Loss of heterozygosity and microsatellite instability at chromosomal sites 1Q and 10Q in morphologically distinct regions of late stage prostate lesions

PURPOSE: We investigated the incidence of loss of heterozygosity (LOH) and microsatellite instability in sporadic prostate cancer and surrounding tissue at loci encompassing the HPC1 and PTEN genes. MATERIALS AND METHODS: Surgical specimens from 63 patients with sporadic stage T3 or T4 prostatic adenocarcinoma were analyzed for LOH and microsatellite instability. Microdissected tissue included morphologically normal foci, benign prostatic hyperplasia (BPH) and prostatic adenocarcinoma. LOH analysis was performed using 4 microsatellite markers that map in the region of the 1q24 to 25 locus of the putative prostate cancer susceptibility gene HPC1 and 4 that map in the region of the 10q23 locus of the PTEN gene. RESULTS: The incidence of LOH on 10q was consistent with that previously reported in prostatic tumors. LOH associated with the PTEN locus was recorded in morphologically normal foci, BPH and adenocarcinoma. Sequence analysis of PTEN in a limited number of lesions revealed mutations in nontumor and tumor tissue. Analysis of the DS10215 locus showed significant LOH in tumor but not in benign tissue, suggestive of a tumor suppressor gene in this region associated with prostatic neoplastic progression. In contrast, no significant LOH was observed in the same tissues at 4 loci on chromosome 1q. In this study we recorded elevated levels of microsatellite instability in benign prostatic tissue with an additional increase associated with prostatic adenocarcinoma. CONCLUSIONS: The low incidence of LOH in the region of the HPC1 locus in all prostate lesions studied suggests that this putative hereditary prostate cancer susceptibility locus does not appear to have a role in sporadic prostate cancer, at least not in the context of LOH. In contrast, analysis of the same tissues for LOH at chromosome 10q confirmed frequent alterations in this region linked to late stage prostate cancer. PTEN mutations in microdissected morphologically normal and BPH tissue showed alterations in nontumor tissue surrounding adenocarcinoma. Microsatellite instability was increased in adenocarcinomas over an elevated background recorded in surrounding tissues.     

Differential Chromosome Allelic Imbalance in the Progression of Human Prostate Cancer

Purpose

It is widely accepted that an accumulation of genetic alterations plays an important role in the genesis of human cancers. We wished to obtain a comprehensive view of the role of genetic changes in prostate cancer.

Materials and Methods

We screened 42 primary prostate tumors for allelic imbalance (AI) on 8 autosomal chromosome arms of interest (5q, 7q, 8p, 10q, 13q, 16q, 17q, 18q) by using 2 DNA probes for restriction fragment length polymorphism (RFLP) and 19 microsatellite markers (CA repeats).

Results

The most frequent allelic imbalances were observed on 8p (58 percent) and 16q (53 percent). AI exceeding 20 percent was also observed at sites on chromosome arms 7q (46 percent), 10q (23 percent), 13q (26 percent), 17q (34 percent) and 18q (39 percent), whereas AI was infrequent on 5q (10 percent).

Conclusions

The data indicate that a relatively large number of chromosome loci play a part in the etiology and progression of this tumor type. Moreover, our findings suggest that inactivation of a putative tumor suppressor gene on 7q and 13q is an early event in prostate tumorigenesis. In contrast, the close link between an invasive phenotype and AI on 10q and 18q suggests that these genetic alterations occur late in prostate tumorigenesis.     

Low frequency of microsatellite instability in hereditary prostate cancer

OBJECTIVE: To investigate whether there is widespread microsatellite instability (MSI) in families with hereditary prostate cancer (HPC). PATIENTS AND METHODS: Eighty-four prostate tumours from 80 Swedish men in 35 families with HPC were screened for genetic instability at microsatellite marker loci BAT-25, BAT-26, BAT-34C4, D2S123 and D17S250. RESULTS: MSI was detected in only five individuals from different families. Three tumours (4%) were unstable at more than two MSI loci and hence classified as high-frequency MSI (MSI-H) according to a previous definition. Interestingly, two of the MSI-H tumours were from patients in families with both HPC and familial colon cancer. CONCLUSIONS: Widespread MSI is a rare event in hereditary prostate cancer, indicating that defective DNA mismatch repair is not an important element in the genesis of HPC.     

