Prevalence and Spectrum of AR Ligand-Binding Domain Mutations Detected in Circulating-Tumor DNA Across Disease States in Men With Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) is typically treated with agents directly or indirectly targeting the androgen receptor (AR) pathway. However, such treatment is limited by resistance mechanisms, including the development of activating mutations in the AR ligand-binding domain (AR-LBD). METHODS: This study evaluated a database of over 15,000 patients with advanced prostate cancer (PC) undergoing comprehensive circulating-tumor DNA analysis (Guardant360, Redwood City, CA) between 2014 and 2021, with associated clinical information from administrative claims (GuardantINFORM database). RESULTS: Of 15,705 patients with PC included, 54% had mCRPC at the time of their blood draw. Of those, 49% had previous treatment with an AR pathway inhibitor (ARPi). AR-LBD mutation prevalence was 15% in patients with mCRPC who were untreated with a next-generation ARPi, 22% in those after one line of ARPi therapy, and 24% in those after two lines of ARPi treatment. Next-generation ARPi treatment yielded an increase in AR L702H and T878A/S mutations after abiraterone, and an increase in AR L702H and F877L mutations after enzalutamide. AR-LBD+ patients demonstrated unique biology, including increased concurrent mutations in the cell-cycle, wingless-related integration site, homologous recombination repair, and phospho-inositide 3-kinase pathways (all P < .0005), and greater low-level (copy number <10) AR amplifications (P = .0041). AR-LBD+ patients exhibited worse overall survival (OS) relative to a matched cohort of AR-LBD- patients (50.1 v 60.7 months, unadjusted log-rank P = .013). CONCLUSION: This large database analysis demonstrates that AR-LBD mutation prevalence increases after next-generation ARPi use. AR-LBD+ tumors demonstrate unique biology (more oncogenic pathway mutations and low-level AR amplification) and reduced OS. These findings inform the development of novel therapies designed to circumvent AR-mediated therapeutic resistance.

Targeted Inhibition of CYP11A1 in Castration-Resistant Prostate Cancer.

BACKGROUND: Prostate cancer is regulated by steroid hormones, even in castration-resistant disease. ODM-208, a novel inhibitor of cytochrome P450 11A1 (which catalyzes the first step of steroid-hormone biosynthesis), was investigated in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). METHODS: CYPIDES is a first-in-human phase 1 (3 + 3 design) and phase 2 study. We administered ODM-208 twice daily with glucocorticoid/mineralocorticoid replacement and ongoing androgen deprivation therapy to adults with previously treated mCRPC, regardless of androgen receptor gene (AR) ligand-binding domain mutations (phase 1) and with activating AR ligand-binding domain mutations (ARmut; phase 2). Safety, pharmacokinetics, steroid-hormone pharmacodynamics, and preliminary efficacy were the key outcomes. RESULTS: Ninety-two patients received one or more doses of ODM-208: 47 in phase 1 (20 [42.6%] with ARmut) and 45 in phase 2 (all ARmut). A dose of ODM-208 of 5 mg twice a day with dexamethasone 1 mg/fludrocortisone 0.1 mg provided a balance between decreased steroidogenesis and toxicity. Treatment-related adrenal insufficiency was the most common toxicity in phase 1 (n=17, 36.2%; necessitating ODM-208 discontinuation in one patient); this toxicity occurred in six patients (13.3%) at 5 mg twice a day in phase 2. Median circulating testosterone levels declined from 3.0 ng/dl (interquartile range, 1.3 to 6.2 ng/dl) at baseline to undetectable levels within the first week of ODM-208 5 mg twice a day treatment in 46 of 53 (87%) patients. A decrease in prostate-specific antigen levels of 50% or more occurred in 14 of 19 (73.7%) patients with ARmut and 2 of 23 (8.7%) patients with AR wild type in phase 1 and in 24 of 45 (53.3%) patients with ARmut in phase 2. CONCLUSIONS: ODM-208 potently inhibited steroid-hormone biosynthesis with the expected toxicity of adrenal insufficiency. Evidence of antitumor activity was observed in this heavily pretreated mCRPC population, especially in those with ARmut. (Funded by Orion Pharma; ClinicalTrials.gov number, NCT03436485.)

Phase I/IIa, open-label, multicentre study to evaluate the optimal dosing and safety of ODM-203 in patients with advanced or metastatic solid tumours.

