). To determine whether the HPC2/ELAC2 gene demonstrates served to be deleted in sporadic cancers (16). Therefore, we set out to significant LOH in sporadic and familial prostate cancers, paired tumor and determine whether allelic loss of HPC2/ELAC2 could be detected in a set normal DNA samples were isolated using microdissection techniques from 44 of both familial and sporadic prostate cancer cases. radical prostatectomy specimens. Cases were analyzed using a panel of markers in the following order: TP53–D17S969–D17S947–(HPC2/ELAC2)– Materials and Methods D17S799–D17S936. LOH was observed in < 10% of cases using the four markers that map to the HPC2/ELAC2 region. However, allelic loss was Patient Material. Forty-four cases of prostate cancer with sufficient areas of observed at the TP53 gene in 25% of informative cases. Taken together, normal and tumor tissue for DNA isolation were identified from the radical inactivation of the HPC2/ELAC2 gene via LOH is a relatively uncommon prostatectomy database at the University of Michigan Health System. For this event in prostate cancer. Future studies will determine whether 17p LOH study, cases were identified from prostatectomies performed between 1995 and occurs in the subset of patients with an inherited mutation in HPC2/ELAC2. 1996. FH was obtained from medical records. Normal and tumor DNA samples were isolated from paraffin-embedded tissue blocks using microdissection tech- Introduction niques. Ten 6-␮m sections were prepared from both normal and tumor tissues for each case. One slide stained with H&E was examined by pathologists (M. A. R. There is substantial epidemiological evidence that prostate cancer has and/or K. J. W.); regions containing at least 70% normal or tumor nuclei were a familial predisposition syndrome, i.e., hereditary prostate cancer outlined and used as a template for subsequent microdissection. Normal and tumor 3, 4 (OMIM 176807; Refs. 1, 2). At least five putative prostate cancer tissues were excised using a single-edged razor blade and digested with proteinase susceptibility loci have been identified using linkage analyses, includ- K overnight. ing HPC1 at 1q24–25 (OMIM 601518; Ref. 3), PCAP at 1q42.2–43 LOH Analysis. DNA was amplified by PCR using a panel of polymorphic (OMIM 602759; Ref. 4), CAPB at 1p36 (OMIM 603688; Ref. 5), markers mapping to the HPC2/ELAC2 region: TP53, D17S969, D17S947, HPCX at Xq27–28 (OMIM 300147; Ref. 6), and HPC20 on chromo- D17S799, and D17S936 (8). Primer sequences were obtained from Human 5 some 20 (7). However, none of these genes has yet been isolated and Genome Database and purchased from Research Genetics (Huntsville, AL). PCR characterized. Recently, another potential prostate cancer suscepti- was performed by use of an MJ Research (Watertown, MA) 96-well programma- ble thermocycler as described previously (14). Briefly, one primer from each bility gene, HPC2/ELAC2 (OMIM 605367), has been identified using primer pair was labeled at its 5Ј end with 32PO by use of [␥32P]-dATP (ICN family based linkage studies (8). A truncating mutation was identified 4 Products, Costa Mesa, CA) and T4 polynucleotide kinase (New England Biolabs, in a large Utah prostate cancer family in which three of five male Inc., Beverly, MA). All of the reaction mixtures contained 2 ␮lof10ϫ PCR carriers were affected with the disease. Several other missense muta- buffer [final concentration 10 mM Tris-HCl (pH 9.0 at 25°C), 50 mM KCl and ௡ ␮ ␮ tions were also identified, and the role of these HPC2/ELAC2 alter- 0.1% Triton X-100], 2 l25mM MgCl2,2 l2mM standard deoxynucleotide ations in prostate carcinogenesis is presently unclear (8–13). triphosphate, 50–100 ng each primer, 1 unit Taq polymerase (Promega Corp., LOH studies have been used to identify chromosomal regions contain- Madison, WI), 7.5–15 ng 32P-labeled primer, 100 ng case DNA, and water in a ing putative tumor suppressor genes and to gain insight into the molecular total volume of 20 ␮l. Annealing temperatures were empirically optimized for genetics of prostate cancer (14, 15). Genetic deletions can involve loss of each primer set. PCR products were analyzed using 8%-polyacrylamide DNA a single allele (LOH) or homozygous deletion of both alleles. In the sequencing gels, with end-labeled MspI-digested pBR322 fragments as size markers. Each PCR