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Perspective: Prostate Cancer Susceptibility Genes

Canada Research Chair in Oncogenetics (J.S., M.D., P.S.), Oncology and Molecular Endocrinology Research Center (J.S., M.D., P.S., F.L.), CHUL Research Center and Laval University, Québec City, G1V 4G2, Canada

Address all correspondence and requests for reprints to: Professor Jacques Simard, Cancer Genomics Laboratory, T3-57, CHUL Research Center, 2705 Laurier Blvd, Québec City, G1V 4G2, Canada. E-mail: . Jacques.Simard{at}crchul.ulaval.ca

	Summary

Top Summary Introduction Mapping putative loci for... A strong candidate prostate... Mutations in the ribonuclase... Risk of prostate cancer... Common low-penetrance allelic... Concluding remarks and future... References

 
In many developed countries, prostate cancer is the most frequently diagnosed malignancy in men. The extent to which the marked racial/ethnic difference in its incidence rate is attributable to screening methods, environmental, hormonal, and/or genetic factors remains unknown. A positive family history is among the strongest epidemiological risk factors for prostate cancer. It is now well recognized that association of candidate genetic markers to this multifactorial malignancy is more difficult than the identification of susceptibility genes for some common cancers such as breast, ovary, and colon cancer. Several reasons may explain such a difficulty: 1) prostate cancer is diagnosed at a late age, thus often making it impossible to obtain DNA samples from living affected men for more than one generation; 2) the presence within high-risk pedigrees of phenocopies, associated with the lack of distinguishing features between hereditary and sporadic forms; and 3) the genetic heterogeneity of this complex disease along with the accompanying difficulty of developing appropriate statistical transmission models taking into account simultaneously multiple susceptibility genes, frequently showing moderate or low penetrance. Despite the localization of seven susceptibility loci, there has been limited confirmatory evidence of linkage for currently known candidate genes. Nonetheless, the discovery of the first prostate cancer susceptibility gene characterized by positional cloning, ELAC2 was achieved taking advantage of the Utah Family Resource. Moreover, common missense mutations in the ELAC2 gene were found to be significantly associated with an increased risk of diagnosis of prostate cancer in some studies. More recently, recombination mapping and candidate gene analysis were used to map several genes, including the 2'-5'-oligoadenylate-dependent ribonuclease L (RNASEL) gene, to the critical region of HPC1. Two deleterious mutations in RNASEL segregate independently with the disease in two of the eight HPC1-linked families. Additional studies using larger cohorts are needed to fully evaluate the role of these two susceptibility genes in prostate cancer risk. Although a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer, some of the familial risks may be due to shared environment and more specifically to common low-penetrance genetic variants. In this regard, it is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action, led to the observation of a significant association between a susceptibility to prostate cancer and common genetic variants, such as those found in 5-reductase type 2 and AR genes.

	Introduction

Top Summary Introduction Mapping putative loci for... A strong candidate prostate... Mutations in the ribonuclase... Risk of prostate cancer... Common low-penetrance allelic... Concluding remarks and future... References

 
Prostate cancer is the most frequently diagnosed noncutaneous malignancy among men in industrialized countries. In the United States, one in eight men will develop prostate cancer during his life. The incidence of prostate cancer varies markedly throughout the world, with United States, Canada, Sweden, Australia, and France having the highest rates (ranging from 48.1 to 137.0 cases per 100,000 person-years as estimated between the 1988–1992 period), whereas most European countries have intermediate rates (23.9 to 31.0 cases per 100,000 person-years). The lowest prevalence is observed in Asian populations (2.3 to 9.8 cases per 100,000 person-years) (1). The extent to which this racial/ethnic difference is attributable to screening methods, environmental, hormonal and/or genetic factors is unknown. Although early detection using prostate-specific antigen and improved treatment have emerged as the most critical strategies to decrease prostate-cancer mortality (2), the potential of early detection through genetic indicators is also particularly relevant. Nevertheless, scientists involved in cancer genomics acknowledge that obvious heterogeneity exits, making the association of candidate genetic markers to this multifactorial malignancy more difficult than the identification of susceptibility genes for some common cancers such as breast, ovary, and colon cancer.

A positive family history is among the strongest epidemiological risk factors for prostate cancer. Familial clustering of prostate cancer was first reported by Morganti et al. (3). Thereafter, various case-control and cohort studies have investigated the role of family history as a risk factor for prostate cancer (see for recent reviews Refs. 4, 5, 6, 7). Much evidence comes from the study of pedigrees having a large number of cases, as those observed in the Utah population (8, 9). The relative risk of prostate cancer increases markedly when the age of the index case decreases or when the number of affected individuals in a cluster increases, which is evidence that this increased risk has a genetic component. For example, the brother of a proband diagnosed at age 50 has a 1.9-fold relative risk of developing prostate cancer compared with the brother of a case diagnosed at age 70 (10). Moreover, having one, two, or three affected first-degree relatives increases the relative risk by 2.2-, 4.9-, and 10.9-fold, respectively (11). It should be noted that family studies offer the opportunity to estimate risks of siblings and parent-offspring pairs but cannot distinguish between genetic and nongenetic causes of familial aggregations of cancer. In contrast, comparisons of the concordance of cancer between monozygotic and dizygotic pairs of twins provide valuable information on whether the familial clustering is due to hereditary or environmental influences. Thus, the importance of inherited predisposition to prostate cancer is also supported by the finding that monozygotic twins have a 4-fold increased concordance rate of prostate cancer compared with dizygotic twins (10). In support of this latter observation, it has recently been estimated, using the combined data from 44,788 pairs of twins listed in Swedish, Danish, and Finnish twin registries, that 42% (95% CI = 29%–50%) of all prostate-cancer risk may be explained by inheritable factors (12).

The first segregation analysis, which included 691 families affected by prostate cancer ascertained through 740 consecutive probands undergoing radical prostatectomy, suggested that inherited predisposition was due to a rare, highly penetrant autosomal dominant allele(s) with a population frequency of 0.003, and with carriers having an 88% cumulative risk of disease by 85 yr of age compared with only 5% in noncarriers (10). The gene accounted for approximately 43% of prostate cancer cases diagnosed before age 55 and 9% of cases diagnosed through age 85. In two other segregation analyses, similar transmission models were proposed (13, 14); however, the Grönberg model proposed a more common allele (1.67%) and a lower life span penetrance (63%). All these studies thus supported the presence of at least one highly penetrant autosomal dominant prostate cancer predisposition gene. However, consistently higher risks observed in brothers of prostate cancer affected relatives compared with sons of affected individuals have led to hypotheses of an X-linked, recessive, and/or imprinted component to the genetics of prostate cancer susceptibility (15, 16).

