Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search.

Despite its high prevalence, very little is known regarding genetic predisposition to prostate cancer. A genome-wide scan performed in 66 high-risk prostate cancer families has provided evidence of linkage to the long arm of chromosome 1 (1q24-25). Analysis of an additional set of 25 North American and Swedish families with markers in this region resulted in significant evidence of linkage in the combined set of 91 families. The data provide strong evidence of a major prostate cancer susceptibility locus on chromosome 1.

Risk of cancer in relatives of prostate cancer probands.

BACKGROUND: It is estimated that there will be more than 244,000 new prostate cancer cases diagnosed and that more than 40,000 men will die of this disease during 1995. Evidence exists for a hereditary predisposition to prostate cancer, but the proportion of cases attributable to the inheritance of a specific gene or genes is not large. Some hereditary cancer syndromes involve more than one tumor site, and some studies have reported a familial association between prostate cancer and other cancers. The presence of other cancers in prostate cancer families may indicate a specific type of hereditary predisposition. PURPOSE: We studied families that were selected because of the presence of prostate cancer to determine whether hereditary prostate cancer is associated with cancers at other sites and possibly with other heritable cancer syndromes. METHODS: Data from two distinct study populations were studied retrospectively. The first population consisted of 690 case patients undergoing radical prostatectomy who were not selected for family history of prostate cancer and 640 control subjects who were the spouses or female companions of the case patients. The second population consisted of 75 multiplex families (i.e., families with multiple cases of prostate cancer) referred because they fulfilled the criteria for hereditary prostate cancer. A comparison between case and control populations for the occurrence of 14 aggregated groups of cancer was performed. Data were analyzed using Poisson regression, and relative risks (RRs) and their 95% confidence intervals (CIs) were calculated. RESULTS: Brothers and fathers of prostate cancer probands have a statistically significant higher risk of prostate cancer than the male first-degree relatives of control subjects (RR = 1.76; 95% CI = 1.28-2.43). Therefore, the risk for prostate cancer is 76% higher among first-degree relatives of prostate cancer patients compared with first-degree relatives of control subjects. This higher risk was not modified by an occurrence of breast cancer in the pedigree. Also, a statistically significant higher risk was found for tumors of the central nervous system in hereditary families (RR = 3.02; 95% CI = 1.08-8.41). Statistically significant higher risks of cancer at other major sites, such as breast, ovary, or endometrium were not observed in these families. CONCLUSIONS: Even among families that were specifically selected because of the presence of prostate cancer, risks for cancer at other sites appeared not to be increased. Therefore, hereditary prostate cancer appears to be a relatively site-specific disease, and it does not seem to be a part of other hereditary cancer syndromes.

Early age at diagnosis in families providing evidence of linkage to the hereditary prostate cancer locus (HPC1) on chromosome 1.

In a recent study of 91 families having at least three first degree relatives with prostate cancer, we reported the localization of a major susceptibility locus for prostate cancer (HPC1) to chromosome 1 [band q24; J. R. Smith et al., Science (Washington DC), 274: 1371-1373, 1996]. There was significant evidence for locus heterogeneity, with an estimate of 34% of the families being linked to this locus. In this report, we investigate the importance of age at diagnosis of prostate cancer and number of affected individuals within a family as variables in the linkage analysis of an expanded set of markers on 1q24. Under two different models for the prostate cancer locus, we find that the evidence for linkage to HPC1 is provided primarily by large (five or more members affected) families with an early average age at diagnosis. Specifically, for 40 North American families with an average age at diagnosis <65 years, the multipoint lod score is 3.96, whereas for 39 families with an older average age at diagnosis, this value is -0.84. Assuming heterogeneity, the proportion of families linked is 66% for the 14 families with the earliest average ages at diagnoses, but it decreases to 7% for the families with the latest ages at diagnoses. A similar age effect is observed in 12 Swedish pedigrees analyzed. To test the hypotheses generated by these analyses, we examined an additional group of 13 newly identified prostate cancer families. Overall, these families provided additional evidence for linkage to this region (nonparametric linkage Z = 1.91; P = 0.04 at marker D1S1660), contributed primarily by the families in this group with early age at diagnosis [nonparametric linkage Z = 2.50 (P = 0.01) at D1S422]. These results are consistent with the existence of a locus in this region that predisposes men to develop early-onset prostate cancer.