BACKGROUND: Genetic alterations in fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) signalling are observed in various tumours. We report a first-in-human phase I/IIa trial evaluating tolerability, pharmacokinetics and preliminary antitumour activity of ODM-203, a novel FGFR and VEGFR inhibitor. METHODS: Open-label, non-randomised, multicentre, phase I/IIa dose escalation and expansion study in patients with advanced or metastatic solid tumours. RESULTS: Overall, 84 patients received treatment; optimal tablet dose was found to be 400 mg/day with food. All patients experienced at least one adverse event; the majority (89.2%) were grade 1 or 2% and 70.4% were considered treatment related. The most commonly reported events were bilirubin increase-related events (75%) and diarrhoea (50%).Overall response rate was 9.2% and median progression-free survival was 16.1 and 12.4 weeks for patients with aberrant or non-aberrant FGFR tumours. Median time on treatment was 10.1 weeks for all patients and 14.5 weeks for patients who received 400 mg tablets. CONCLUSION: This study suggests ODM-203 400 mg/day results in sufficient plasma concentrations and acceptable tolerability in most patients. Preliminary signs of therapeutic activity of ODM-203 in patients with solid tumours was observed. TRIAL REGISTRATION NUMBER: NCT02264418.

ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity.

Alterations in the gene encoding for the FGFR and upregulation of the VEGFR are found often in cancer, which correlate with disease progression and unfavorable survival. In addition, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-molecule FGFR kinase inhibitors are currently in clinical development. ODM-203 is a novel, selective, and equipotent inhibitor of the FGFR and VEGFR families. In this report we show that ODM-203 inhibits FGFR and VEGFR family kinases selectively and with equal potency in the low nanomolar range (IC50 6-35 nmol/L) in biochemical assays. In cellular assays, ODM-203 inhibits VEGFR-induced tube formation (IC50 33 nmol/L) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC50 50-150 nmol/L). In vivo, ODM-203 shows strong antitumor activity in both FGFR-dependent xenograft models and in an angiogenic xenograft model at similar well-tolerated doses. In addition, ODM-203 inhibits metastatic tumor growth in a highly angiogenesis-dependent kidney capsule syngenic model. Interestingly, potent antitumor activity in the subcutaneous syngenic model correlated well with immune modulation in the tumor microenvironment as indicated by marked decrease in the expression of immune check points PD-1 and PD-L1 on CD8 T cells and NK cells, and increased activation of CD8 T cells. In summary, ODM-203 shows equipotent activity for both FGFR and VEGFR kinase families and antitumor activity in both FGFR and angigogenesis models.

Structure-guided discovery of 1,3,5 tri-substituted benzenes as potent and selective matriptase inhibitors exhibiting in vivo antitumor efficacy.

Matriptase is a serine protease implicated in cancer invasion and metastasis. Expression of matriptase is frequently dysregulated in human cancers and matriptase has been reported to activate latent growth factors such as hepatocyte growth factor/scatter factor, and proteases such as urokinase plasminogen activator suggesting that matriptase inhibitors could have therapeutic potential in treatment of cancer. Here we report a structure-based approach which led to the discovery of selective and potent matriptase inhibitors with benzene as central core having 1,3,5 tri-substitution pattern. X-ray crystallography of one of the potent analogs in complex with matriptase revealed strong hydrogen bonding and salt-bridge interactions in the S1 pocket, as well as strong CH-π contacts between the P2/P4 cyclohexyl and Trp215 side-chain. An additional interaction of the pendant amine at cyclohexyl with Gln175 side-chain results in substantial improvement in matriptase inhibition and selectivity against other related serine proteases. Compounds 15 and 26 showed tumor growth inhibition in a subcutaneous DU-145 prostate cancer mouse model. These compounds could be useful as tools to further explore the biology of matriptase as a drug target.

NMD and microRNA expression profiling of the HPCX1 locus reveal MAGEC1 as a candidate prostate cancer predisposition gene.