	Mapping putative loci for prostate cancer susceptibility genes

Top Summary Introduction Mapping putative loci for... A strong candidate prostate... Mutations in the ribonuclase... Risk of prostate cancer... Common low-penetrance allelic... Concluding remarks and future... References

 
Several reasons may explain the difficulty of identification of prostate cancer susceptibility genes (4, 5, 6, 7, 8). Prostate cancer is typically diagnosed at a late age, thus often making it difficult to obtain DNA samples from living affected men for more than one generation. Moreover, the presence within high-risk pedigrees of men who have developed a cancer that is sporadic and not due to an inherited germline mutation (phenocopies), associated with the lack of distinguishing features between hereditary and sporadic forms, is another significant problem. Indeed, a sporadic case can incorrectly be used to narrow a putative region of linkage, thus misleading scientists to focus their search for candidate genes in the wrong chromosomal region. Finally, the genetic heterogeneity of the trait along with the accompanying difficulty of developing appropriate statistical transmission models taking into account multiple susceptibility genes, many of which are moderate or low penetrance, is perhaps the most important problem (4, 5, 6, 7).

To date, the localization of six prostate cancer susceptibility loci, HPC1 at 1q24 (17, 18), PCAP at 1q42 (19), HPCX at Xq27 (20), CAPB at 1p36 (18, 21), HPC20, at 20q13 (22) and ELAC2 at 17p11 (23) have been described and then tested on independent data sets. Another recently published study presents evidence for linkage to a new locus, at 8p22–23 (24), which is of interest knowing that several lines of evidence have implicated the short arm of chromosome 8 as harboring genes important for prostate cancer (25) (Fig. 1). Several independent studies have confirmed a linkage at HPC1 locus (26, 27), whereas other studies found no significant evidence for linkage (5, 28, 29, 30). The initial study using 91 families from North America and Sweden, suggested that HPC1 accounts for up to 34% of prostate cancer families with four or more cases (17). A subsequent pooled analysis of 772 families (27) demonstrated the actual proportion to be much lower, at 6%. In this meta-analysis, a disproportionate amount of linkage was derived from families characterized by male-to-male disease transmission, early age at diagnosis (65 yr or less) and having five or more affected members. Another recent study appeared to confirm HPC1 linkage for a subset of hereditary prostate cancer (HPC) families that had a prevalence of high-grade or advanced-stage prostate cancer and that were not likely to be linked to PCAP, HPCX, or CAPB (31).

View larger version (21K): [in this window] [in a new window]   Figure 1. Localization of prostate cancer susceptibility loci reported in the literature. HPC1 at 1q24 (17 18 ), PCAP at 1q42 (19 ), HPCX at Xq27 (20 ), CAPB at 1p36 (18 21 ), HPC20 at 20q13 (22 ), 8p22–23 (24 ), and ELAC2 at 17p11 (23 ).

A recent study was able to identify several significant linkage peaks, including reported regions such as HPC1 and PCAP and several novel loci, by modeling locus heterogeneity among affected sib pairs with prostate cancer using Gleason score, age at onset, male-to-male transmission and/or number of affected first-degree family members as covariates that serve as surrogate measures of interfamily linkage differences (33).

To replicate the findings of Gibbs et al. (21) concerning the third HPC susceptibility locus on chromosome 1, CABP, an independent study including 13 HPC families with prostate cancer and brain cancer found no evidence of linkage (34). Furthermore, another independent study of 207 HPC families, including nine with prostate and brain cancer, also found no evidence of linkage but observed a suggestive evidence of linkage in those families with early onset (<66 yr of age) prostate cancer (35).

The results obtained for the fourth predisposing locus, HPC20, suggested the strongest evidence of linkage in families with less than five affected individuals, a later age of onset and no male-to-male transmission (22). Although an independent study of 159 HPC families reported evidence of linkage to HPC20 in families fitting the same criteria as those originally described (36), two other studies were unable to provide statistically significant support for the existence of HPC20 at 20q13 in their data sets (32, 37).

The HPCX results were strongly significant with a LOD score of 4.6 and both parametric and nonparametric multipoint analyses were consistent. Linkage to this locus was estimated to account for 16% of prostate cancers in the data set of 360 families (20). Another study reported a positive LOD score over a 30-centimorgan region containing HPCX, with the greatest evidence for linkage in a subset of families with no evidence of male-to-male (NMM) transmission and early-onset of prostate cancer (under 65 yr of age) (38). The linkage to HPCX has also been observed in 57 Finnish HPC families, especially in those families with NMM and an age of diagnosis after 65 yr of age (30). In another independent study of 186 HPC families, 81 families with NMM transmission contributed disproportionately to the observed linkage (39). Their results were in agreement with a small percentage of the 81 families being linked to Xq27–28, but not to the extent of 16%. Nevertheless, there have been difficulties in confirming these findings in an independent data set, with only 5% of families projected to be linked (5). It is also of interest to note that putative susceptibility loci HPCX, HPC1, and PCAP are unlikely to contribute significantly to hereditary prostate cancer in Iceland (40).

	A strong candidate prostate cancer predisposition gene at chromosome 17p

Top Summary Introduction Mapping putative loci for... A strong candidate prostate... Mutations in the ribonuclase... Risk of prostate cancer... Common low-penetrance allelic... Concluding remarks and future... References

 
The discovery of the first prostate cancer susceptibility gene characterized by positional cloning was achieved through a long-standing collaboration between Myriad Genetics and several academic groups, taking advantage of the Utah Family Resource, which has proven to be an invaluable asset for cloning of cancer susceptibility genes in the past (9, 41, 42, 43). A genome-wide search for prostate cancer predisposition loci using a small set of Utah high risk prostate cancer pedigrees and a set of 300 polymorphic markers done by Cannon-Albright’s group (23) provided evidence for linkage to a locus on chromosome 17p (Fig. 2). These pedigrees were not selected for early age of cancer onset but consisted of a subset of families ascertained using the Utah Population Database. The density of markers in the region was increased and the analysis expanded to 33 pedigrees. Analysis of the additional data using a dominant model integrated with Utah age-specific incidence, yielded a maximum two-point LOD score of 4.5 and a maximum three-point LOD score of 4.3 (23).

View larger version (22K): [in this window] [in a new window]   Figure 2. Recombinant, physical and transcript map centered at the human ELAC2 locus on chromosome 17p. a), Key recombinants. Under the arrows, which represent meiotic recombinant, are indicated the number of the kindred in which the recombinant occurred and, in parentheses, the number of cases carrying the haplotype on which the recombinant occurred. b), BAC contig tilling path across the interval. The T7 end of each BAC is denoted with an arrowhead. c), Candidate genes are identified in the interval and below an expanded view of the structure of the ELAC2 gene (23 ).