Immunogenetic analysis suggests different pathogenesis for obese and lean African-Americans with diabetic ketoacidosis.

OBJECTIVE: When presenting with diabetic ketoacidosis (DKA), lean and obese patients differ in their subsequent clinical course. Although lean patients tend to remain insulin dependent, most obese patients recover endogenous insulin secretion and discontinue insulin therapy. The aim of this study was to determine whether obese African-American patients with DKA could be determined to have type 1 or type 2 diabetes based on insulin secretion or the presence of immunological and genetic markers. RESEARCH DESIGN AND METHODS: This was a prospective study that analyzed the clinical characteristics, insulin secretion indices, immunological markers (islet cell, GAD, ICA512, and insulin autoantibodies), and HLA susceptibility genes (DR/DQ) in 131 patients with DKA (77 obese and 54 lean), 51 obese patients with hyperglycemia but no DKA, and 25 nondiabetic subjects. All subjects were African-American. Beta-cell function was evaluated by the C-peptide response to glucagon (1 mg i.v.) within 48 h of resolution of DKA or hyperglycemia. RESULTS: The acute C-peptide response was lower in obese DKA patients (1.0+/-0.1 ng/ml) than in obese patients with hyperglycemia (1.7+/-0.2 ng/ml, P < 0.01), but was higher than that in lean DKA patients (0.2+/-0.1 ng/ml, both P < 0.01). The overall prevalence of autoantibodies in obese subjects with DKA (17%) and obese subjects with hyperglycemia (16%) was lower than that in lean subjects with DKA (65%, P < 0.01). Obese patients with hyperglycemia and positive autoantibodies had lower rates of insulin secretion than those without antibodies. Regardless of body weight, all DKA patients with GAD autoantibodies carried the DQB1*0201 allele. However, there were no significant differences in HLA distribution between the three patient groups. CONCLUSIONS: Our results indicate that most obese African-American patients with DKA have type 2 diabetes characterized by higher insulin secretion, the absence of autoimmune markers, and a lack of HLA genetic association. In contrast, most lean African-American patients with DKA have metabolic and immunological features of type 1 diabetes. At presentation, assessment of beta-cell function and determination of autoimmune markers allow for correct classification of diabetes in African-Americans with hyperglycemic crises.

Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk.

The 8p22 through p23 region has been identified as a potential site for genes associated with prostate cancer. The gene LZTS1 has been mapped to the 8p22 through p23 region and identified as a potential tumor suppressor based on loss of heterozygosity studies using primary esophageal tumors. Sequence analysis of mRNA from various tumors has revealed multiple mutations and aberrant mRNA transcripts. The most recent report associates LZTS1 function with stabilization of p34(cdc2) during the late S-G2/M stage of mitosis, affecting normal cell growth. In this study, a detailed DNA sequence analysis of LZTS1 was performed in a screening panel consisting of sporadic and hereditary prostate cancer (HPC) cases and unaffected controls. Twenty-four SNP, 15 of which were novel, were identified in germline DNA. Four coding SNP were identified. Eleven informative SNP were genotyped in 159 HPC probands, 245 sporadic prostate cancer cases, and 222 unaffected controls. Four of these SNP were statistically significant for association with prostate cancer (P < or = 0.04). These results add evidence supporting a role of LZTS1 in prostate cancer risk.

Differences in metabolic and hormonal milieu in diabetic- and alcohol-induced ketoacidosis.

