The recognition that prostate cancer clusters within families has led to the search for prostate cancer susceptibility genes. Recently, the HPC2/ELAC2 gene on chromosome 17p has been identified as a potential prostate cancer predisposition gene using both family based as well as case-control studies. Many cancer susceptibility genes act as tumor suppressor genes in which inactivation of one allele in the tumor can be detected via loss of heterozygosity (LOH). To determine whether the HPC2/ELAC2 gene demonstrates significant LOH in sporadic and familial prostate cancers, paired tumor and normal DNA samples were isolated using microdissection techniques from 44 radical prostatectomy specimens. Cases were analyzed using a panel of markers in the following order: TP53–D17S969–D17S947–(HPC2/ELAC2)–D17S799–D17S936. LOH was observed in < 10% of cases using the four markers that map to the HPC2/ELAC2 region. However, allelic loss was observed at the TP53 gene in 25% of informative cases. Taken together, inactivation of the HPC2/ELAC2 gene via LOH is a relatively uncommon event in prostate cancer. Future studies will determine whether 17p LOH occurs in the subset of patients with an inherited mutation in HPC2/ELAC2.

There is substantial epidemiological evidence that prostate cancer has a familial predisposition syndrome, i.e., hereditary prostate cancer (OMIM3, 4 176807; Refs. 1, 2). At least five putative prostate cancer susceptibility loci have been identified using linkage analyses, including HPC1 at 1q24–25 (OMIM 601518; Ref. 3), PCAP at 1q42.2–43 (OMIM 602759; Ref. 4), CAPB at 1p36 (OMIM 603688; Ref. 5), HPCX at Xq27–28 (OMIM 300147; Ref. 6), and HPC20 on chromosome 20 (7). However, none of these genes has yet been isolated and characterized. Recently, another potential prostate cancer susceptibility gene, HPC2/ELAC2 (OMIM 605367), has been identified using family based linkage studies (8). A truncating mutation was identified in a large Utah prostate cancer family in which three of five male carriers were affected with the disease. Several other missense mutations were also identified, and the role of these HPC2/ELAC2 alterations in prostate carcinogenesis is presently unclear (8, 9, 10, 11, 12, 13).

LOH studies have been used to identify chromosomal regions containing putative tumor suppressor genes and to gain insight into the molecular genetics of prostate cancer (14, 15). Genetic deletions can involve loss of a single allele (LOH) or homozygous deletion of both alleles. In the setting of LOH, the remaining allele is presumed to be nonfunctional, either because of a preexisting inherited mutation or because of a secondary sporadic mutation. If the newly identified hereditary prostate cancer gene HPC2/ELAC2 functions as a tumor suppressor gene in prostate cancer, we hypothesized that deletion of 17p may be observed in some familial prostate cancer cases. Furthermore, tumor suppressor genes important in the pathogenesis of hereditary cancers are sometimes observed to be deleted in sporadic cancers (16). Therefore, we set out to determine whether allelic loss of HPC2/ELAC2 could be detected in a set of both familial and sporadic prostate cancer cases.

Patient Material.

Forty-four cases of prostate cancer with sufficient areas of normal and tumor tissue for DNA isolation were identified from the radical prostatectomy database at the University of Michigan Health System. For this study, cases were identified from prostatectomies performed between 1995 and 1996. FH was obtained from medical records. Normal and tumor DNA samples were isolated from paraffin-embedded tissue blocks using microdissection techniques. Ten 6-μm 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. and/or K. J. W.); regions containing at least 70% normal or tumor nuclei were outlined and used as a template for subsequent microdissection. Normal and tumor tissues were excised using a single-edged razor blade and digested with proteinase K overnight.

LOH Analysis.

DNA was amplified by PCR using a panel of polymorphic markers mapping to the HPC2/ELAC2 region: TP53, D17S969, D17S947, D17S799, and D17S936(8). Primer sequences were obtained from Human Genome Database5 and purchased from Research Genetics (Huntsville, AL). PCR was performed by use of an MJ Research (Watertown, MA) 96-well programmable thermocycler as described previously (14). Briefly, one primer from each primer pair was labeled at its 5′ end with 32PO4 by use of [γ32P]-dATP (ICN Products, Costa Mesa, CA) and T4 polynucleotide kinase (New England Biolabs, Inc., Beverly, MA). All of the reaction mixtures contained 2 μl of 10 × PCR buffer [final concentration 10 mm Tris-HCl (pH 9.0 at 25°C), 50 mm KCl and 0.1% Triton® X-100], 2 μl 25 mm MgCl2, 2 μl 2 mm standard deoxynucleotide triphosphate, 50–100 ng each primer, 1 unit Taq polymerase (Promega Corp., Madison, WI), 7.5–15 ng 32P-labeled primer, 100 ng case DNA, and water in a total volume of 20 μl. Annealing temperatures were empirically optimized for each primer set. PCR products were analyzed using 8%-polyacrylamide DNA sequencing gels, with end-labeled MspI-digested pBR322 fragments as size markers. Each PCR reaction was scored visually for LOH (defined as an ∼50% loss of one tumor allele) by three observers (Y. Q. W., H. C., K. A. C.).

