Role of HPC2/ELAC2 in hereditary prostate cancer

The HPC2/ELAC2 gene on chromosome 17p was recently identified as a candidate gene for hereditary prostate cancer (HPC). To confirm these findings, we screened 300 prostate cancer patients (2 affected members/family) from 150 families with HPC for potential germ-line mutations using conformation-sensitive gel electrophoresis, followed by direct sequence analysis. The minimum criteria for our families with HPC was the presence of 3 affected men with prostate cancer. A total of 23 variants were identified, including 13 intronic and 10 exonic changes. Of the 10 exonic changes, 1 truncating mutation was identified, a Glu216Stop nonsense mutation. This nonsense variant was found in 2 of 3 affected men in a single family. The remaining nine alterations included five missense, three silent, and one variant in the 3' untranslated region. To additionally test for potential associations of polymorphic variants and increased risk for disease, we genotyped two common polymorphisms, Ser217Leu and Ala541Thr, in 446 prostate cancer patients from 164 families with HPC and 502 population-based controls. The frequency of the Leu217 variant was similar for patients (32.3%) and controls (31.8%), as was the frequency of the Thr541 variant (5.4% among patients versus 5.2% among controls). In contrast to previous reports, we found no association of the joint effects of Leu271 and Thr541 (odds ratio, 1.04; 95% confidence interval, 0.57-1.89). Overall, our results did not reveal any association between these two common polymorphisms and the risk for HPC. The finding of a nonsense mutation in the HPC2/ELAC2 gene confirms its potential role in genetic susceptibility to prostate cancer. However, our data also suggest that germ-line mutations of the HPC2/ELAC2 are rare in HPC and that the variants Leu217 and Thr541 do not appear to influence the risk for HPC. Cumulatively, these results suggest that alterations within the HPC2/ELAC2 gene play a limited role in genetic susceptibility to HPC.     

Loss of heterozygosity of the putative prostate cancer susceptibility gene HPC2/ELAC2 is uncommon in sporadic and familial prostate cancer.

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.     

Polymorphisms in the prostate cancer susceptibility gene HPC2/ELAC2 in multiplex families and healthy controls.

Two polymorphisms in the newly cloned prostate cancer susceptibility gene, HPC2/ELAC2, are suspected to be associated with an increased risk of developing the disease. These missense variants result in a serine (S) to leucine (L) substitution at amino acid residue 217 and an alanine (A) to threonine (T) substitution at residue 541. We genotyped these polymorphisms in 257 multiplex prostate cancer sibships and in 355 race-matched healthy unrelated controls. A significant increase in the frequency of the T allele is seen in the prostate cancer subjects compared with controls. There is, however, little evidence for excess clustering of the T allele within the multiplex families known to be segregating this allele, and there is no evidence for linkage of prostate cancer to the HPC2/ELAC2 region of chromosome 17p11.2 in these families. The T allele shows no association with either Gleason score or age-of-onset in segregating families.     

Association of HPC2/ELAC2 polymorphisms with risk of prostate cancer in a population-based study.

Genetic polymorphism in HPC2/ELAC2 was recently associated with risk of sporadic prostate cancer. To determine the contribution of two HPC2/ELAC2 missense variants (Ser217Leu and Ala541Thr) to the risk of developing prostate cancer, we conducted a population-based case-control study of middle-aged men (40-64 years). Cases (n=591) were ascertained from the Seattle-Puget Sound Surveillance, Epidemiology, and End Results Cancer Registry and Controls (n=538) from the same general population were identified through random-digit dialing. Subjects were residents of King County, Washington, and were frequency matched on age. Cases (32%) had a slightly higher frequency of the Leu217 variant compared with controls (29%), but there were no differences in the frequency of the Thr541 allele (4%). When considering joint genotypes, white men homozygous for the Leu217 variant on an Ala541/Ala541 background had an increased risk of prostate cancer [odds ratio (OR)=1.84; 95% confidence interval (CI), 1.11-3.06]. Different risk profiles were also observed when cases were stratified by disease aggressiveness. Men with at least one Leu217 allele had an elevated risk (OR=1.34; 95% CI, 1.02-1.76) of less aggressive prostate cancer (localized stage and Gleason score < or = 7), with a stronger association among men with two Leu217 alleles (OR=1.73; 95% CI, 1.08-2.77). The Ala541Thr polymorphism was not associated with risk, and neither variant was associated with more aggressive prostate cancer phenotypes. We estimate that the Ser217Leu genotype may account for approximately 14% of less aggressive prostate cancer cases and 9% of all sporadic cases in the general United States population of white men 相似文献   