PURPOSE: Diabetic ketoacidosis (DKA) and alcoholic ketoacidosis (AKA) are two medical emergencies characterized by elevated total ketone body concentration. We aimed to determine differences in pathogenesis of ketoacidosis and its metabolic consequences by comparing both at presentation and during treatment, the different metabolic products and hormones involved in the ketoacidotic state. MATERIALS AND METHODS: We studied 12 patients with DKA and 8 patients with AKA. On admission and every 4 hours for 24 hours during treatment, samples were drawn for determination of serum ketone bodies, lactate and pyruvate, insulin, and counterregulatory hormones (glucagon, cortisol, growth hormone, and catecholamines). RESULTS: At presentation, with a similar beta-hydroxybutyrate concentration, patients with DKA had a higher plasma glucose (32 mmol/L vs. 6.6 mmol/L), lower beta-hydroxybutyrate/acetoacetate ratio (3:1 vs. 7:1), and a lower lactate/pyruvate ratio (11:1 vs. 19:1) than patients with AKA (all, P < .01). The mean time to resolve ketoacidosis in patients with AKA (6 +/- 1 hour) was significantly shorter than in patients with DKA (16 +/- 2 hours). At presentation, the mean insulin concentration in patients with DKA and AKA were similarly decreased (7.8 +/- 2 and 10.3 +/- 3 microU/mL, P = not significant [NS]). The mean glucagon level before therapy was 203 +/- 15 pg/mL and 188 +/- pg/mL for patients with DKA and AKA, respectively (P = NS). Levels of cortisol, growth hormone, and epinephrine at presentation and during the first 8 hours of treatment were higher in patients with DKA; however, the difference in these values did not reach statistical significance. During therapy, levels of counterregulatory hormones declined at similar rates and returned to normal values after resolution of ketoacidosis. CONCLUSIONS: Our results indicate that, in addition to a history of diabetes or alcoholism, patients with DKA and AKA differ in their metabolic parameters more than in their hormonal profile. The metabolic profile of DKA is characterized by a higher plasma glucose concentration, and lower beta-hydroxybutyrate to acetoacetate and lactate to pyruvate ratios compared with patients with AKA. The initial hormonal profile in both ketoacidotic states is characterized by similarly decreased insulin levels and elevated levels of counterregulatory hormones.

Classification of spelling errors and their relationship to reading ability, sex, grade placement, and intelligence.

A simple scheme for the classification of spelling errors was applied to the errors of four groups of children, totaling 483 subjects, in grades 3 to 12. The subjects in two of the groups, Group I and Group IV, consisted of individuals who attended special schools for children with dyslexia or specific reading disability (SRD). Group II included school age siblings of subjects in Group I, and Group III included subjects drawn from regular school programs. It was shown that (a) type of spelling error is independent of sex, (b) there are no consistent effects of IQ or grade level on type of spelling error, and (c) disabled readers as a group are more likely to produce dysphonetic errors than are normal readers. Although the type of spelling error produced by children who had a spelling disability only was shown to be similar to that of normal readers and to differ from that of disabled readers as a group, disabled readers were shown to differ among themselves, lending strong support to the use of spelling error type as a characteristic for identifying subgroups.

Vitamin D receptor polymorphisms and lethal prostate cancer.