The average age at prostate cancer diagnosis for the 44 men with prostate cancer in this report was 60 +/− 7.8 years (range 43–80 years). Fourteen of the participants (32%) were of AA descent. Although FH information was unavailable in 12 cases, 10 of the men (23%) reported that at least one first-degree family member was affected with prostate cancer. In 41 of the 44 cases (93%), tumors were graded as either Gleason 6 or 7 (17). The remaining three cases were scored as Gleason 8 or 9 tumors.

Four polymorphic markers mapping to HPC2/ELAC2 region were selected for this analysis (Table 1). An intragenic TP53 polymorphism (18) was used as positive control for tumor DNA samples. The expected heterozygosity of all of the markers was > 60%. The order of the markers is: TP53D17S969D17S947–(HPC2/ELAC2)–D17S799D17S936. The closest marker for HPC2/ELAC2 gene is D17S947, which is 89-Kb telomeric to this gene.

LOH was not observed at three of the four markers in the HPC2/ELAC2 region in any of the 44 prostate cancer cases (D17S947, D17S799, or D17S936; Fig. 1). However, 2 of 34 (6%) informative cases showed LOH at D17S969; neither of these men reported a FH of prostate cancer. Both of these tumors were noninformative at the next closest marker, D17S947; therefore, allelic loss at the HPC2/ELAC2 gene cannot be entirely excluded in these two cases.

Because a low frequency of LOH in the region of HPC2/ELAC2 was observed in the 44 prostate cancer cases, LOH at TP53 was 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 ∼7 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 ∼9% 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 (θ = 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 genetic heterogeneity of hereditary prostate cancer. However, by focusing on a subset of families that either: (a) had four or more cases that shared a haplotype and had individual family LOD scores > 1.0; or (b) had six or more cases that shared a haplotype, irrespective of LOD score, the researchers identified a likely candidate. This gene is one of two human genes that were found to be homologues of Escherichia coli elaC, and it was named HPC2/ELAC2(8). HPC2/ELAC2 is a member of an uncharacterized gene family predicted to have metal-dependent hydrolase activity; however, the specific function of the HPC2/ELAC2 gene is presently unknown.

To determine whether HPC2/ELAC2 allelic loss occurred in sporadic prostate cancer, we selected a series of 44 cases from the University of Michigan Health Systems Radical Prostatectomy Database. On the basis of previous studies, we predicted that ∼25% of these men would have a FH of prostate cancer (2). However, the likelihood that any of the men with a FH of prostate cancer actually carried a germ-line HPC2/ELAC2 gene mutation is low, because these mutations have been shown to be relatively rare even in multiplex prostate cancer families. For example, HPC2/ELAC2 mutation screening has been performed on > 450 affected family members from four large studies of hereditary prostate cancer to date, and only two truncating mutations have been identified (8, 10, 12, 13). Therefore, our study results are consistent with the hypothesis that inactivating somatic mutations occur only in those patients harboring deleterious germ-line HPC2/ELAC2 mutations. Larger studies of hereditary prostate cancer specimens will be needed to address this possibility.

Six of our prostate cancer cases demonstrated allelic loss at TP53, and two tumors revealed LOH at a marker between TP53 and HPC2/ELAC2, namely D17S969. This observation raises the possibility that 17p allelic loss results in the loss of genes in addition to TP53. The mitogen-activated protein kinase kinase 4 gene, or MKK4, at 17p11.2 has been implicated in both tumor suppression and metastasis suppression; this gene is immediately adjacent to D17S969. Teng et al.(23) identified MKK4 mutations in human pancreatic, breast, colon, and testis cancer cell lines that also demonstrated 17p LOH, thus suggesting a role for this gene in the pathogenesis of a number of different tumor types. Yoshida et al.(24) have shown that the metastatic potential of the rat prostate cancer cell line AT6.1 can be suppressed via transfection of MKK4. Additional studies of prostate cancer metastases demonstrated LOH in 5 of 16 informative samples including one case in which the region of deletion did not extend to the distal portion of TP53(25). Fine mapping of this region of 17p using a larger panel of clinical prostate cancer cases will clarify the role of TP53 and MKK4 in prostate carcinogenesis and metastasis.