BACKGROUND: Several predisposition loci for hereditary prostate cancer (HPC) have been suggested, including HPCX1 at Xq27-q28, but due to the complex structure of the region, the susceptibility gene has not yet been identified. METHODS: In this study, nonsense-mediated mRNA decay (NMD) inhibition was used for the discovery of truncating mutations. Six prostate cancer (PC) patients and their healthy brothers were selected from a group of HPCX1-linked families. Expression analyses were done using Agilent 44 K oligoarrays, and selected genes were screened for mutations by direct sequencing. In addition, microRNA expression levels in the lymphoblastic cells were analyzed to trace variants that might alter miRNA expression and explain partly an inherited genetic predisposion to PC. RESULTS: Seventeen genes were selected for resequencing based on the NMD array, but no truncating mutations were found. The most interesting variant was MAGEC1 p.Met1?. An association was seen between the variant and unselected PC (OR = 2.35, 95% CI = 1.10-5.02) and HPC (OR = 3.38, 95% CI = 1.10-10.40). miRNA analysis revealed altogether 29 miRNAs with altered expression between the PC cases and controls. miRNA target analysis revealed that 12 of them also had possible target sites in the MAGEC1 gene. These miRNAs were selected for validation process including four miRNAs located in the X chromosome. The expressions of 14 miRNAs were validated in families that contributed to the significant signal differences in Agilent arrays. CONCLUSIONS: Further functional studies are needed to fully understand the possible contribution of these miRNAs and MAGEC1 start codon variant to PC.

ARLTS1 germline variants and the risk for breast, prostate, and colorectal cancer.

Recently, a nonsense alteration Trp149Stop in the ARLTS1 gene was found more frequently in familial cancer cases versus sporadic cancer patients and healthy controls. Here, the role of Trp149Stop or any other ARLTS1 germline variant was evaluated on breast, prostate, and colorectal cancer risk. The whole gene was screened for germline alterations in 855 familial cancer patients. The five observed variants were further screened in 1169 non-familial cancer patients as well as in 809 healthy population controls. The Trp149Stop was found at low frequencies (0.5-1.2%) in all patient subgroups versus 1.6% in controls, and the mutant allele did not co-segregate with disease status in families with multiple affected individuals. The CC genotype in the Cys148Arg variant was slightly more common among both familial and sporadic breast (odds ratio (OR), 1.48; 95% confidence interval (CI), 1.16-1.87; P=0.001) and prostate cancer patients (OR, 1.50; 95% CI, 1.13-1.99; P=0.005) when compared to controls. A novel ARLTS1 variant Gly65Val was found at higher frequency among familial prostate cancer patients (8 of 164, 4.9%) than in controls (13 of 809, 1.6%; OR, 3.14; 95% CI, 1.28-7.70, P=0.016). However, after adjusting for multiple testing, none of these results were still significant. No association was found with any of the variants and colorectal cancer risk. Our results suggest that Trp149Stop is not a predisposition allele in breast, prostate, or colorectal cancer in the Finnish population, and, while the Gly65Val variant may increase familial prostate cancer risk and the Cys148Arg change may affect both breast and prostate cancer risk, the evidence is not strong in these data.

Lactase persistence, dietary intake of milk, and the risk for prostate cancer in Sweden and Finland.

Prostate carcinoma is the most common cancer in men. Its primary pathogenesis is mostly unknown. Dairy products containing lactose have been suggested to be risk factors for prostate cancer. Digestion of lactose is dependent on lactase activity in the intestinal wall. A single nucleotide polymorphism C to T residing 13,910 bp upstream of the lactase gene has been shown to associate with the developmental down-regulation of lactase activity underlying persistence/nonpersistence trait. To find out whether lactase persistence is related to the risk for prostate cancer, we genotyped 1,229 Finnish and 2,924 Swedish patients and their 473 Finnish and 1,842 Swedish controls using solid-phase minisequencing. To explore if dairy products have an association with prostate cancer, we analyzed the milk consumption in the Swedish study consisting of 1,499 prostate cancer patients and 1,130 controls (Cancer Prostate in Sweden I study) using a questionnaire. Only the consumption of low-fat milk was found to be associated with increased risk of prostate cancer [odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.16-2.39]. A statistically significantly higher (P < 0.01) lactose intake was observed among subjects with high lactase activity (C/T and T/T genotypes) compared with those with low lactase activity (C/C genotype). Lactase persistence did not associate with increased risk for prostate carcinoma in the Finnish (OR, 1.11; 95% CI, 0.83-1.47; P = 0.488) or in the Swedish populations (OR, 1.16; 95% CI, 0.91-1.46; P = 0.23). In conclusion, lactase persistence/nonpersistence contains no risk for prostate cancer. Analysis of different milk products showed some evidence for low-fat milk as a potential risk factor for prostate cancer.

KLF6 IVS1 -27G>A variant and the risk of prostate cancer in Finland.