PURPOSE: Reports in the osteoporosis literature demonstrating the increased activity of specific alleles of the vitamin D receptor and epidemiological data linking vitamin D levels with prostate cancer have stimulated research into possible associations between vitamin D receptor genotype and the development of prostate cancer. Recent studies showed that patients homozygous for a less active vitamin D receptor have a 4 to 5 times increased risk of localized prostate cancer. In 1 study this association was strongest in patients with advanced disease. To understand better the relationship between advanced disease and the vitamin D receptor we compared the vitamin D receptor genotype of 41 patients who died of prostate cancer to 41 controls with no clinical evidence of prostate cancer. MATERIALS AND METHODS: Noncancerous deoxyribonucleic acid was isolated from lethal prostate cancer and control cohorts. To determine the TaqI restriction fragment length polymorphism a 740 base pairs (bp) segment of the vitamin D receptor was amplified by PCR, digested with TaqI endonuclease and resolved on an agarose gel. Depending on the presence or absence of a TaqI restriction site at codon 352 in each allele, products were digested into 2 fragments of 495 and 245 bp (T allele) or 3 fragments of 290, 245 and 205 bp (t allele). Individuals were classified as TT, Tt or tt. To determine the size of the poly-A microsatellite repeat an approximately 410 bp fragment was amplified by polymerase chain reaction using [gamma-32P] labeled primers, resolved by gel electrophoresis and sized by autoradiography. Fragments 410 bps or greater corresponded to repeats 18 bps or greater (L allele) and fragments less than 410 bps corresponded to repeats less than 18 bps (S allele). Individuals were classified as LL, LS or SS. RESULTS: The TaqI restriction fragment length polymorphism and poly-A microsatellite repeat were in strong linkage disequilibrium, indicating that both polymorphic markers identified the same vitamin D receptor genotype in the majority of cases. Using the TaqI restriction fragment length polymorphism 33 of 41 controls (80.5%) and 35 of 41 cases (85.3%) were heterozygous (Tt) or homozygous (TT) for the less active vitamin D receptor allele, while 8 of 41 controls (19.5%) and 6 of 41 cases (14.6%) were homozygous (tt) for the more active vitamin D receptor allele. Using the poly-A microsatellite repeat 32 of 40 controls (80%) and 32 of 38 cases (84.2%) were heterozygous (LS) or homozygous (LL) for the less active vitamin D receptor allele, while 8 of 40 controls (20.0%) and 6 of 38 cases (15.8%) were homozygous (SS) for the more active vitamin D receptor allele. There was no statistically significant difference in the distribution of either marker between cases and controls. CONCLUSIONS: We failed to demonstrate an association between vitamin D receptor genotype and lethal prostate cancer. Our data do not support the hypothesis that specific vitamin D receptor genotypes are associated with an aggressive prostate cancer phenotype. Further studies that take into account cofactors important in vitamin D activity and/or a better definition of prostate cancer phenotype may explain the discrepancy between our findings and those of a previous study.

Derivation and validation of a quantitative definition of specific reading disability for adults.

One hundred and fifty-four adult relatives of children with specific reading disability, and a group of 90 adults matched for age, sex, educational level and IQ, were given a battery of intelligence, reading and spelling tests and a questionnaire on their reading history, habits and attitudes. Data obtained from the latter group were used to derive multiple regression equations for the prediction of reading and spelling scores. An index was derived for each adult, expressing actual scores relative to those predicted. A definition of severe and borderline reading disability was validated, using the scores from the questionnaire.

Role of NFkappaB in the regulation of macrophage colony stimulating factor by tumor necrosis factor-alpha in ST2 bone stromal cells.

Expression of MCSF in bone is important to the regulation of osteoclastogenesis. We show here that tumor necrosis factor-alpha (TNFalpha) increases the production of both soluble (sMCSF) and membrane-bound (mMCSF) macrophage colony stimulating factor by ST2 bone stromal cells. Treatment of ST2 cells with TNFalpha caused sMCSF levels to increase by 394+/-5% from basal; mMCSF rose by 316+/-66% from 30+/-10 per 100,000 cells in the same time. These increases were consistent with increased expression of mRNAs encoding both isoforms. Increases in MCSF mRNA are also seen after stimulation with dexamethasone. To investigate the potential role of NFkappaB in this TNFalpha effect, we treated cells with sodium salicylate (NaS), an inhibitor of NFkappaB translocation. NaS decreased TNFalpha-stimulated NFkappaB activation by 50% as assessed by EMSA. Despite inhibition of NFkappaB signaling, NaS enhanced TNFalpha-stimulated MCSF secretion and did not prevent TNFalpha-stimulated increases in sMCSF mRNA, suggesting that NFkappaB was not involved in TNFalpha effect on the gene. TNFalpha failed to stimulate transcription of a 774 nucleotide MCSF promoter-luciferase reporter transfected into ST2 cells which contained the NFkappaB consensus sequence. Deletion of the seven nucleotides containing the NFkappaB homology response sequence from the MCSF promoter increased basal gene transcription by twofold. TNFalpha thus contributes to an osteoclastogenic environment through upregulation of bone expression of both MCSF isoforms. Our data suggests that NFkappaB is not the major signaling pathway through which this occurs.