In summary, our data demonstrate that inactivation of the HPC2/ELAC2 gene via LOH is a relatively uncommon event in prostate cancer. If HPC2/ELAC2 is a tumor suppressor gene, other mechanisms of inactivation should be considered including methylation. Future studies should be directed toward determining whether somatic inactivation of the remaining normal allele occurs in the subset of patients with an inherited mutation in HPC2/ELAC2, therefore implicating this gene as a tumor suppressor gene.

Fig. 1.

Results of LOH analysis using chromosome 17p markers. The cases used in the analysis are listed on the left with the markers across the top. FH is coded as follows: +, FH positive; −, FH negative; 0, FH unknown; ▪, tumors with LOH at a specific marker; □, cases in which both alleles were retained in the tumor; , noninformative cases. Repeated PCR assays of tumors 9 and 40 with marker D17S947 were inconclusive ().

Fig. 1.

Results of LOH analysis using chromosome 17p markers. The cases used in the analysis are listed on the left with the markers across the top. FH is coded as follows: +, FH positive; −, FH negative; 0, FH unknown; ▪, tumors with LOH at a specific marker; □, cases in which both alleles were retained in the tumor; , noninformative cases. Repeated PCR assays of tumors 9 and 40 with marker D17S947 were inconclusive ().

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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 18 U.S.C. Section 1734 solely to indicate this fact.

1

Supported by USPHS Grants P50-CA69568 (Specialized Programs of Research Excellence) and R01-CA79596.

3

The abbreviations used are: OMIM, Online Mendelian Inheritance in Man; LOH, loss of heterozygosity; FH, family history; AA, African-American; C, Caucasian.

4

Online Mendelian Inheritance in Man. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins, University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000, Internet address: http://www.ncbi.nlm.nih.gov/omim/.

5

Internet address: http://www.gdb.org.

6

C. Bettis, K. A. Cooney, unpublished observations.

Table 1

Markers selected for HPC2/ELAC2 LOH analysis

The map order and distances were obtained from the National Center for Biotechnology Information web page.7
Markers Variation type Maximum heterozygosity Location on chr. 17 gene sequence 
TP53 Variable number of tandem repeats 69% 9400–9416 Kbp 
D17S969 Tetranucleotide repeat a 15060 Kbp 
D17S947 Dinucleotide repeat 89% 16186 Kbp 
D17S799 Dinucleotide repeat 69% 16551 Kbp 
D17S936 Dinucleotide repeat 60% 16813 Kbp 
The map order and distances were obtained from the National Center for Biotechnology Information web page.7
Markers Variation type Maximum heterozygosity Location on chr. 17 gene sequence 
TP53 Variable number of tandem repeats 69% 9400–9416 Kbp 
D17S969 Tetranucleotide repeat a 15060 Kbp 
D17S947 Dinucleotide repeat 89% 16186 Kbp 
D17S799 Dinucleotide repeat 69% 16551 Kbp 
D17S936 Dinucleotide repeat 60% 16813 Kbp 
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
TP53D17S969D17S947D17S799D17S936
 Informative cases LOH cases Informative cases LOH cases Informative cases LOH cases  Informative cases LOH cases Informative cases LOH cases 
All cases (n = 44) 24 (55%) 6 (25%) 34 (77%) 2 (6%) 34 (81%)  36 (82%) 20 (46%) 
FH + (n = 10) 4 (40%) 3 (75%) 6 (60%) 9 (90%)  7 (70%) 3 (30%) 
FH − (n = 22) 14 (64%) 2 (14%) 18 (82%) 2 (11%) 17 (77%)  21 (95%) 12 (55%) 
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
TP53D17S969D17S947D17S799D17S936
 Informative cases LOH cases Informative cases LOH cases Informative cases LOH cases  Informative cases LOH cases Informative cases LOH cases 
All cases (n = 44) 24 (55%) 6 (25%) 34 (77%) 2 (6%) 34 (81%)  36 (82%) 20 (46%) 
FH + (n = 10) 4 (40%) 3 (75%) 6 (60%) 9 (90%)  7 (70%) 3 (30%) 
FH − (n = 22) 14 (64%) 2 (14%) 18 (82%) 2 (11%) 17 (77%)  21 (95%) 12 (55%) 
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