Loss of heterozygosity in chromosomal region 16q24.3 associated with progression of prostate cancer

BACKGROUND: The molecular mechanisms underlying the development and progression of prostate cancer have remained poorly understood. To find out potential genetic markers likely to underlie tumor progression, the pattern of allelic loss on chromosome arm 16q in matched primary, locally recurrent, and metastatic prostate cancer specimens was analyzed in the present study. METHODS: The frequency of loss of heterozygosity (LOH) in 74 tumor specimens (62 primary cancer foci and 12 metastatic tumors) collected from 33 prostate cancer patients was determined by fragment analysis using 17 polymorphic microsatellite markers. RESULTS: The overall frequency of patients showing allelic loss at one or more loci on 16q was 68% (21/31) in primary tumors and 90% (28/31) in recurrent tumors. Of the individual markers, D16S520, locating in region 16q24.3, exhibited a statistically significant development of LOH during disease recurrence (P < 0.01). Regarding distant metastases, instead, there seemed to be no allelic loss events exclusively typical of metastatic tumors at 16q. CONCLUSIONS: The data suggest the location of gene(s) related to prostate cancer progression at 16q24.3.     

Genomic scan of 12 hereditary prostate cancer families having an occurrence of pancreas cancer

BACKGROUND: Prostate cancer is a genetically heterogeneous disease. Using the occurrence of other cancers in hereditary prostate cancer (HPC) families is a promising strategy for developing genetically homogeneous data sets that can enhance the ability to identify susceptibility loci using linkage analysis. METHODS: Twelve HPC families with the co-occurrence of adenocarcinoma of the pancreas were selected from the Prostate Cancer Genetic Research Study (PROGRESS). Non-parametric linkage analysis for a prostate/pancreas cancer susceptibility phenotype was performed using 441 genome-wide microsatellite markers. RESULTS: No statistically significant linkage signal was detected in this analysis. The strongest linkage signals, as measured by Kong and Cox LOD score (KC LOD), were observed on chromosomes 2q37.2-q37.3 (KC LOD = 1.01; P = 0.02) and 16q23.2 (KC LOC = 1.05; P = 0.01). CONCLUSIONS: Despite the lack of statistically significant findings, four chromosomal regions, three of which (2q, 16q, 17q) were previously noted as harboring potential susceptibility loci, showed suggestive linkage results in this scan.     

The clinical phenotype of hereditary versus sporadic prostate cancer: HPC definition revisited

BACKGROUND

The definition of hereditary prostate cancer (HPC) is based on family history and age at onset. Intuitively, HPC is a serious subtype of prostate cancer but there are only limited data on the clinical phenotype of HPC. Here, we aimed to compare the prognosis of HPC to the sporadic form of prostate cancer (SPC).

METHODS

HPC patients were identified through a national registry of HPC families in the Netherlands, selecting patients diagnosed from the year 2000 onward (n = 324). SPC patients were identified from the Netherlands Cancer Registry (NCR) between 2003 and 2006 for a population‐based study into the genetic susceptibility of PC (n = 1,664). Detailed clinical data were collected by NCR‐registrars, using a standardized registration form. Follow‐up extended up to the end of 2013. Differences between the groups were evaluated by cross‐tabulations and tested for statistical significance while accounting for familial dependency of observations by GEE. Differences in progression‐free and overall survival were evaluated using χ² testing with GEE in a proportional‐hazards model.

RESULTS

HPC patients were on average 3 years younger at diagnosis, had lower PSA values, lower Gleason scores, and more often locally confined disease. Of the HPC patients, 35% had high‐risk disease (NICE‐criteria) versus 51% of the SPC patients. HPC patients were less often treated with active surveillance. Kaplan–Meier 5‐year progression‐free survival after radical prostatectomy was comparable for HPC (78%) and SPC (74%; P = 0.30). The 5‐year overall survival was 85% (95%CI 81–89%) for HPC versus 80% (95%CI 78–82%) for SPC (P = 0.03).

CONCLUSIONS

HPC has a favorable clinical phenotype but patients more often underwent radical treatment. The major limitation of HPC is the absence of a genetics‐based definition of HPC, which may lead to over‐diagnosis of PC in men with a family history of prostate cancer. The HPC definition should, therefore, be re‐evaluated, aiming at a reduction of over‐diagnosis and overtreatment among men with multiple relatives diagnosed with PC. Prostate 76:897–904, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.     