Biological aggressiveness of hereditary prostate cancer: long-term evaluation following radical prostatectomy.

PURPOSE: We answer the question of whether, following radical prostatectomy, prostate cancer in patients with a family history of prostate cancer relapses biochemically at the same rate as prostate cancer in appropriately matched patients with no family history. MATERIALS AND METHODS: The study was performed in 2 parts. In both parts prostate specific antigen (PSA) progression was defined as a postoperative elevation in serum PSA greater than 0.2 ng./ml. Part 1 included 656 patients who underwent radical prostatectomy by the same surgeon. Men with a family history of prostate cancer in a father or brother (94) were compared to those with no history of prostate cancer in a father or brother (562). Part 2 comprised 52 men with a family history of prostate cancer consistent with hereditary prostate cancer (HPC). HPC is defined as a family with 3 generations affected, 3 first-degree relatives affected or 2 relatives affected before age 55 years. Each member of this HPC group was matched by postoperative Gleason score and postoperative pathological stage with a patient who also underwent radical prostatectomy in the same time frame by the same surgeon but who reported no family history of prostate cancer by telephone interview and questionnaire. RESULTS: In part 1, 94 probands (14%) reported a history of prostate cancer in the father or in at least 1 brother. The remaining 562 probands (85%) reported no known history of prostate cancer in the father or brother(s). There was no statistically significant difference in the probability of maintaining an undetectable PSA between these 2 groups. In part 2, 45 of 52 pairs (87%) were matched identically for all matching criteria. Mean follow time for the sporadic and hereditary groups was 5.4 and 5.1 years, respectively. There was no statistically significant difference in the probability of maintaining an undetectable PSA between the 2 groups. CONCLUSIONS: Men with an affected father or brother, or those with a family history consistent with HPC have the same outcome following radical prostatectomy as men with no family history of the disease. Combined with our previous studies, these findings suggest that there is no biologically important difference between hereditary and sporadic prostate cancers.

Hereditary prostate cancer in African American families: linkage analysis using markers that map to five candidate susceptibility loci.

African American men have the highest incidence of prostate cancer in the world. Despite this statistic, linkage studies designed to localise prostate cancer susceptibility alleles have included primarily men of Caucasian descent. In this report, we performed a linkage analysis using 33 African American prostate cancer families from two independent research groups. In total, 126 individuals (including 89 men with prostate cancer) were genotyped using markers that map to five prostate cancer susceptibility loci, namely HPC1 at 1q24-25, PCAP at 1q42.2-43, CAPB at 1p36, HPC20 on chromosome 20, and HPCX at Xq27-28. Multipoint mode-of-inheritance-free linkage analyses were performed using the GENEHUNTER software. Some evidence of prostate cancer was detected to HPC1 using all families with a maximum NPL Z score of 1.12 near marker D1S413 (P=0.13). Increased evidence of linkage was observed in the 24 families with prostate cancer diagnosis prior to age 65 years and in the 20 families with male-to-male transmission. Some evidence of prostate cancer linkage was also detected at markers mapping to PCAP, HPC20, and HPCX. Continued collection and analysis of African American prostate cancer families will lead to an improved understanding of inherited susceptibility in this high-risk group.