reaction was scored visually for LOH (defined as an ϳ50% loss of one tumor allele) by three observers (Y. Q. W., H. C., K. A. C.). Received 7/17/01; accepted 10/30/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with Results and Discussion 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by USPHS Grants P50-CA69568 (Specialized Programs of Research The average age at prostate cancer diagnosis for the 44 men with Excellence) and R01-CA79596. ϩ Ϫ 2 To whom requests for reprints should be addressed, at 7310 CCGC, 1500 East prostate cancer in this report was 60 / 7.8 years (range 43–80 years). Medical Center Drive, Ann Arbor, MI 48109-0946. Phone: (734) 764-2248; Fax: Fourteen of the participants (32%) were of AA descent. Although FH (734) 615-2719; E-mail: [email protected]. information was unavailable in 12 cases, 10 of the men (23%) reported 3 The abbreviations used are: OMIM, Online Mendelian Inheritance in Man; LOH, loss of heterozygosity; FH, family history; AA, African-American; C, Caucasian. that at least one first-degree family member was affected with prostate 4 Online Mendelian Inheritance in Man. McKusick-Nathans Institute for Genetic cancer. In 41 of the 44 cases (93%), tumors were graded as either Gleason Medicine, Johns Hopkins, University (Baltimore, MD) and National Center for Biotech- nology Information, National Library of Medicine (Bethesda, MD), 2000, Internet address: http://www.ncbi.nlm.nih.gov/omim/. 5 Internet address: http://www.gdb.org. 8651

Table 1 Markers selected for HPC2/ELAC2 LOH analysis on a subset of families that either: (a) had four or more cases that shared The map order and distances were obtained from the National Center for Biotechnol- Ͼ 7 a haplotype and had individual family LOD scores 1.0; or (b) had six ogy Information web page. or more cases that shared a haplotype, irrespective of LOD score, the Maximum Location on chr. 17 researchers identified a likely candidate. This gene is one of two human Markers Variation type heterozygosity gene sequence genes that were found to be homologues of Escherichia coli elaC, and it TP53 Variable number of tandem repeats 69% 9400–9416 Kbp D17S969 Tetranucleotide repeat —a 15060 Kbp was named HPC2/ELAC2 (8). HPC2/ELAC2 is a member of an unchar- D17S947 Dinucleotide repeat 89% 16186 Kbp acterized gene family predicted to have metal-dependent hydrolase ac- D17S799 Dinucleotide repeat 69% 16551 Kbp tivity; however, the specific function of the HPC2/ELAC2 gene is pres- D17S936 Dinucleotide repeat 60% 16813 Kbp ently unknown. To determine whether HPC2/ELAC2 allelic loss occurred in sporadic prostate cancer, we selected a series of 44 cases from the 6 or 7 (17). The remaining three cases were scored as Gleason 8 or 9 University of Michigan Health Systems Radical Prostatectomy Data- tumors. base. On the basis of previous studies, we predicted that ϳ25% of Four polymorphic markers mapping to HPC2/ELAC2 region were these men would have a FH of prostate cancer (2). However, the selected for this analysis (Table 1). An intragenic TP53 polymorphism likelihood that any of the men with a FH of prostate cancer actually (18) was used as positive control for tumor DNA samples. The carried a germ-line HPC2/ELAC2 gene mutation is low, because these expected heterozygosity of all of the markers was Ͼ 60%. The order mutations have been shown to be relatively rare even in multiplex of the markers is: TP53–D17S969–D17S947–(HPC2/ELAC2)– prostate cancer families. For example, HPC2/ELAC2 mutation screen- D17S799–D17S936. The closest marker for HPC2/ELAC2 gene is ing has been performed on Ͼ 450 affected family members from four D17S947, which is 89-Kb telomeric to this gene. large studies of hereditary prostate cancer to date, and only two LOH was not observed at three of the four markers in the HPC2/ truncating mutations have been identified (8, 10, 12, 13). Therefore, ELAC2 region in any of the 44 prostate cancer cases (D17S947, our study results are consistent with the hypothesis that inactivating D17S799,orD17S936; Fig. 1). However, 2 of 34 (6%) informative somatic mutations occur only in those patients harboring deleterious cases showed LOH at D17S969; neither of these men reported a FH germ-line HPC2/ELAC2 mutations. Larger studies of hereditary pros- of prostate cancer. Both of these tumors were noninformative at the