HPC2/ELAC2 polymorphisms and prostate cancer risk: analysis by age of onset of disease

The candidate prostate cancer susceptibility gene HPC2/ELAC2 has two common coding polymorphisms: (Ser-->Leu 217) and (Ala-->Thr 541). The Thr541 variant in the HPC2/ELAC2 gene has previously been reported to be at an increased frequency in prostate cancer cases. To evaluate this hypothesis we genotyped 432 prostate cancer patients (including 262 patients diagnosed 55 years (OR=1.27, 95% CI 0.59-2.74). We conclude that any association between the Thr541 variant and prostate cancer is likely to be weak.     

Association of susceptibility alleles in ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer severity in European American and African American men.

Reported associations of ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer have been inconsistent and understudied in African Americans. We evaluated the role of 16 sequence variants in these genes with prostate cancer using 888 European American and 131 African American cases, and 473 European American and 163 African American, controls. We observed significant differences in ELAC2, RNASEL, and MSR1 allele frequencies by race. However, we did not observe significant associations between prostate cancer and any variants examined for both races combined. Associations were observed when stratified by race, family history, or disease severity. European American men homozygous for MSR1 IVS7delTTA had an elevated risk for localized stage [odds ratio, (OR), 3.5; 95% confidence interval (95% CI), 1.4-6.9], low-grade (OR, 3.2; 95% CI, 1.4-7.3) disease overall, and with low-grade (OR, 2.9; 95% CI, 1.2-7.2) or late-stage disease (OR, 5.2; 95% CI, 1.1-25.7) in family history-negative African Americans. MSR1 Arg293X was associated with family history-negative high-grade disease (OR, 4.0; 95% CI, 1.1-14.1) in European Americans. RNASEL Arg462Gln was associated with low-grade (OR, 1.5; 95% CI, 1.04-2.2) and early-stage (OR, 1.5; 95% CI, 1.02-2.1) disease in family history-negative European Americans. In family history-positive individuals, Arg462Gln was inversely associated with low-grade (OR, 0.43; 95% CI, 0.21-0.88) and low-stage (OR, 0.46; 95% CI, 0.22-0.95) disease. In African Americans, Arg462Gln was associated with positive family history high-stage disease (OR, 14.8; 95% CI, 1.6-135.7). Meta-analyses revealed significant associations of prostate cancer with MSR1 IVS7delTTA, -14,742 A>G, and Arg293X in European Americans; Asp174Tyr in African Americans; RNASEL Arg462Gln in European American's overall and in family history-negative disease; and Glu265X in family history-positive European Americans. Therefore, MSR1 and RNASEL may play a role in prostate cancer progression and severity.     

Ser217Leu polymorphism of the HPC2/ELAC2 gene associated with prostatic cancer risk in Japanese men