Polymorphisms in the CYP1B1 gene are associated with increased risk of prostate cancer.

CYP1B1 has been evaluated as a candidate gene for various cancers because of its function in activating environmental procarcinogens and catalysing the conversion of oestrogens to genotoxic catechol oestrogens. To test the hypothesis that genetic polymorphisms in the CYP1B1 gene may associate with the risk for prostate cancer (CaP), we compared the allele, genotype, and haplotype frequencies of 13 single nucleotide polymorphisms (SNPs) of CYP1B1 among 159 hereditary prostate cancer (HPC) probands, 245 sporadic CaP cases, and 222 unaffected men. When each of the SNPs was analysed separately, marginally significant differences were observed for allele frequencies between sporadic cases and controls for three consecutive SNPs (-1001C/T, -263G/A, and -13C/T, P=0.04-0.07). Similarly, marginally significant differences between sporadic cases and controls in the frequency of variant allele carriers were observed for five consecutive SNPs (-1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T, P=0.02-0.08). Interestingly, when the combination of these five SNPs was analysed using a haplotype approach, a larger difference was found (P=0.009). One frequent haplotype (C-G-C-C-G of -1001C/T, -263G/A, -13C/T, +142C/G, and +355G/T) was associated with an increased risk for CaP, while the other frequent haplotype (T-A-T-G-T) was associated with a decreased risk for CaP. These findings suggest that genetic polymorphisms in CYP1B1 may modify the risk for CaP.

Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus.

CONTEXT: Approximately 9% of prostate cancer cases have been estimated to result from inheritance of mutated prostate cancer susceptibility genes. Few data exist as to whether there are clinical differences between prostate cancers that are inherited and those that occur in the general population. OBJECTIVE: To investigate phenotypic characteristics of families potentially linked to the hereditary prostate cancer 1 (HPC1) locus on chromosome 1q24-25. DESIGN: Retrospective case study in which clinical data were extracted from medical and pathological records. FAMILIES: A total of 74 North American families with hereditary prostate cancer. Prostate cancer cases from the National Cancer Data Base were used as a reference population for comparison. MAIN OUTCOME MEASURES: The families were divided into 2 groups: either potentially linked (33 families with 133 men with prostate cancer), and thus likely to be carrying an altered HPC1 gene, or potentially unlinked (41 families with 172 men with prostate cancer), on the basis of haplotype analysis in the region of HPC1. The age at diagnosis of prostate cancer, serum prostate-specific antigen levels, digital rectal examination status, stage, grade, primary treatment of prostate cancers, and occurrence of other cancers were compared between the groups. RESULTS: The mean age at diagnosis of prostate cancer for men in potentially linked families was significantly lower than for men in potentially unlinked families (63.7 vs 65.9 years, respectively, P=.01; mean age at diagnosis in the reference population was 71.6 years). Higher-grade cancers (grade 3) were more common in potentially linked families, and advanced-stage disease was found in 41% of the case patients in potentially linked families compared with 31% in both the potentially unlinked families and the reference groups (P=.03 for the latter comparison). In the other clinical parameters, we found no significant differences between the groups. A modest excess of breast cancer and colon cancer was found in potentially linked families in comparison with potentially unlinked families, but this difference was not statistically significant. CONCLUSIONS: Families that provide evidence for segregation of an altered HPC1 gene are characterized by multiple cases of prostate cancer that, in most respects, are indistinguishable from nonhereditary cases. However, 3 characteristics were observed: younger age at diagnosis, higher-grade tumors, and more advanced-stage disease. Our study shows that a significant fraction of hereditary prostate cancers are diagnosed in advanced stages, emphasizing the clinical importance of early detection in men potentially carrying prostate cancer susceptibility genes. These findings support the current recommendations to screen men with a positive family history of prostate cancer beginning at age 40 years.

No evidence for a role of BRCA1 or BRCA2 mutations in Ashkenazi Jewish families with hereditary prostate cancer.