tate cancer specimens will be needed to address this possibility. next closest marker, D17S947; therefore, allelic loss at the HPC2/ Six of our prostate cancer cases demonstrated allelic loss at TP53, and ELAC2 gene cannot be entirely excluded in these two cases. two tumors revealed LOH at a marker between TP53 and HPC2/ELAC2, Because a low frequency of LOH in the region of HPC2/ELAC2 namely D17S969. This observation raises the possibility that 17p allelic was observed in the 44 prostate cancer cases, LOH at TP53 was loss results in the loss of genes in addition to TP53. The mitogen- measured to ensure the accuracy of microdissection in eliminating contamination of tumor specimens by tissue containing normal DNA (e.g., lymphocytes, stroma). The TP53 tumor suppressor gene is frequently inactivated in human cancer, and it is located ϳ7 million bp telomeric to HPC2/ELAC2 on chromosome 17p. LOH at TP53 was detected in 6 of 24 (25%) of informative cases (Table 2). This result is consistent with data from our laboratory as well as others (19).6 Of note, three of four informative cases with a positive FH of prostate cancer demonstrated LOH at TP53. Prostate cancer is the most commonly diagnosed nonskin cancer in the United States. It is estimated that one in five men will be diagnosed with prostate cancer at some point in their lives (20), and 15–20% of these men will die from the disease. Therefore, characterizing the molecular basis for this common cancer is imperative to develop new methods for treating and perhaps preventing this lethal cancer. In the past decade, investigators have struggled to localize genes responsible for this complex disease. Because FH is an important risk factor for prostate cancer, many groups have focused on family based studies to characterize disease susceptibility alleles. Segregation analysis of familial prostate cancer predicts the existence of at least one or more autosomal dominant susceptibility loci. It is estimated that rare high-risk alleles at such loci account for ϳ9% of all patients with prostate cancer and for as many as half of the patients in whom diagnosis is made at an early age (1). HPC2/ELAC2 was identified by taking advantage of the Utah Family Resource, a set of extended pedigrees that has proven invaluable for mapping and cloning cancer genes in the past (21, 22). HPC2/ELAC2 was originally mapped in a set of 33 prostate cancer families with a maximum two-point LOD score of 4.5 at marker D17S1289 (␪ ϭ 0.07). However, when the data set was expanded to 127 families, the LOD score in the same region was no longer significant. This example illustrates the Fig. 1. Results of LOH analysis using chromosome 17p markers. The cases used in the genetic heterogeneity of hereditary prostate cancer. However, by focusing analysis are listed on the left with the markers across the top. FH is coded as follows: ϩ, FH positive; Ϫ, FH negative; 0, FH unknown; f, tumors with LOH at a specific marker; Ⅺ, cases in which both alleles were retained in the tumor; p, noninformative cases. 6 C. Bettis, K. A. Cooney, unpublished observations. Repeated PCR assays of tumors 9 and 40 with marker D17S947 were inconclusive (t). 8652

Table 2 Summary of HPC2/ELAC2 LOH Analysis The chromosome 17p markers are illustrated in order from left to right. The HPC2/ELAC2 gene is located between markers D17S947 and D17S799. Informative cases were the number of cases in which both alleles were visible in normal tissue (heterozygotes). The percentage of cases exhibiting LOH was defined as the number of LOH cases/number of informative cases. HPC2/ELAC2 TP53 D17S969 D17S947 2 D17S799 D17S936 Informative LOH Informative LOH Informative LOH Informative LOH Informative LOH cases cases cases cases cases cases cases cases cases cases All cases (n ϭ 44) 24 (55%) 6 (25%) 34 (77%) 2 (6%) 34 (81%) 0 36 (82%) 0 20 (46%) 0 FH ϩ (n ϭ 10) 4 (40%) 3 (75%) 6 (60%) 0 9 (90%) 0 7 (70%) 0 3 (30%) 0 FH Ϫ (n ϭ 22) 14 (64%) 2 (14%) 18 (82%) 2 (11%) 17 (77%) 0 21 (95%) 0 12 (55%) 0 activated protein kinase kinase 4 gene, or MKK4, at 17p11.2 has been Peterson, K. T., Reid, J. E., Richards, S., Schroeder, M., Smith, R., Snyder, S. 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Yu-Qun Wu, Hong Chen, Mark A. Rubin, et al.

Cancer Res 2001;61:8651-8653.

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