OBJECTIVES: A recent report demonstrated that KLF6 IVS1 -27G>A substitution increases the transcription of alternatively spliced isoforms; this action was suggested to be associated with prostate cancer (pCA). To evaluate these findings among the Finnish population, a total of 3348 samples were analysed. METHODS: The variant was genotyped in 164 patients with familial pCA, 852 patients with unselected pCA, 459 patients with benign prostate hyperplasia (BPH), 923 male population controls, and 950 men from a Finnish prostate-specific antigen (PSA) screening trial with PSA levels less than 1.0ng/ml. Odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) were calculated by using logistic regression to estimate pCA risk. RESULTS: Association testing revealed no significant differences between familial prostate cancer patients and population controls (OR: 0.84; 95%CI, 0.56-1.28; p=0.42), unselected cases and controls (OR: 0.95; 95%CI, 0.76-1.19; p=0.63), or BPH cases and controls (OR: 1.12; 95%CI, 0.86-1.46; p=0.39). pCA and BPH cases were also compared with PSA-screened controls. None of these analyses revealed any significant associations. CONCLUSIONS: Our results do not support the suggested association of KLF6 IVS1 -27G>A germline polymorphism with pCA risk and also suggest that the variant is not a risk allele for BPH in the Finnish population.

Role of the Nijmegen breakage syndrome 1 gene in familial and sporadic prostate cancer.

The Nijmegen breakage syndrome 1 (NBS1) gene, which participates in DNA double strand break repair, has been postulated to be a susceptibility factor for a number of cancers, including prostate cancer. Numerous mutations have been identified in NBS1, including the founder mutation 657del5. In this study, a number of analyses were done to determine whether mutations in NBS1 are associated with an increased risk for prostate cancer. The frequency of the 657del5 mutation in both familial prostate cancer cases (1,819 affected men among 909 families) and sporadic prostate cancer cases (1,218 affected men) collected from five centers participating in the International Consortium for Prostate Cancer Genetics were compared with that found in 697 normal controls. Seven individuals were identified to carry the mutation among the 3,037 cases screened: four in the familial group (three from one family and one from another) and three in the sporadic cases. The carrier frequency was 0.22% (2 of 909) for the probands and 0.25% (3 of 1,218) for the sporadic cases of prostate cancer. The 657del5 mutation was not detected in either the 293 unaffected members of the prostate cancer families or in the 697 control samples tested. The entire NBS1 gene was also sequenced in 20 of the youngest affected individuals from the Finnish group of familial cases to identify the presence of possible mutations in this high-risk group. One rare (D95N) and one common (E185Q) missense alteration was identified. More detailed analyses of the E185Q polymorphism, along with a third rare variant (R215W), failed to show an association with prostate cancer. Because the 657del5 mutation was absent from the control population, we are unable to determine if this alteration predisposes to prostate cancer. However, our data does suggest that mutations within NBS1, and in particular, 657del5, do not significantly contribute to the overall prostate cancer burden within our patient samples.

Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors.

Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T(1)-T(2)) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 -34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3 -252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.

Hemochromatosis gene mutations among Finnish male breast and prostate cancer patients.

Hereditary hemochromatosis (HH), the most common genetic disease in northern Europeans, is an autosomal recessive disorder of iron metabolism. The association between hepatocellular carcinoma and HFE homozygosity is well documented, but recently HFE hetero- and homozygosity has also been linked to nonhepatocellular malignancies, including female breast cancer. We hypothesized that C282Y and H63D mutations in the HFE gene could contribute to male breast cancer (MBC) and prostate cancer (PC) susceptibility at the population level in Finland. We screened the 2 major HFE mutations, H63D and C282Y, from 116 MBC cases diagnosed in Finland between 1967 and 1996, 843 consecutive unselected PC cases diagnosed at the Pirkanmaa Hospital District between 1999 and 2001 and 480 anonymous blood donor controls by minisequencing. Our results indicate that the frequencies of the HFE mutations do not significantly differ between MBC and PC patients and the population-based controls. No significantly altered risks for MBC or PC among carriers of the 2 variants were observed. However, HFE mutations were seen twice as often among carriers of a common BRCA2 mutation 9346(-2)A-->G compared with the rest of the MBC cases, indicating that HFE may be an MBC risk modifier gene among BRCA2 mutation carriers. In conclusion, our results indicate a minor role for the HFE mutations C282Y and H63D in the causation of MBC and PC, but carriers of both BRCA2 9346(-2)A-->G and an HFE mutation may be at an increased risk.