BACKGROUND: Two genes responsible for hereditary breast cancer (BRCA1 and BRCA2) have been identified, and predisposing mutations identified. Several studies have provided evidence that germline mutations in BRCA1 and BRCA2 confer an increased risk of prostate cancer. Based on these findings, one might expect to find an increased frequency of mutations in these genes in family clusters of prostate cancer. The Ashkenazi Jewish population is unique in that it has an approximate 2% incidence of specific founder BRCA1 and BRCA2 mutations (i.e., 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2). METHODS: To address the question of whether or not mutations in either of these genes were overrepresented in prostate cancer families, we searched for these mutations in germline DNA samples collected from affected and unaffected members of 18 Ashkenazi Jewish families, each having at least 3 first-degree relatives affected with prostate cancer. RESULTS: No mutations were found in the BRCA1 gene in any of the 47 individuals tested. One individual possessed a BRCA2 mutation (6174delT). This individual was unaffected at the time of analysis, but had an affected paternal uncle, and an affected first cousin, neither of whom harbored the mutant gene. CONCLUSIONS: In this sample of Ashkenazi prostate cancer families, the frequency of founder BRCA1 and BRCA2 mutations was not elevated, suggesting that such mutations will account for only a small, perhaps minimal, fraction of familial prostate cancer.

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.

Evidence for a prostate cancer linkage to chromosome 20 in 159 hereditary prostate cancer families.

Prostate cancer is the most common malignancy diagnosed in men in the US. Genetic susceptibility to prostate cancer has been well documented. A region at chromosome 20q13 (HPC20) has been reported to be linked to a prostate cancer susceptibility gene. To confirm this finding, we genotyped 16 markers spanning approximately 95 cM on chromosome 20 in 159 hereditary prostate cancer (HPC) families. Positive (but not statistically significant) linkage scores were observed from 20pter to 20q11, with the highest non-parametric linkage (NPL) score for the complete dataset of 1.02 (P=0.15) being observed at D20S195 at 20q11. Evidence for linkage from parametric analyses with a dominant or a recessive model was weak. Interestingly, consistent with the original findings of linkage to 20 g higher linkage scores were observed in the subsets of families with a later age at diagnosis (> or =65 years; n=80, NPL=1.94, P=0.029 at D20S186), fewer than five affected family members (n=69, NPL=1.74, P=0.037 at D20S889), or without male-to-male disease transmission (n=60, NPL=1.01, P=0.15 at D20S117). The region with positive linkage scores spanned approximately 60 cM from 20pter to 20q11 in these subsets of families. Our results are consistent with a prostate cancer susceptibility locus on chromosome 20.

Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22-23.

Multiple lines of evidence have implicated the short arm of chromosome 8 as harboring genes important in prostate carcinogenesis. Although most of this evidence comes from the identification of frequent somatic alterations of 8p loci in prostate cancer cells (e.g., loss of heterozygosity), studies have also suggested a role for 8p genes in mediation of inherited susceptibility to prostate cancer. To further examine this latter possibility, we performed linkage analyses, in 159 pedigrees affected by hereditary prostate cancer (HPC), using 24 markers on the short arm of chromosome 8. In the complete set of families, evidence for prostate cancer linkage was found at 8p22-23, with a peak HLOD of 1.84 (P=.004), and an estimate of the proportion of families linked (alpha) of 0.14, at D8S1130. In the 79 families with average age at diagnosis >65 years, an allele-sharing LOD score of 2.64 (P=.0005) was observed, and six markers spanning a distance of 10 cM had LOD scores >2.0. Interestingly, the small number of Ashkenazi Jewish pedigrees (n=11) analyzed in this study contributed disproportionately to this linkage. Mutation screening in HPC probands and association analyses in case subjects (a group that includes HPC probands and unrelated case subjects) and unaffected control subjects were carried out for the putative prostate cancer-susceptibility gene, PG1, previously localized to the 8p22-23 region. No statistical differences in the allele, genotype, or haplotype frequencies of the SNPs or other sequence variants in the PG1 gene were observed between case and control subjects. However, case subjects demonstrated a trend toward higher homozygous rates of less-frequent alleles in all three PG1 SNPs, and overtransmission of a PG1 variant to case subjects was observed. In summary, these results provide evidence for the existence of a prostate cancer-susceptibility gene at 8p22-23. Evaluation of the PG1 gene and other candidate genes in this area appears warranted.