View larger version (39K): [in this window] [in a new window]   Figure 3. A schematic multiple protein alignment of ELAC superfamily members including the ELAC1, PSO2, and CPSF73 families and the ELAC2 orthologs. The conserved motifs are indicated by black boxes. Localization of known motifs are outlined by an arrow. Homo sapiens (human), Pan troglodytes (chimpanzee), Gorilla gorilla (gorilla), Macaca fascicularis (cynomolgus monkey), Mus musculus (mouse), Rattus norvegicus (rat), Drosophila melanogaster (fruit fly), Caenorhabditis elegans (nematodes), Saccharomyces cerevisiae (yeast), Arabidopsis thaliana (thale cress), Escherichia coli (enterobacteria), Synechocystis sp. (cyanobacteria), Methanothermobacter thermautotrophicus (eurvarchaeotes).

View larger version (22K): [in this window] [in a new window]   Figure 4. Location of sequence variants in ELAC2 and RNASEL genes. Dark gray boxes indicate homologies to known protein domains. Positions of mutations for both proteins are shown by a line in reference to amino acid sequences. High penetrance mutations of the ELAC2 are identified by a box, whereas common low penetrance mutations are encircled. The significance of the other missense mutations detected in ELAC2 is still unknown. Mutations of RNASEL, indicated by boxes, segregate with prostate cancer in two HPC1-linked families. The functional significance of missense mutations shown under the RNASEL protein’s diagram is unknown (49 ).

In another independent study, mutation screening by SSCP in the probands of 66 HPC families from Finland revealed 17 sequence variants, four of which were located in exons, including the two previously described variants. These 17 variants also included one silent base substitution and the novel Glu622Val variant; however, no truncating mutations were found (47). A homozygous carrier of the missense Glu622Val was diagnosed with prostate cancer at the exceptionally young age of 45 yr. They then analyzed the frequency of these three missense variants in 1365 individuals, including hereditary (n = 107), and unselected prostate cancer subjects (n = 467), individuals having benign prostatic hyperplasia (n = 223) and population controls (568 healthy male blood donors). The Leu217 and Thr541 alleles were not significantly associated with an increased risk of prostate cancer, although the latter variant was associated with benign prostatic hyperplasia. More interestingly, the Glu622Val variant had a 1.0% population prevalence but a significantly higher frequency in prostate cancer cases (3% odds ratio 2.94; 95% CI 1.05–8.23).

Finally, Xu et al. (48) analyzed 93 HPC families for mutations across the gene and studied, using association analysis, a population-sample of 249 patients with sporadic prostate cancer and 222 unaffected male controls. The results of this study led them to reject the three alternative hypotheses of 1) a highly penetrant, major prostate cancer-susceptibility gene at 17p11; 2) the allelic variants Leu217 or Thr541 of ELAC2 as high-penetrance mutations; and 3) the variants Leu217 or Thr541 as low-penetrance, risk-modifying alleles. However, they did observe a higher rate of Leu217 homozygous carriers in patients than in control subjects. The authors indicate that considering the impact of genetic heterogeneity, phenocopies, and incomplete penetrance on the linkage and association studies of prostate cancer and on the power to detect linkage and association in their study sample, their results cannot rule out the possibility of a highly penetrant prostate cancer gene at this locus that only segregates in a small number of pedigrees, nor can they rule out a prostate cancer-modifier gene that confers a lower-than-reported risk. Additional larger studies are needed to fully evaluate the role of this gene in prostate cancer risk.

These independent studies are thus consistent with our original data suggesting that truncation of the ELAC2 protein, caused by germline mutations, is unlikely to be a common cause of prostate cancer among high-risk families. Furthermore, it is not yet known what fraction of the pedigrees harbors subtle gene rearrangements or regulatory mutations (23). The identification of the first prostate cancer susceptibility gene cloned after a genome wide scan of high-risk families, and for which there is evidence that both frameshift and missense mutations are disease associated, provides an important tool to understand the mechanisms underlying the molecular basis of prostate cancer and offers the possibility to study the genetic aspects of tumor initiation and progression.

	Mutations in the ribonuclase (RNAse) L gene (RNASEL) in HPC1-linked families

Top Summary Introduction Mapping putative loci for... A strong candidate prostate... Mutations in the ribonuclase... Risk of prostate cancer... Common low-penetrance allelic... Concluding remarks and future... References

 
Recently, Trent’s team (49) used recombination mapping and candidate gene analysis to map several genes, including the 2'-5'-oligoadenylate-dependent RNASEL gene, to the critical region of HPC1. RNase L is a constitutively expressed latent endoribonuclease that mediates the antiviral and proapoptotic activities of the interferon-inducible 2–5A system. They initially screened a set of DNA samples consisting of one individual from each 26 high-risk families, which included 8 families that showed linkage to HPC1 locus and that had at least four affected individuals sharing an HPC1 haplotype. The nonsense mutation, E265X, and the mutation of the initiation codon M1I segregate independently with the disease in two of the 8 HPC1-linked families. It should be noted that the E265X mutation was carried by all four affected individuals tested in family 065, whereas the M1I mutation did not segregate fully with the disease in family 097, thus raising some doubt about the real contribution of these mutations in HPC1 linkage analysis. The frequency of these mutations was studied in control populations. They found one E265X heterozygote in 144 normal control individuals and two E265X heterozygotes in 186 unaffected white men with no family history of prostate cancer and normal serum prostate-specific antigen levels. Moreover, mutation screening of DNA samples from 258 men with nonfamilial prostate cancer revealed two E265X heterozygotes. Thus, this mutation is found in the control population with an estimated allele frequency of 0.5% and no difference in allele prevalence between affected individuals and controls were identified. In contrast, they did not find the M1I mutation in 518 control/unaffected individuals and in 180 men with nonhereditary prostate cancer. In addition to these two mutations, these authors have also detected seven missense mutations with unknown functional significance (Fig. 4). Finally, they observed that microdissected tumors with the E265X mutation showed loss of heterozygozity, loss of RNase L protein, and reduction of the activity of this protein in lymphoblasts from heterozygotes compared with family members who were homozygous for the wild-type allele. The low frequency of deleterious mutations in the RNASEL gene is consistent with the high rate of heterogeneity in familial prostate cancer. The discovery of other functionally significant mutations in this candidate gene using independent data sets will be necessary to confirm this gene as the prostate cancer susceptibility gene in HPC1-linked families.