The HPC2/ELAC2 gene may be associated with hereditary/familial prostate cancer (PCa). Two common missense variants (Ser217Leu and Ala541Thr) have been reported in the gene. We performed mutational, allelotyping and expression analyses and a molecular epidemiological study to clarify the relations between this gene and prostatic diseases, including PCa and benign prostatic hyperplasia (BPH) in Japanese men. We screened for mutations in 109 patients with PCa including 11 patients from 1 hereditary and 9 familial PCa. Loss of heterozygosity and expression were analyzed. An epidemiological study was done in sporadic PCa (n=98) and BPH (n=143) using 1 novel (Ser627Leu) and 2 previously described polymorphisms of the HPC2/ELAC2 gene. Somatic or germline mutations were not confirmed in any cases of PCa. Loss of heterozygosity at 2 microsatellites, D17S1289 and D17S520, was detected in 1 of 38 and 1 of 35 cases, respectively. Expression analysis revealed decreased or absent mRNA expression in 6 of 38 tumors. Epidemiologic analysis showed that a Leu allele at codon 217 was significantly more frequent in patients with PCa than in controls (10.2% vs. 3.5%, odds ratio = 3.11; 95% confidence interval, 1.22-7.90). At codon 541, all patients with PCa or BPH and all control subjects had the Ala/Ala genotype. At codon 627, the incidence of the Leu variant was slightly, but not significantly, higher in patients with BPH than in controls (7.0% vs. 2.8%, odds ratio = 2.59, 95% confidence interval, 0.94-7.13, not statistically significant). We concluded that germline/somatic mutations of HPC2/ELAC2 are uncommon in PCa. Similarly, allelic imbalances at the gene locus and changes in expression are rare. Although no difference in allele frequency at Ser217Leu between patients with PCa and controls has been reported in a Western population, this polymorphism is a potential indicator of PCa risk in Japanese men and it should be examined in other ethnic groups.     

Linkage and association of CYP17 gene in hereditary and sporadic prostate cancer.

Androgens are essential for prostate development, growth and maintenance and the association between androgen levels and prostate cancer is well established. Since the CYP17 gene encodes the enzyme cytochrome P450c17alpha, which mediates 17alpha-hydroxylase and 17,20-lyase activities in the androgen biosynthesis pathway, sequence variations in the gene and association with increased risk to prostate cancer has been studied. In particular, several groups have studied the association between a polymorphism in the 5' promoter region and prostate cancer using a population-based association approach. However, the results from these studies were inconclusive. To further study this polymorphism and its possible role in hereditary prostate cancer (HPC), we performed a genetic linkage analysis and family-based association analysis in 159 families, each of which contains at least 3 first-degree relatives with prostate cancer. In addition, we performed a population-based association analysis to compare the risk of this polymorphism to hereditary and sporadic prostate cancer in 159 HPC probands, 249 sporadic prostate cancer patients and 211 unaffected control subjects. Evidence for linkage at the CYP17 gene region was found in the total 159 HPC families (LOD = 1.3, p = 0.01, at marker D10S222). However, family-based association tests did not provide evidence for overtransmission of either allele of the CYP17 polymorphism to affected individuals in the HPC families. The allele and genotype frequencies of the polymorphism were not statistically different among the HPC probands, sporadic cases and unaffected control subjects. In conclusion, our results suggest that the CYP17 gene or other genes in the region may increase the susceptibility to prostate cancer in men; however, the polymorphism in the 5' promoter region has a minor role if any in increasing prostate cancer susceptibility in our study sample.     

Associations of Polymorphisms in HPC2/ELAC2 and SRD5A2 Genes with Benign Prostate Hyperplasia in Turkish Men

Benign prostate hyperplasia (BPH) is the most common benign tumor in elderly men for which the HPC2/ELAC2 and SRD5A2 genes are known genetic factors. The HPC2/ELAC2 gene features Ser217Leu andAla541Thr polymorphisms and the SRD5A2 gene Ala49Thr and Val89Leu polymorphisms. The aim of this studywas to examine relationships between these polymorphisms and BPH in Turkish men using amplification bythe polymerase chain reaction (PCR) method. Polymorphisms were determined by using restriction fragmentlength polymorphism (RFLP) with suitable restriction: TaqIα, Fnu4HI, Mwo I and Rsa I. We found statisticallysignificant relationship between the SRD5A2 gene Ala49Thr (OR=2.3; CI 95%, 1.04-5.1; p=0.01<0.05) , but notthe other polymorphisms, and BPH. For the first time, our data demonstrate that correlation between SRD5A2gene Ala49Thr and polymorphism are statistically significant in Turkish men with BPH.     

Genetic analysis of the RNASEL gene in hereditary, familial, and sporadic prostate cancer.