Two-locus genome-wide linkage scan for prostate cancer susceptibility genes with an interaction effect.

Prostate cancer represents a significant worldwide public health burden. Epidemiological and genetic epidemiological studies have consistently provided data supporting the existence of inherited prostate cancer susceptibility genes. Segregation analyses of prostate cancer suggest that a multigene model may best explain familial clustering of this disease. Therefore, modeling gene-gene interactions in linkage analysis may improve the power to detect chromosomal regions harboring these disease susceptibility genes. In this study, we systematically screened for prostate cancer linkage by modeling two-locus gene-gene interactions for all possible pairs of loci across the genome in 426 prostate cancer families from Johns Hopkins Hospital, University of Michigan, University of Umeå, and University of Tampere. We found suggestive evidence for an epistatic interaction for six sets of loci (target chromosome-wide/reference marker-specific P< or =0.0001). Evidence for these interactions was found in two independent subsets from within the 426 families. While the validity of these results requires confirmation from independent studies and the identification of the specific genes underlying this linkage evidence, our approach of systematically assessing gene-gene interactions across the entire genome represents a promising alternative approach for gene identification for prostate cancer.

Hereditary prostate cancer in Finland: fine-mapping validates 3p26 as a major predisposition locus.

In a recent genome-wide linkage (GWL) analysis of Finnish families at high risk for prostate cancer, we found two novel putative susceptibility loci at 3p25-p26 and 11q14. Here, we report the fine-mapping of these two critical regions at high resolution with 39 microsatellite markers in 16 families, including multiplex families that were not used in the GWL scan. The maximum multipoint HLOD was 3.39 at 3p26 and 1.42 at 11q14. The highest LOD scores were seen around markers D3S1270 and D3S4559 (alpha=0.89), covering approximately two megabases. The two known genes in this region CHL1 (cell adhesion molecule with homology to L1CAM) and CNTN6 (contactin 6) were screened for exonic mutations in the families showing the strongest linkage, but no disease-segregating sequence variants were observed. The recombination map pointed to a region proximal to the area of best linkage, suggesting that more genes may need to be investigated as candidates. These results provide strong evidence for the existence of a prostate cancer susceptibility gene at 3p26 in Finnish prostate cancer families. This locus has not been strongly linked with hereditary prostate cancer in other populations. However, the mildly positive 3p LOD scores in a recent GWL analysis of patients from the United States suggest that the locus may also be important in other populations.

Kruppel-like factor 6 germ-line mutations are infrequent in Finnish hereditary prostate cancer.

PURPOSE: Recently, Kruppel-like factor 6 gene (KLF6) has been shown to be inactivated in up to 77% of prostate carcinomas. KLF6 has an important role in regulating cell growth and differentiation. The function and high mutation frequency in sporadic prostate carcinomas make KLF6 an attractive candidate for prostate cancer predisposition and, therefore, DNA samples from 69 Finnish prostate cancer families were analyzed for KLF6 mutations. MATERIALS AND METHODS: DNA samples from 69 Finnish prostate cancer families were screened for mutations in the KLF6 gene using single-strand conformation polymorphism analysis and confirmatory sequencing. RESULTS: In 8 (11.6%) families single-strand conformation polymorphism shifts were present. Sequencing revealed 6 201G>A (R201R) polymorphisms, as well as a -4C>A and a 956T>C alteration in the 5'- and 3'-untranslated regions, respectively. Nonsense or missense mutations were not found. CONCLUSIONS: Our data suggest that KLF6 germ-line mutations are of marginal importance in prostate cancer predisposition in Finland.

Germline mutation analysis of the androgen receptor gene in Finnish patients with prostate cancer.

PURPOSE: Steroid hormones, particularly androgens, are suspected to have a major role in prostate carcinogenesis. Since androgen receptor mediates androgenic effects on cells and recent studies suggest that the androgen receptor gene is a putative prostate cancer susceptibility locus, we screened the coding region of the androgen receptor gene for germline mutations using the genomic DNA of patients with prostate cancer. MATERIALS AND METHODS: DNA samples from 38 patients with early onset prostate cancer and 36 from Finnish prostate cancer families showing no male-to-male transmission of prostate cancer were analyzed for mutations in the androgen receptor gene using single strand conformation polymorphism analysis and subsequent sequencing. RESULTS: R726L substitution in the hormone binding region of androgen receptor was found in 1 prostate cancer family but no previously uncharacterized germline mutations were detected. CONCLUSIONS: Our results indicate that constitutional androgen receptor mutations explain only a small fraction of familial and early onset prostate cancer cases in Finland.