	Risk of prostate cancer in BRCA1 and BRCA2 carriers

Top Summary Introduction Mapping putative loci for... A strong candidate prostate... Mutations in the ribonuclase... Risk of prostate cancer... Common low-penetrance allelic... Concluding remarks and future... References

 
Epidemiological studies of prostate and breast cancer have revealed that clustering of these cancers occurs in certain families (50, 51). Anderson and Badzioch (50) observed a doubling of breast cancer risk in families with prostate cancer history. An estimated relative risk of prostate cancer of 3.33 was calculated for obligate male carriers of a deleterious BRCA1 mutation when compared with the general population in a cooperative study using 33 BRCA1-linked breast/ovarian cancer families (52). In another more recent study from the Breast Cancer Linkage Consortium including 173 breast/ovarian families with a deleterious BRCA2 mutation, a significantly increased risk (RR = 4.65) for prostate cancer was observed. Furthermore, this risk was even higher before age 65 (RR = 7.33) and the estimated cumulative incidence before 70 was 7.5%–33%, depending on which reference population was used (53). Moreover, the founder Icelandic BRCA2 mutation (999del5) was also associated with increased risk of prostate cancer (54, 55). The relative risk of prostate cancer was calculated to be 4.6 in first-degree relatives and 2.5 in second-degree relatives (55). On the other hand, another population-based estimate shows a cumulative risk for 999del5 mutation carriers of only 7.6% at age 70 (56). Several analyses of germline DNA from prostate cancer cases with or without a family history have revealed that there is no increased frequency of the founder Ashkenazi Jewish BRCA1, and BRCA2 mutations over that expected in this population (57, 58, 59, 60). However, DNA samples from affected individuals in 38 prostate cancer familial clusters were analyzed for germline mutations in BRCA1 and BRCA2 genes to assess the potential contribution of each of these genes to familial prostate cancer (61). No germline mutations were found in BRCA1, but two novel deletions were found in BRCA2. These authors proposed that germline mutations in BRCA2 may therefore account for about 5% of prostate cancers in familial clusters. A recent study in a Swedish family in which the father and four of his sons were diagnosed with prostate cancer at the exceptionally early ages of 51, 52, 56, 58, and 63, respectively, supports an increased risk of prostate cancer in BRCA2 carriers (62). Finally, in another study, BRCA1 and BRCA2 mutation screening was performed on the prostate cancer proband and on an additional family member affected with breast or prostate cancer from each of the 22 cancer families (63). None of the 43 samples screened contained a protein truncating mutation in either BRCA1 or BRCA2. It is important to note that, in contrast to the UK study described above (61), these American families were selected from a large collection of high-risk prostate cancer families (at least three cases of prostate cancer) for having at least two cases of breast or ovarian cancer, to maximize the odds of detecting mutations in BRCA1 or BRCA2 (61).

	Common low-penetrance allelic variants of genes involved in androgen biosynthesis and action

Top Summary Introduction Mapping putative loci for... A strong candidate prostate... Mutations in the ribonuclase... Risk of prostate cancer... Common low-penetrance allelic... Concluding remarks and future... References

 
In the general population, we observe an interindividual variability in the susceptibility to cancer; however, little is known about the underlying genes contributing to this variability. Although a number of rare highly penetrant loci contribute to the Mendelian inheritance of prostate cancer as described above, some of the familial risks may be due to shared environment and more specifically to common low-penetrance genetic variants, which alter predisposition to prostate cancer. Prostate cancer has proven to be the most hormone-sensitive cancer to hormonal manipulation (2). It is not surprising that analyses of genes encoding key proteins involved in androgen biosynthesis and action, led to the observation of a significant association between common genetic variants and a susceptibility to prostate cancer (6, 7, 64, 65). Such analyses provided some understanding of how common low-penetrance polymorphisms present in a number of these candidate genes were involved in prostate cancer onset, progression, and response to treatment for the disease.

Because androgen action in prostate cells is mediated through an interaction with AR, it was first suggested that abnormalities in the AR gene could play a key role in prostate proliferation and differentiation as well as in carcinogenesis. In this regard, the precise molecular events leading from androgen-sensitive prostate cancer to androgen-refractory prostate cancer are of special interest (see Refs. 66, 67, 68, 69 for reviews). Indeed, some of the pathways identified appear to directly involve the modulation of AR’s ability to respond to specific ligands. Accounting for more than half of the AR, the NH₂-terminal transactivation domain is encoded by the exon 1. Within this domain, there are two polymorphic microsatellite trinucleotide repeats, namely a CAG repeat and a downstream GGN polymorphism encoding variable length polyglutamine and polyglycine regions, respectively. The CAG repeat varies in length between 11 and 31 repeats in the germline DNA of normal men (see Ref. 66 for a review) and shows an inverse relationship between the length of repeats and the transcriptional activity of the AR (70, 71, 72). Accordingly, a series of studies show an association between shorter AR CAG repeat lengths (a short CAG has been defined as ranging from <17 to <23 repeats, depending on the study) and increased prostate cancer risk, although it is not entirely clear whether the association is with diagnosis of prostate cancer, response to endocrine therapy or severity of disease. On the other hand, several other studies suggested that CAG repeat length is not associated to prostate cancer risk, age of onset, histological grade and stage of disease at diagnosis or several clinical parameters, including response to hormonal therapy, time to progression after hormonal therapy, disease-free survival, and overall survival (see Ref. 66 for a recent review). Finally, a recent study compared repeat lengths of 140 men with prostate cancer to their brothers without disease from 51 high-risk sibships, stratified by median age at diagnosis of affected men within each sibship. Men with both a short CAG repeat length (<22) and a short GGN repeat length (< or =16) array were not at higher risk (OR = 1.06) compared with men with two long repeats (CAG repeat > or =22 and a GGN repeat >16), thus suggesting that the CAG and GGN repeats in the AR gene do not play a major role in familial prostate cancer (73).

One of the best candidate genes is the 5-reductase type II gene (SRD5A2), which catalyzes the conversion of testosterone into the more active androgen dihydrotestosterone (DHT) and maps to 2p22–23 (74). Intraprostatic DHT is the most meaningful parameter of androgen action in prostatic tissue (Fig. 5). Indeed, the importance of intracrine formation of active androgens is in concordance with the observation that after elimination of testicular androgens by medical or surgical castration, the intraprostatic concentration of DHT remains approximately 40% of that measured in the prostate of intact 65-yr-old men, thus leaving important amounts of free androgen to continue stimulating the growth of the prostate cancer (75). However, male pseudohermaphrodites with 5-reductase deficiency caused by mutations in the SRD5A2 gene exhibit external genital ambiguity and hypoplastic prostate, thus supporting the crucial role of this enzyme in normal prostate development. Modulation of 5-reductase activity may account for part of the substantial racial/ethnic disparity in prostate cancer risk (76, 77, 78). Furthermore, one variant, Ala49Thr has been reported to increase the catalytic activity of this enzyme (79) and is associated with an increased risk of advanced prostate cancer (80, 81, 82). This low-penetrance allele appears to increase the risk of prostate cancer in African-Americans, Latinos, and Italians by 7.2- (P < 0.001), 3.6- (P < 0.04), and 7.7- (P < 0.11) fold, respectively (80, 81, 82). In contrast, the prevalence of the A49T variant in 449 Finnish prostate cancer patients was 6.0%, not significantly differing from 6.3% observed in 223 patients with BPH or 5.8% in 588 population-based controls (83). Furthermore, there was no association between A49T and the family history of the Finnish patients nor with tumor stage or grade (83). Finally, the T allele was not observed in a population-based case control study in China after the genotyping of 191 cases and 304 controls (84). It is also of interest to know that substantial pharmacogenetic variations among the SRD5A2 sequence variants were observed when three competitive inhibitors (finasteride, GG745, and PNU157706) were tested, thus providing relevant information to take into account when prescribing such inhibitors for the chemoprevention or treatment of prostate diseases (79, 80).