Linkage of prostate cancer susceptibility loci to chromosome 1.

Three prostate cancer susceptibility genes have been reported to be linked to different regions on chromosome 1: HPC1 at 1q24-25, PCAP at 1q42-43, and CAPB at 1p36. Replication studies analyzing each of these regions have yielded inconsistent results. To evaluate linkage across this chromosome systematically, we performed multipoint linkage analyses with 50 microsatellite markers spanning chromosome 1 in 159 hereditary prostate cancer families (HPC), including 79 families analyzed in the original report describing HPC1 linkage. The highest lod scores for the complete dataset of 159 families were observed at 1q24-25 at which the parametric lod score assuming heterogeneity (hlod) was 2.54 (P=0.0006) with an allele sharing lod of 2.34 (P=0.001) at marker D1S413, although only weak evidence was observed in the 80 families not previously analyzed for this region (hlod=0.44, P=0.14, and allele sharing lod=0.67, P=0.08). In the complete data set, the evidence for linkage across this region was very broad, with allele sharing lod scores greater than 0.5 extending approximately 100 cM from 1p13 to 1q32, possibly indicating the presence of multiple susceptibility genes. Elsewhere on chromosome 1, some evidence of linkage was observed at 1q42-43, with a peak allele sharing lod of 0.56 (P=0.11) and hlod of 0.24 (P=0.25) at D1S235. For analysis of the CAPB locus at 1p36, we focused on six HPC families in our collection with a history of primary brain cancer; four of these families had positive linkage results at 1p36, with a peak allele sharing lod of 0.61 (P=0.09) and hlod of 0.39 (P=0.16) at D1S407 in all six families. These results are consistent with the heterogeneous nature of hereditary prostate cancer, and the existence of multiple loci on chromosome 1 for this disease.

Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer.

To investigate the relationship between HPC2/ELAC2 and prostate cancer risk, we performed the following analyses: (1) a linkage study of six markers in and around the HPC2/ELAC2 gene at 17p11 in 159 pedigrees with hereditary prostate cancer (HPC); (2) a mutation-screening analysis of all coding exons of the gene in 93 probands with HPC; (3) family-based and population-based association study of common HPC2/ELAC2 missense variants in 159 probands with HPC, 249 patients with sporadic prostate cancer, and 222 unaffected male control subjects. No evidence for linkage was found in the total sample, nor in any subset of pedigrees based on characteristics that included age at onset, number of affected members, male-to-male disease transmission, or race. Furthermore, only the two previously reported missense changes (Ser217Leu and Ala541Thr) were identified by mutational analysis of all HPC2/ELAC exons in 93 probands with HPC. In association analyses, family-based tests did not reveal excess transmission of the Leu217 and/or Thr541 alleles to affected offspring, and population-based tests failed to reveal any statistically significant difference in the allele frequencies of the two polymorphisms between patients with prostate cancer and control subjects. The results of this study lead us 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 HPC2/ELAC2 as high-penetrance mutations, and (3) the variants Leu217 or Thr541 as low-penetrance, risk-modifying alleles. However, we did observe a trend of higher Leu217 homozygous carrier rates in patients than in control subjects. 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 our study sample, our 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 we rule out a prostate cancer-modifier gene that confers a lower-than-reported risk. Additional larger studies are needed to more fully evaluate the role of this gene in prostate cancer risk.