PURPOSE: The RNASEL gene has been proposed as a candidate gene for the HPC1 locus through a positional cloning and candidate gene approach. Cosegregation between the truncating mutation E265X and disease in a hereditary prostate cancer (HPC) family and association between prostate cancer risk and the common missense variant R462Q has been reported. To additionally evaluate the possible role of RNASEL in susceptibility to prostate cancer risk, we performed a comprehensive genetic analysis of sequence variants in RNASEL in the Swedish population. EXPERIMENTAL DESIGN: Using 1624 prostate cancer cases and 801 unaffected controls, the truncating mutation E265X and five common sequence variants, including the two missense mutations R462Q and D541E, were evaluated for association between genotypes/haplotypes and prostate cancer risk. RESULTS: The prevalence of E265X carriers among unaffected controls and prostate cancer patients was almost identical (1.9 and 1.8% in controls and cases, respectively), and evidence for segregation of E265X with disease was not observed within any HPC family. Overall, the analyses of common sequence variants provided limited evidence for association with prostate cancer risk. We found a marginally significant inverse association between the missense mutation D541E and sporadic prostate cancer risk (odds ratio, 0.77; 95% confidence interval, 0.59-1.00) and reduced risk of prostate cancer in carriers of two different haplotypes being completely discordant. CONCLUSIONS: Considering the high quality in genotyping and the size of this study, these results provide solid evidence against a major role of RNASEL in prostate cancer etiology in Sweden.     

CHEK2 variants associate with hereditary prostate cancer

Recently, variants in CHEK2 gene were shown to associate with sporadic prostate cancer in the USA. In the present study from Finland, we found that the frequency of 1100delC, a truncating variant that abrogates the kinase activity, was significantly elevated among 120 patients with hereditary prostate cancer (HPC) (four out of 120 (3.3%); odds ratio 8.24; 95% confidence interval 1.49-45.54; P=0.02) compared to 480 population controls. Suggestive evidence of segregation between the 1100delC mutation and prostate cancer was seen in all positive families. In addition, I157T variant had significantly higher frequency among HPC patients (13 out of 120 (10.8%); odds ratio 2.12; 95% confidence interval 1.06-4.27; P=0.04) than the frequency 5.4% seen in the population controls. The results suggest that CHEK2 variants are low-penetrance prostate cancer predisposition alleles that contribute significantly to familial clustering of prostate cancer at the population level.     

Loss of expression of FANCD2 protein in sporadic and hereditary breast cancer

Fanconi anemia (FA) is a recessive disorder associated with progressive pancytopenia, multiple developmental defects, and marked predisposition to malignancies. FA is genetically heterogeneous, comprising at least 12 complementation groups (A–M). Activation of one of the FA proteins (FANCD2) by mono-ubiquitination is an essential step in DNA damage response. As FANCD2 interacts with BRCA1, is expressed in proliferating normal breast cells, and FANCD2 knockout mice develop breast tumors, we investigated the expression of FANCD2 in sporadic and hereditary invasive breast cancer patients to evaluate its possible role in breast carcinogenesis. Two tissue microarrays of 129 and 220 sporadic breast cancers and a tissue microarray containing 25 BRCA1 germline mutation-related invasive breast cancers were stained for FANCD2. Expression results were compared with several clinicopathological variables and tested for prognostic value. Eighteen of 96 (19%) sporadic breast cancers and two of 21 (10%) BRCA1-related breast cancers were completely FANCD2-negative, which, however, still showed proliferation. In the remaining cases, the percentage of FANCD2-expressing cells correlated strongly with mitotic index and percentage of cells positive for the proliferation markers Ki-67 and Cyclin A. In immunofluorescence double staining, coexpression of FANCD2 and Ki-67 was apparent. In survival analysis, high FANCD2 expression appeared to be prognostically unfavorable for overall survival (p = 0.03), independent from other major prognosticators (p = 0.026). In conclusion, FANCD2 expression is absent in 10–20% of sporadic and BRCA1-related breast cancers, indicating that somatic inactivating (epi)genetic events in FANCD2 may be important in both sporadic and hereditary breast carcinogenesis. FANCD2 is of independent prognostic value in sporadic breast cancer. Petra van der Groep and Michael Hoelzel contributed equally to this study.     

Differential expression of genes related to androgen and estrogen metabolism in hereditary versus sporadic prostate cancer.