Chromosome 8q24 risk variants in hereditary and non-hereditary prostate cancer patients

BACKGROUND: Multiple variants in three regions at 8q24 are consistently found to be associated with prostate cancer (PCa) risk in population-based association studies. The role that these variants may play in familial prostate cancer risk has not been extensively investigated. METHODS: We evaluated 12 SNPs at three 8q24 regions using population-based association and family-based linkage and association methods in hereditary PCa (HPC) probands and their families, non-HPC patients, and unaffected screened controls, all recruited at Johns Hopkins Hospital. RESULTS: For multiple variants in Region 1 (e.g., rs1447295) and Region 2 (e.g., rs16901979), we found statistically significantly higher frequencies of previously identified risk alleles and genotypes in HPC probands than in unaffected controls. Furthermore, in Region 2 the risk alleles were statistically significantly more frequent in HPC probands than in non-HPC patients. Family-based transmission tests found risk alleles of SNPs in Region 2, but not in Regions 1 and 3, were significantly over-transmitted to affected men in these families. We found little evidence supporting PCa linkage at 8q24 in 168 HPC families, in part explained by the observation of multiple, different risk allele-containing haplotypes segregating in the vast majority of these families. CONCLUSIONS: Our study further supports the presence of PCa susceptibility loci at 8q24, particular at Region 2, and also provides evidence that these SNPs play an important role in familial prostate cancer. Large family-based studies are needed to confirm our novel findings.     

Men with family history of prostate cancer have a higher risk of disease recurrence after radical prostatectomy

Purpose

We aimed to determine if family history (FH) of prostate cancer (PC) influenced cancer control after radical prostatectomy (RP).

Methods

Patients were evaluated in a prospectively-collected PC family database: The focus was on hereditary prostate cancer (HPC) defined by Johns Hopkins criteria and sporadic prostate cancer (SPC), rigorously defined by absence of prostate cancer in ≥ 2 brothers aged ≥ 60 years. Additionally, patients with first-degree (FPC) and non-first-degree PC (non-FPC) were assessed. Endpoints were biochemical recurrence-free survival (BRFS) and prostate cancer-specific survival (CSS). Finally, clinico-pathological characteristics were compared and multiple proportional hazards regression was used to identify prognostic factors.

Results

In total 11,654 patients were included (807 HPC, 2251 FPC, 8072 non-FPC and 524 SPC). Familial imposition (HPC/FPC) was associated with a younger age at diagnosis. Thus, HPC patients were diagnosed 2.9 years earlier than SPC patients with more locally advanced tumors (≥ pT3). With a median follow up of 6.2 years (range 0–31.5) BRFS was significantly different when stratified by FH. In pairwise analyses BRFS differed significantly for HPC compared to SPC (HR = 1.27). Consecutively FH was identified as prognostic factor for BRFS (p = 0.021) together with age, PSA, pathologic characteristics and adjuvant androgen deprivation. Analyses of CSS did not show a difference.

Conclusion

Patients with FH of PC are likely to be diagnosed earlier and present a higher proportion of locally advanced disease. In addition, men with FH are at higher risk of biochemical recurrence after surgery but reveal similar outcomes regarding prostate cancer-specific survival.

     

Known susceptibility SNPs for sporadic prostate cancer show a similar association with “hereditary” prostate cancer

Background

More than 70 single nucleotide polymorphisms (SNPs) have been reported to be associated with prostate cancer (PC) risk; these were mainly identified in the general population with predominantly sporadic PC (SPC). Previous studies have suggested similar associations between a selection of these SNPs and hereditary PC (HPC). Our aim was to evaluate the effect of all known PC risk SNPs and their discriminative value for SPC and HPC.

Methods

Seventy‐four PC susceptibility SNPs (reported in literature up to June 2014) were genotyped in a population‐based series of 620 SPC patients, 312 HPC patients from the national Dutch registry and 1819 population‐based referents. Association analyses were performed using logistic regression, focusing on directional consistency of the odds ratios (ORs) with those in the original reports, that is, whether the OR was in the same direction as in the original report. Discriminative performance was evaluated by a genetic risk score used in logistic regression and receiver operating characteristic (ROC) curve analyses.

Results

Directional consistency was seen for 62 SNPs in SPC and 64 SNPs in HPC, 56 of which overlapped. ORs were mostly higher for HPC with 22 ORs >1.25 versus 5 for SPC. Discriminative performance was better for HPC with an area under the ROC curve of 0.73 versus 0.64 for SPC.