View larger version (35K): [in this window] [in a new window]   Figure 5. Major enzymatic pathways involved in the formation and inactivation of androgens in human and the relative importance (%) of adrenal steroid precursors in the intraprostatic concentration of DHT in adult men. A-DIONE, Androstanedione; ADT, androsterone; ADT-G, androsterone glucuronide; ADT-S, androsterone sulfate; AR, androgen receptor; CYP17, cytochrome P450c17, 17-hydroxylase/17,20 lyase; DHEA, dehydroepiandrosterone; DHEA-S, dehydroepiandrosterone sulfate; epi-ADT, epi-androsterone; P450scc, cholesterol side-chain cleavage enzyme; PREG, pregnenolone; PROG, progesterone; RoDH-1, retinol dehydrogenase type 1; TESTO, testosterone; UGT, uridine diphosphate glucuronosyltransferase; 3-DIOL, 5-androstane-3, 17ß-diol; 3-DIOL-G, 5-androstane-3, 17ß-diol glucuronide; 3 HSD-1,-3, 3 hydroxysteroid dehydrogenase type 1, type 3; 3(ß) HSE, 3(ß) hydroxysteroid epimerase; 3ß-DIOL, 5-androstane-3ß, 17ß-diol; 3ß HSD-1, -2, 3ß HSD/5/4-isomerase type 1, type 2; 4-DIONE, androstenedione; 5-DIOL, androst-5-ene-3ß,17ß-diol; 5-DIOL-S, androst-5-ene-3ß,17ß-diol sulfate; 17ß HSD-1, -2, -3, -4, -5, 17ß-HSD type 1, type 2, type 3, type 4, type 5.

	Concluding remarks and future strategies

Top Summary Introduction Mapping putative loci for... A strong candidate prostate... Mutations in the ribonuclase... Risk of prostate cancer... Common low-penetrance allelic... Concluding remarks and future... References

 
The clearest conclusion emerging from the linkage studies described above is perhaps that no single susceptibility locus mapped to date is by itself responsible for a large portion of familial prostate cancers, at least not with the combination of penetrance and clinical features that allowed linkage to and positional cloning of the so-far known colon and breast cancer predisposition genes. Thus, locus heterogeneity is a major parameter in the identification or confirmation of linkage for many data sets. Indeed, the possible existence of multiple prostate cancer genes may well explain why there has been limited confirmatory evidence of linkage for currently known highly penetrant susceptibility loci/genes. As methods for statistical modeling improve, geneticists will have better tools to deal with the apparent extreme heterogeneity within data sets (7, 33, 93).

To clarify the role of low-penetrance polymorphisms in prostate cancer development and progression, association studies using larger cohorts of preferably more than 1,000 blood samples from prostate cancer cases vs. ethnically matched controls, and well-characterized clinical data, will thus be important (6). It will also be necessary to investigate, using various complementary genetic epidemiological approaches, the potential role of the other key steroidogenic enzymes involved in the formation and/or inactivation of androgens, such as the numerous 3ß-hydroxysteroid dehydrogenase (HSD)/isomerases, 17ß-HSDs, 3-HSDs uridine diphosphate glucuronosyltransferases, etc. (Fig. 5). We should also take into account the potential gene-gene and gene-environment interactions of low- or moderate-penetrance genes, which likely cumulate to contribute to an overall prostate cancer risk and to disease characteristics. In this regard, when several SNPs occur in the same gene/locus or chromosomal region, it will be crucial to establish in each individual tested using haplotyping, if possible, an exhaustive genomic profiling for all selected sequence variants. This will allow a better estimate of their global contribution in various mechanisms involved in prostate cancer, such as in pathways involved in the fine control of intracellular androgen bioavailability and in the signal transduction of their cell-specific action.

In parallel, characterization of gene expression profiles that molecularly distinguish prostatic neoplasms may identify new target candidate genes involved in prostate cancer risk in addition to elucidate useful new clinical biomarkers leading to an improved classification of prostate cancer. This will be of special interest if such signature may help to distinguish hereditary vs. sporadic prostate carcinomas, as it has recently been achieved for breast cancer (94). Moreover, the integration of gene expression data with the knowledge of the human genome sequence as well as those of experimental models will be useful to accelerate positional cloning approaches that are often hampered by incomplete phenotypic penetrance, small pedigree size, and limited access to DNA samples from affected individuals. The elucidation of transcriptomes of normal and tumoral prostate tissues can effectively focus efforts on a manageable subset of genes, thus facilitating the candidate gene approaches, especially when genetic maps cover a broad chromosomal region as frequently observed for prostate cancer susceptibility loci. Integrating both expression and functional information may further speed gene discovery via the candidate gene approach as recently suggested for retinal disease genes (95).

We are at the very early phases of functional genomics, and rapid advances are also anticipated in more quantitative proteomics and bioinformatics, which should dramatically increase the likelihood of finding clinically relevant candidate genes, gene clusters, and signaling pathways that will translate into better diagnostic or more targeted therapeutic strategies for men with prostate cancer.

	Acknowledgments

 
J. Simard is chairholder of the Canada Research Chair in Oncogenetics, funded by the Canada Research Chair Program. We would like to thank Professor Van Luu-The for helpful discussion.

	Footnotes

 
Abbreviations: DHT, Dihydrotestosterone; HPC, hereditary prostate cancer; HSD, hydroxysteroid dehydrogenase; NMM, no evidence of male-to-male; RNAse, ribonuclease; RNASEL, RNAse L gene.

Received March 12, 2002.

Accepted for publication March 26, 2002.