Germ-line alterations in MSR1 gene and prostate cancer risk.

PURPOSE: The MSR1 gene maps to 8p22-23, a novel susceptibility locus for hereditary prostate cancer (HPC). Mutations in MSR1 have been reported to associate with prostate cancer (PRCA) risk. Here we report a follow-up study from Finland to evaluate the association between PRCA and MSR1 gene. EXPERIMENTAL DESIGN: The youngest affected patient from each of 120 HPC families was initially used for the screening of MSR1 mutations by single-strand conformational polymorphism analysis. Selected variants of MSR1 gene were then screened in 537 unselected PRCA cases and in 480 controls. RESULTS: Among 120 HPC families, five MSR1 sequence variants were identified. The carrier frequencies of the R293X, P275A, and -14743A>G variants were compared between the probands with HPC, unselected PRCA cases, and healthy male blood donors. No significant differences were observed. The odds ratios for R293X, P275A, and -14743A>G mutations were also calculated to estimate the PRCA risk. No significantly elevated or lowered risks for PRCA among these three variants were detected. However, the mean age at diagnosis of the R293X mutation carriers among HPC probands was significantly lower compared with noncarriers (55.4 versus 65.4 years; t test, P = 0.04). The same trend was observed among unselected PRCA cases (65.7 versus 68.7 years; t test, P = 0.37). CONCLUSIONS: Our results do not support a major role for the MSR1 gene in the causation of hereditary or unselected PRCAs but suggest a possible modifying role in cancer predisposition.

Androgen receptor CAG polymorphism and prostate cancer risk.

Recent studies have suggested that polymorphisms of the androgen receptor gene ( AR) may influence the risk of prostate cancer (PC) development and progression. Here, we analyzed the length of the CAG repeat of the AR gene in 1363 individuals, including patients with PC, benign prostate hyperplasia (BPH), and population controls. There was a tendency for short CAG repeats to be associated with PC. The Odds Ratio (OR) for PC was 1.47 ( P=0.05) when individuals with short CAG repeats (18). CAG repeat length was not significantly associated with family history, disease stage, grade, age at diagnosis, prostate-specific antigen (PSA) level at diagnosis, or prognosis of the patients. Unexpectedly, short CAG repeats were significantly less common in patients with BPH compared with controls (OR=0.47, P=0.03). Our results suggest that the CAG polymorphism of the AR gene is unlikely to have a major role in the development or progression of PC in the Finnish population. The association of CAG repeats with the risk of BPH warrants further study.

Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer.

The RNASEL gene (2',5'-oligoisoadenylate-synthetase dependent) encodes a ribonuclease that mediates the antiviral and apoptotic activities of interferons. The RNASEL gene maps to the hereditary-prostate-cancer (HPC)-predisposition locus at 1q24-q25 (HPC1) and was recently shown to harbor truncating mutations in two families with linkage to HPC1. Here, we screened for RNASEL germline mutations in 66 Finnish patients with HPC, and we determined the frequency of the changes in the index patients from 116 families with HPC, in 492 patients with unselected prostate cancer (PRCA), in 223 patients with benign prostatic hyperplasia (BPH), and in 566 controls. A truncating mutation, E265X, was found in 5 (4.3%) of the 116 patients from families with HPC. This was significantly higher (odds ratio [OR] =4.56; P=.04) than the frequency of E265X in controls (1.8%). The highest mutation frequency (9.5%) was found in patients from families with four or more affected members. Possible segregation was detected only in a single family. However, the median age at disease onset for E265X carriers was 11 years less than that for noncarriers in the same families. In addition, of the four missense variants found, R462Q showed an association with HPC (OR=1.96; P=.07). None of the variants showed any differences between controls and either patients with BPH or patients with PRCA. We conclude that, although RNASEL mutations do not explain disease segregation in Finnish families with HPC, the variants are enriched in families with HPC that include more than two affected members and may also be associated with the age at disease onset. This suggests a possible modifying role in cancer predisposition. The impact that the RNASEL sequence variants have on PRCA burden at the population level seems small but deserves further study.