Conclusions

A large overlap was found for the associations between low‐penetrance susceptibility SNPs and SPC and HPC, suggesting a similarity in genetic etiology. This warrants a reconsideration of “HPC” and a restrictive policy toward prostate‐specific antigen testing in men with a positive family history. Genetic risk scores might be used for PC risk stratification on the population level. Prostate 75: 474–483, 2015 © 2014 The Authors. The Prostate published by Wiley Periodicals, Inc.     

Loss of heterozygosity at 7q31.1 and 12p13-12 in advanced prostate cancer

BACKGROUND: Allelic losses on chromosome arms 2q, 3p, 5q, 6q, 7q, 8p, 9p, 10p, 10q, 11p, 11q, 12p, 13q, 16q, 17p, 17q, 18q, and 21q are reportedly associated with progression and/or initiation of prostate cancer. In the present study, we performed a polymerase chain reaction (PCR) analysis of polymorphic microsatellite loci on the human chromosomes 7 and 12p13-12 in prostate cancer tissue to investigate the extent of involvement of these regions, which may contain putative tumor suppressor genes. METHODS: Tissue samples were obtained at autopsy from 17 men who died of hormone-refractory prostate cancer at Chiba University, Japan, and affiliated hospitals between June of 1992 and June of 1995. DNA from normal tumor or metastatic tissue was used as the template for PCR amplification of a set of 16 polymorphic microsatellite loci on human chromosome 7 and 6 loci on the human chromosome region 12p13-12. RESULTS: The frequencies of cases with loss of heterozygosity (LOH) at 7q31.1 were 8% in primary tumor tissue and 11% in metastatic tissue. The frequencies of cases with LOH at 12p13-12 were 12% in primary tumor tissue and 25% in metastatic tumor tissue. CONCLUSIONS: In the present study, the frequencies of LOH at 7q31.1 were lower than in Western patients, suggesting that LOH in this region is not related to progression of prostate cancer in Japanese patients. The frequency of LOH at 12p13-12 was similar to that reported in Western countries, indicating that 12p13-12 may contain a tumor suppressor gene of prostate cancer.     

Genome linkage screen for prostate cancer susceptibility loci: results from the Mayo Clinic Familial Prostate Cancer Study

Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a twofold to threefold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Several putative loci identified by genetic linkage have been reported to exist on chromosomes 1 (HPC1, PCAP, and CAPB), X (HPCX), 17 (HPC2), and 20 (HPC20), with genes RNASEL (HPC1) and ELAC2 (HPC2) tentatively defined. In this study, we report our genome linkage scan in 160 prostate cancer families, using the ABI Prism Linkage Mapping Set Version 2 with 402 microsatellite markers. The most significant linkage was found for chromosome 20, with a recessive model heterogeneity LOD score (HLOD) of 4.77, and a model-free LOD score (LOD - ZLR) of 3.46 for the entire group of pedigrees. Linkage for chromosome 20 was most prominent among families with a late age of diagnosis (average age at diagnosis >/= 66 years; maximum LOD - ZLR = 2.82), with <5 affected family members (LOD - ZLR = 3.02), with presence of hereditary prostate cancer (LOD - ZLR = 2.81), or with no male-to-male transmission of disease (LOD - ZLR = 3.84). No other chromosome showed significant evidence for linkage. However, chromosomes 6 and X showed suggestive results, with maximum LOD - ZLR values of 1.38 and 1.36, respectively. Subset analyses suggest additional chromosomal regions worth further follow-up.     

Evaluation of SRD5A2 sequence variants in susceptibility to hereditary and sporadic prostate cancer

BACKGROUND: The 5 alpha-reductase type II (SRD5A2) catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone (DHT), and is thus believed to be the key enzyme for the control of intracellular DHT level in the prostate. Several single nucleotide polymorphisms (SNPs) in the SRD5A2 gene have been found to alter enzymatic activities and were associated with prostate cancer risk or clinical features in several case-control studies. However, the role of SRD5A2 sequence variants in the susceptibility to hereditary prostate cancer (HPC) has not been evaluated to date. METHODS: Three SNPs in the SRD5A2 gene (A49T, V89L, and C682G) and two microsatellite markers near SRD5A2 were genotyped in 159 HPC families to assess their linkage to prostate cancer. In addition, the three SNPs were also genotyped in 245 sporadic cases and 222 unaffected controls to assess their association with hereditary and sporadic prostate cancer. RESULTS: Weak evidence for linkage in the SRD5A2 chromosomal region was observed in the 159 HPC families (HLOD = 0.87, P = 0.04). Stronger evidence for linkage was observed in Caucasian families (HLOD = 1.10, P = 0.02). When stratified by the SNP A49T, no significant evidence for linkage was observed in families with or without the "T" allele. Similarly, family-based association tests failed to observe significant over-transmission of any risk alleles of SNPs A49T, V89L, and C682G to affected offspring. Finally, no significant differences in the distributions of SNPs A49T, V89L, and C682G were found among the HPC probands, sporadic cases, and controls. CONCLUSIONS: Polymorphisms of SRD5A2 are unlikely to significantly increase susceptibility to hereditary or sporadic prostate cancer in the study populations.     