	References

Top Summary Introduction Mapping putative loci for... A strong candidate prostate... Mutations in the ribonuclase... Risk of prostate cancer... Common low-penetrance allelic... Concluding remarks and future... References

 

1. Hsing AW, Tsao L, Devesa SS 2000 International trends and patterns of prostate cancer incidence and mortality. Int J Cancer 85:60–67[CrossRef][Medline]
2. Labrie F, Cancer of the prostate. In: Pollock R, ed. The UICC manual of clinical oncology, 8th ed., in press
3. Morganti G, Gianferrari L, Cresseri A, Arrigoni G, Lovati G 1956 Recherches clinico-statistiques et génétiques sur les néoplasies de la prostate. Acta Genet 6:304–305
4. Eeles R 1999 The UK Familial Prostate Study Co-ordinating Group & The CRC/BPG UK Familial Prostate Study Collaborators. Prostate Cancer Prostatic Dis 2:9–15[CrossRef][Medline]
5. Ostrander EA, Stanford JL 2000 Genetics of prostate cancer: too many loci, too few genes. Am J Hum Genet 67:1367–1375[CrossRef][Medline]
6. Singh R ER, Durocher F, Simard J, Edwards S, Badzioch M, Kote-Jarai Z, Teare D, Ford D, Dearnaley D, Ardern-Jones A, Murkin A, Dowe A, Shearer R, Kelly J, The CRC/BPG UK Familial Prostate Cancer Study Collaborators, Labrie F, Easton D, Narod SA, Tonin PN, Foulkes WD 2000 High risk genes predisposing to prostate cancer—do they exist? Prostate Cancer Prostatic Dis 3:241–247[CrossRef][Medline]
7. Nwosu V, Carpten J, Trent JM, Sheridan R 2001 Heterogeneity of genetic alterations in prostate cancer: evidence of the complex nature of the disease. Hum Mol Genet 10:2313–2318[Abstract/Free Full Text]
8. Eeles RA, Cannon-Albright L 1996 Familial prostate cancer and its management. In: Eeles RA, Ponder BAJ, Easton DF, Horwich A, eds. Genetic predisposition to cancer. Chapter 22. London: Chapman & Hall Medical; 320–332
9. Cannon L, Bishop DT, Skolnick M, Hunt S, Lyon JL, Smart CR 1982 Genetic epidemiology of prostate cancer in the Utah Mormon genealogy. Cancer Surv 1:47–69
10. Carter BS, Beaty TH, Steinberg GD, Childs B, Walsh PC 1992 Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci USA 89:3367–3371[Abstract/Free Full Text]
11. Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC 1990 Family history and the risk of prostate cancer. Prostate 17:337–347[Medline]
12. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K 2000 Environmental and heritable factors in the causation of cancer— analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85[Abstract/Free Full Text]
13. Schaid DJ, McDonnell SK, Blute ML, Thibodeau SN 1998 Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62:1425–1438[CrossRef][Medline]
14. Gronberg H, Isaacs SD, Smith JR, Carpten JD, Bova GS, Freije D, Xu J, Meyers DA, Collins FS, Trent JM, Walsh PC, Isaacs WB 1997 Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAMA 278:1251–1255[Abstract]
15. Narod SA, Dupont A, Cusan L, Diamond P, Gomez JL, Suburu R, Labrie F 1995 The impact of family history on early detection of prostate cancer. Nat Med 1:99–101[CrossRef][Medline]
16. Monroe KR, Yu MC, Kolonel LN, Coetzee GA, Wilkens LR, Ross RK, Henderson BE 1995 Evidence of an X-linked or recessive genetic component to prostate cancer risk. Nat Med 1:827–829[CrossRef][Medline]
17. Smith JR, Freije D, Carpten JD, Gronberg H, Xu J, Isaacs SD, Brownstein MJ, Bova GS, Guo H, Bujnovszky P, Nusskern DR, Damber JE, Bergh A, Emanuelsson M, Kallioniemi OP, Walker-Daniels J, Bailey-Wilson JE, Beaty TH, Meyers DA, Walsh PC, Collins FS, Trent JM, Isaacs WB 1996 Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274:1371–1374[Abstract/Free Full Text]
18. Xu J, Zheng SL, Chang B, Smith JR, Carpten JD, Stine OC, Isaacs SD, Wiley KE, Henning L, Ewing C, Bujnovszky P, Bleeker ER, Walsh PC, Trent JM, Meyers DA, Isaacs WB 2001 Linkage of prostate cancer susceptibility loci to chromosome 1. Hum Genet 108:335–345[CrossRef][Medline]
19. Berthon P, Valeri A, Cohen-Akenine A, Drelon E, Paiss T, Wohr G, Latil A, Millasseau P, Mellah I, Cohen N, Blanche H, Bellane-Chantelot C, Demenais F, Teillac P, Le Duc A, de Petriconi R, Hautmann R, Chumakov I, Bachner L, Maitland NJ, Lidereau R, Vogel W, Fournier G, Mangin P, Cohen D, Cussenot O 1998 Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2–43. Am J Hum Genet 62:1416–1424[CrossRef][Medline]
20. Xu J, Meyers D, Freije D, Isaacs S, Wiley K, Nusskern D, Ewing C, Wilkens E, Bujnovszky P, Bova GS, Walsh P, Isaacs W, Schleutker J, Matikainen M, Tammela T, Visakorpi T, Kallioniemi OP, Berry R, Schaid D, French A, McDonnell S, Schroeder J, Blute M, Thibodeau S, Grönberg H, Emanuelsson M, Damber J-E, Smith J, Bailey-Wilson J, Carpten J, Stephan D, Gillanders E, Amundson I, Kaino T, Freas-Lutz D, Baffor-Bonnie A, Van Aucken A, Sood R, Collins F, Brownstein M, Trent J 1998 Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 20:175–179[CrossRef][Medline]
21. Gibbs M, Stanford JL, McIndoe RA, Jarvik GP, Kolb S, Goode EL, Chakrabarti L, Schuster EF, Buckley VA, Miller EL, Brandzel S, Li S, Hood L, Ostrander EA 1999 Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am J Hum Genet 64:776–787[CrossRef][Medline]
22. Berry R, Schroeder JJ, French AJ, McDonnell SK, Peterson BJ, Cunningham JM, Thibodeau SN, Schaid DJ 2000 Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am J Hum Genet 67:82–91[CrossRef][Medline]