The hereditary predisposition to prostate cancer is rare and accounts for <5% of cases. Except for younger age at diagnosis, no phenotypic features have been clearly associated with hereditary prostate cancer. The aim of the study was to analyze the expression of genes related to androgen and estrogen metabolism in both hereditary and sporadic prostate cancers in patients matched for clinicopathologic features. Tissues were obtained from patients included in a national familial prostate cancer registry. From the 120 cases of hereditary forms suggesting autosomal dominant Mendelian inheritance, 21 patients were treated by radical prostatectomy for whom formalin-fixed tissue was available. Twenty-one sporadic cases were then matched according to age, Gleason score, and pathologic stage. Immunohistochemistry was done on tissue microarray using antibodies directed against androgen receptor (AR), estrogen receptor alpha (ERA), estrogen receptor beta, 5alpha-reductase I and II, aromatase, and the proliferation marker Ki67. The percentage of AR-positive cancer cells was higher in hereditary cancer compared with sporadic cases (P < 0.004). In contrast, the mean number of ERA-positive stromal cells was lower in hereditary versus sporadic cancer (P < 0.03). This differential expression of AR and ERA suggests that a specific pattern of hormone receptors is associated with hereditary predisposition to prostate cancer.     

Screening for prostate cancer in Dutch hereditary prostate cancer families

It is common belief that in families with hereditary prostate cancer (HPC), unaffected men should be screened periodically with PSA, but little is known about the effects of such screening. We studied test and tumor characteristics in unaffected 50-75-year-old screenees from HPC families. In the Netherlands, 153 verified HPC families are registered; 132 unaffected men in these families were not under surveillance for prostate cancer and gave informed consent for PSA testing by their GP and referral to a urologist in the case of a PSA level >or= 3.0 ng/ml. Results were compared to published data from the Rotterdam and G?teborg sections of the European Randomized Study of Screening for Prostate Cancer (ERSPC). A PSA >or= 3.0 ng/ml was found in 20 men: referral rate, 15.1% (ERSPC Rotterdam: 20.1%; ERSPC G?teborg: 12.0%). Only 3 cases of prostate cancer were diagnosed in these men: detection rate in the first screening round 2.3% (ERSPC Rotterdam: 5.3%; ERSPC G?teborg: 2.3%). Frequent opportunistic PSA testing made it impossible to estimate the detection rates in subsequent screening rounds. In the first and subsequent PSA screening rounds, 11 cases of cancer were detected. All but 1 had favorable tumor characteristics (cT1c/pT2; Gleason < 7). These results raise the question as to whether men from all HPC families should be considered at high-risk. We suggest that the same PSA testing guidelines should apply to HPC families and the general population. A more aggressive screening policy in HPC families does not seem to be justified.     

Joint effect of HSD3B1 and HSD3B2 genes is associated with hereditary and sporadic prostate cancer susceptibility

3beta-hydroxysteroid dehydrogenases (HSD3Bs), encoded by the HSD3B gene family at 1p13, have long been hypothesized to have a major role in prostate cancer susceptibility. The recent reports of a prostate cancer linkage at 1p13 provided additional evidence that HSD3B genes may be prostate cancer susceptibility genes. To evaluate the possible role of HSD3B genes in prostate cancer, we screened a panel of DNA samples collected from 96 men with or without prostate cancer for sequence variants in the putative promoter region, exons, exon-intron junctions, and 3'-untranslated region of HSD3B1 and HSD3B2 genes by direct sequencing. Eleven single nucleotide polymorphisms (SNPs) were identified, four of which, including a missense change (B1-N367T), were informative. These four SNPs were further genotyped in a total of 159 hereditary prostate cancer probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Although a weak association between prostate cancer risk and a missense SNP (B1-N367T) was found, stronger evidence for association was found when the joint effect of the two genes was considered. Men with the variant genotypes at either B1-N367T or B2-c7519g had a significantly higher risk to develop prostate cancer, especially the hereditary type of prostate cancer. Most importantly, the subset of hereditary prostate cancer probands, whose families provided evidence for linkage at 1p13, predominantly contributed to the observed association. Additional studies are warranted to confirm these findings.