23. Tavtigian SV, Simard J, Teng DH, Abtin V, Baumgard M, Beck A, Camp NJ, Carillo AR, Chen Y, Dayananth P, Desrochers M, Dumont M, Farnham JM, Frank D, Frye C, Ghaffari S, Gupte JS, Hu R, Iliev D, Janecki T, Kort EN, Laity KE, Leavitt A, Leblanc G, McArthur-Morrison J, Pederson A, Penn B, Peterson KT, Reid JE, Richards S, Schroeder M, Smith R, Snyder SC, Swedlund B, Swensen J, Thomas A, Tranchant M, Woodland AM, Labrie F, Skolnick MH, Neuhausen S, Rommens J, Cannon-Albright LA 2001 A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet 27:172–180[CrossRef][Medline]
24. Xu J, Zheng SL, Hawkins GA, Faith DA, Kelly B, Isaacs SD, Wiley KE, Chang B, Ewing CM, Bujnovszky P, Carpten JD, Bleecker ER, Walsh PC, Trent JM, Meyers DA, Isaacs WB 2001 Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22–23. Am J Hum Genet 69:341–350[CrossRef][Medline]
25. Abate-Shen C, Shen MM 2000 Molecular genetics of prostate cancer. Genes Dev 14:2410–2434[Free Full Text]
26. Neuhausen SL, Farnham JM, Kort E, Tavtigian SV, Skolnick MH, Cannon-Albright LA 1999 Prostate cancer susceptibility locus HPC1 in Utah high-risk pedigrees. Hum Mol Genet 8:2437–2442[Abstract/Free Full Text]
27. Xu J 2000 International Consortium for Prostate Cancer Genetics. Combined analysis of hereditary prostate cancer linkage to 1q24–25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics (published erratum appears in Am J Hum Genet 2000;67:541–542) 66:945–957
28. Eeles RA, Durocher F, Edwards S, Teare D, Badzioch M, Hamoudi R, Gill S, Biggs P, Dearnaley D, Ardern-Jones A, Dowe A, Shearer R, McLennan DL, Norman RL, Ghadirian P, Aprikian A, Ford D, Amos C, King TM, Labrie F, Simard J, Narod SA, Easton D, Foulkes WD 1998 Linkage analysis of chromosome 1q markers in 136 prostate cancer families. The Cancer Research Campaign/British Prostate Group U.K. Familial Prostate Cancer Study Collaborators. Am J Hum Genet 62:653–658[CrossRef][Medline]
29. Goode EL, Stanford JL, Chakrabarti L, Gibbs M, Kolb S, McIndoe RA, Buckley VA, Schuster EF, Neal CL, Miller EL, Brandzel S, Hood L, Ostrander EA, Jarvik GP 2000 Linkage analysis of 150 high-risk prostate cancer families at 1q24–25. Genet Epidemiol 18:251–275[CrossRef][Medline]
30. Schleutker J, Matikainen M, Smith J, Koivisto P, Baffoe-Bonnie A, Kainu T, Gillanders E, Sankila R, Pukkala E, Carpten J, Stephan D, Tammela T, Brownstein M, Bailey-Wilson J, Trent J, Kallioniemi OP 2000 A genetic epidemiological study of hereditary prostate cancer (HPC) in Finland: frequent HPCX linkage in families with late-onset disease. Clin Cancer Res 6:4810–4815[Abstract/Free Full Text]
31. Goode EL, Stanford JL, Peters MA, Janer M, Gibbs M, Kolb S, Badzioch MD, Hood L, Ostrander EA, Jarvik GP 2001 Clinical characteristics of prostate cancer in an analysis of linkage to four putative susceptibility loci. Clin Cancer Res 7:2739–2749[Abstract/Free Full Text]
32. Cancel-Tassin G, Latil A, Valeri A, Mangin P, Fournier G, Berthon P, Cussenot O 2001 PCAP is the major known prostate cancer predisposing locus in families from south and west Europe. Eur J Hum Genet 9:135–142[CrossRef][Medline]
33. Goddard KA, Witte JS, Suarez BK, Catalona WJ, Olson JM 2001 Model-free linkage analysis with covariates confirms linkage of prostate cancer to chromosomes 1 and 4. Am J Hum Genet 68:1197–1206[CrossRef][Medline]
34. Berry R, Schaid DJ, Smith JR, French AJ, Schroeder JJ, McDonnell SK, Peterson BJ, Wang ZY, Carpten JD, Roberts SG, Tester DJ, Blute ML, Trent JM, Thibodeau SN 2000 Linkage analyses at the chromosome 1 loci 1q24–25 (HPC1), 1q42.2–43 (PCAP), and 1p36 (CAPB) in families with hereditary prostate cancer. Am J Hum Genet 66:539–546[CrossRef][Medline]
35. Badzioch M, Eeles R, Leblanc G, Foulkes WD, Giles G, Edwards S, Goldgar D, Hopper JL, Bishop DT, Moller P, Heimdal K, Easton D, Simard J 2000 Suggestive evidence for a site specific prostate cancer gene on chromosome 1p36. The CRC/BPG UK Familial Prostate Cancer Study Coordinators and Collaborators. The EU Biomed Collaborators. J Med Genet 37:947–949[Free Full Text]
36. Zheng SL, Xu J, Isaacs SD, Wiley K, Chang B, Bleecker ER, Walsh PC, Trent JM, Meyers DA, Isaacs WB 2001 Evidence for a prostate cancer linkage to chromosome 20 in 159 hereditary prostate cancer families. Hum Genet 108:430–435[CrossRef][Medline]
37. Bock CH, Cunningham JM, McDonnell SK, Schaid DJ, Peterson BJ, Pavlic RJ, Schroeder JJ, Klein J, French AJ, Marks A, Thibodeau SN, Lange EM, Cooney KA 2001 Analysis of the prostate cancer-susceptibility locus HPC20 in 172 families affected by prostate cancer. Am J Hum Genet 68:795–801[CrossRef][Medline]
38. Lange EM, Chen H, Brierley K, Perrone EE, Bock CH, Gillanders E, Ray ME, Cooney KA 1999 Linkage analysis of 153 prostate cancer families over a 30-cM region containing the putative susceptibility locus HPCX. Clin Cancer Res 5:4013–4020[Abstract/Free Full Text]
39. Peters MA, Jarvik GP, Janer M, Chakrabarti L, Kolb S, Goode EL, Gibbs M, DuBois CC, Schuster EF, Hood L, Ostrander EA, Stanford JL 2001 Genetic linkage analysis of prostate cancer families to Xq27–28. Hum Hered 51:107–113[CrossRef][Medline]
40. Bergthorsson JT, Johannesdottir G, Arason A, Benediktsdottir KR, Agnarsson BA, Bailey-Wilson JE, Gillanders E, Smith J, Trent J, Barkardottir RB 2000 Analysis of HPC1, HPCX, and PCaP in Icelandic hereditary prostate cancer. Hum Genet 107:372–375[CrossRef][Medline]
41. Cannon-Albright LA, Goldgar DE, Meyer LJ, Lewis CM, Anderson DE, Fountain JW, Hegi ME, Wiseman RW, Petty EM, Bale AE, Olopade OI, Diaz MO, Kwiatkowski DJ, Piepkorn MW, Zone JJ, Skolnick MH 1992 Assignment of a locus for familial melanoma, MLM, to chromosome 9p13- p22. Science 258:1148–1152[Abstract/Free Full Text]
42. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, Bell R, Rosenthal J, Hussey C, Tran T, McClure M, Frye C, Hattier T, Phelps R, Haugen-Strano A, Katcher H, Yakumo K, Gholami Z, Shaffer D, Stone S, Bayer S, Wray C, Bogden R, Dayananth P, Ward J, Tonin P, Narod S, Bristow PK, Noris FH, Helvering L, Morrison P, Rosteck P, Lai M, Barrett JC, Lewis C, Neuhausen S, Cannon-Albright L, Goldgar D, Wiseman R, Kamb A, Skolnick MH 1994 A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71[Abstract/Free Full Text]
43. Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D, Fields P, Marshall G, Narod S, Lenoir GM, Lynch H, Feunteun J, Devilee P, Cornelisse CJ, Menko FH, Daly PA, Ormiston W, McManus R, Pye C, Lewis CM, Cannon-Albright LA, Peto J, Ponder BAJ, Skolnick MH, Easton DF, Goldgar DE, Stratton MR 1994 Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science 265:2088–2090[Abstract/Free Full Text]
44. Rebbeck TR, Walker AH, Zeigler-Johnson C, Weisburg S, Martin AM, Nathanson KL, Wein AJ, Malkowicz SB 2000 Association of HPC2/ELAC2 genotypes and prostate cancer. Am J Hum Genet 67:1014–1019[CrossRef][Medline]
45. Suarez BK, Gerhard DS, Lin J, Haberer B, Nguyen L, Kesterson NK, Catalona WJ 2001 Polymorphisms in the prostate cancer susceptibility gene HPC2/ELAC2 in multiplex families and healthy controls. Cancer Res 61:4982–4984[Abstract/Free Full Text]
46. Wang L, McDonnell SK, Elkins DA, Slager SL, Christensen E, Marks AF, Cunningham JM, Peterson BJ, Jacobsen SJ, Cerhan JR, Blute ML, Schaid DJ, Thibodeau SN 2001 Role of HPC2/ELAC2 in hereditary prostate cancer. Cancer Res 61:6494–6499[Abstract/Free Full Text]
47. Rokman A, Ikonen T, Mononen N, Autio V, Matikainen MP, Koivisto PA, Tammela TL, Kallioniemi OP, Schleutker J 2001 ELAC2/HPC2 involvement in hereditary and sporadic prostate cancer. Cancer Res 61:6038–6041[Abstract/Free Full Text]
48. Xu J, Zheng SL, Carpten JD, Nupponen NN, Robbins CM, Mestre J, Moses TY, Faith DA, Kelly BD, Isaacs SD, Wiley KE, Ewing CM, Bujnovszky P, Chang B, Bailey-Wilson J, Bleecker ER, Walsh PC, Trent JM, Meyers DA, Isaacs WB 2001 Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer. Am J Hum Genet 68:901–911[CrossRef][Medline]
49. Carpten J, Nupponen N, Isaacs S, Sood R, Robbins C, Xu J, Faruque M, Moses T, Ewing C, Gillanders E, Hu P, Bujnovszky P, Makalowska I, Baffoe-Bonnie A, Faith D, Smith J, Stephan D, Wiley K, Brownstein M, Gildea D, Kelly B, Jenkins R, Hostetter G, Matikainen M, Schleutker J, Klinger K, Connors T, Xiang Y, Wang Z, De Marzo A, Papadopoulos N, Kallioniemi OP, Burk R, Meyers D, Gronberg H, Meltzer P, Silverman R, Bailey-Wilson J, Walsh P, Isaacs W, Trent J 2002 Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat Genet 30:181–184[CrossRef][Medline]
50. Anderson DE, Badzioch MD 1992 Breast cancer risks in relatives of male breast cancer patients. J Natl Cancer Inst 84:1114–1117[Abstract/Free Full Text]
51. Tulinius H, Egilsson V, Olafsdottir GH, Sigvaldason H 1992 Risk of prostate, ovarian, and endometrial cancer among relatives of women with breast cancer. Br Med J 305:855–857
52. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE 1994 Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343:692–695[CrossRef][Medline]
53. 1999 Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91:1310–1316
54. Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, Tulinius H, Ogmundsdottir HM, Eyfjord JE 1996 A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 13:117–119[CrossRef][Medline]
55. Sigurdsson S, Thorlacius S, Tomasson J, Tryggvadottir L, Benediktsdottir K, Eyfjord JE, Jonsson E 1997 BRCA2 mutation in Icelandic prostate cancer patients. J Mol Med 75:758–761[CrossRef][Medline]
56. Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Wacholder S, Tulinius H, Eyfjord JE 1998 Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 352:1337–1339[CrossRef][Medline]
57. Lehrer S, Fodor F, Stock RG, Stone NN, Eng C, Song HK, McGovern M 1998 Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer. Br J Cancer 78:771–773[Medline]
58. Hubert A, Peretz T, Manor O, Kaduri L, Wienberg N, Lerer I, Sagi M, Abeliovich D 1999 The Jewish Ashkenazi founder mutations in the BRCA1/BRCA2 genes are not found at an increased frequency in Ashkenazi patients with prostate cancer. Am J Hum Genet 65:921–924[CrossRef][Medline]
59. Wilkens EP, Freije D, Xu J, Nusskern DR, Suzuki H, Isaacs SD, Wiley K, Bujnovsky P, Meyers DA, Walsh PC, Isaacs WB 1999 No evidence for a role of BRCA1 or BRCA2 mutations in Ashkenazi Jewish families with hereditary prostate cancer. Prostate 39:280–284[CrossRef][Medline]
60. Nastiuk KL, Mansukhani M, Terry MB, Kularatne P, Rubin MA, Melamed J, Gammon MD, Ittmann M, Krolewski JJ 1999 Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men. Prostate 40:172–177[CrossRef][Medline]
61. Gayther SA, de Foy KA, Harrington P, Pharoah P, Dunsmuir WD, Edwards SM, Gillett C, Ardern-Jones A, Dearnaley DP, Easton DF, Ford D, Shearer RJ, Kirby RS, Dowe AL, Kelly J, Stratton MR, Ponder BA, Barnes D, Eeles RA 2000 The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res 60:4513–4518[Abstract/Free Full Text]
62. Gronberg H, Ahman AK, Emanuelsson M, Bergh A, Damber JE, Borg A 2001 BRCA2 mutation in a family with hereditary prostate cancer. Genes Chromosomes Cancer 30:299–301[CrossRef][Medline]
63. Sinclair CS, Berry R, Schaid D, Thibodeau SN, Couch FJ 2000 BRCA1 and BRCA2 have a limited role in familial prostate cancer. Cancer Res 60:1371–1375[Abstract/Free Full Text]
64. Ross RK, Coetzee GA, Pearce CL, Reichardt JK, Bretsky P, Kolonel LN, Henderson BE, Lander E, Altshuler D, Daley G 1999 Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. Eur Urol 35:355–361[CrossRef][Medline]
65. Makridakis NM, Reichardt JK 2001 Mole