Analysis of Allelic Imbalance in Patients With Colorectal Cancer According to Stage and Presence of Synchronous Liver Metastases

OBJECTIVE: To investigate the relationship between number and location of allelic imbalances (AI) and local tumor progression according to Astler-Coller classification. SUMMARY BACKGROUND DATA: Spontaneous errors in DNA replication (i.e., allelic imbalance or microsatellite instability) have been suggested to play an important role in carcinomatous transformation as reflecting alterations of gene function. METHODS: One hundred two consecutive patients with colorectal carcinoma undergoing surgical resection were included in this study. Patients were distributed according to the Astler-Coller classification as stages A (n = 7), B1 (n = 15), B2 (n = 24), C (n = 31), and D (n = 25). Fluorescent polymerase chain reaction was performed on frozen tumor, normal colon mucosa, and blood DNA at 35 microsatellite markers. Allelic imbalance frequency was compared with tumor staging. RESULTS: The percentage of AI was significantly higher in stage D than in A/B1 and B2. In addition, the percentage of AI was significantly higher in 10 synchronous colorectal liver metastases than in stage A/B1 and B2 tumors. However, the allelotyping revealed a subgroup of A/B1 tumors with a high AI frequency. Statistical analysis showed that the presence of AI at microsatellites D1S305, D2S138, D3S1282, D17S790, and D22S928 presented a significantly positive correlation with stages. CONCLUSION: The frequency of AI significantly correlates with tumor progression of colorectal cancer. Primary tumors with synchronous colorectal liver metastases showed a higher percentage of AI, suggesting that a frequency of AI greater than 35% with this selection of markers indicates a high risk of local progression and of development of metastases.     

Allelic losses at 8p, 10q, 11p, 13q, 16q, 17p,and 18q in prostatic carcinomas: The impact of zonal location,Gleason grade,and tumour multifocality

Molecular genetic investigations have made it clear that the development and progression of prostate cancer is associated with losses of genetic material in certain chromosomal arms. However, there are only few data about the question of whether the zonal location, a higher Gleason grade, or multifocality of the tumour have any influence on the pattern of allelic losses. In the present study, 48 tumour foci from 32 radical prostatectomy specimens were investigated for allelic losses at chromosomes 8p, 10q, 11p, 13q, 16q, 17p, and 18q with a set of 20 microsatellite markers. The results were analysed for the zonal location of the tumour foci and the presence of a Gleason grade 4 differentiation. Overall, focal allelic losses at 8p, 10q, 11p, 13q, 16q, 17p, and 18q were observed in 62.5%, 17.2%,. 3.2%, 18.8%, 40%, 9.7%, and 22.6% of the 32 cases, respectively. Comparing the frequencies of allelic losses with the zonal location or the Gleason grade, no highly significant correlations were found at any chromosomal locus investigated. However, the observation of different patterns of allelic losses in 12 of 14 cases containing more than one tumour focus indicates a high rate of genetic heterogeneity. We conclude that allelic losses at the chromosomal loci investigated are not strongly associated with a specific zonal location or a higher Gleason grade of prostatic carcinoma. Genetic heterogeneity of multiple tumour foci within one gland might contribute to the difficulties in predicting the prognosis for this common malignancy.     

Genome-wide scan for linkage in finnish hereditary prostate cancer (HPC) families identifies novel susceptibility loci at 11q14 and 3p25-26

BACKGROUND: In order to identify predisposition loci to hereditary prostate cancer (HPC), we performed a genome-wide linkage analysis using samples from a genetically homogeneous population, with 13 Finnish multiplex prostate cancer families. METHODS: Altogether 87 DNA samples were genotyped from 13 families. Logarithm-of-odds (LOD) scores were calculated for all autosomes using FASTLINK and GENEHUNTER designating all unaffected men and all women as unknown. RESULTS: The highest LOD scores in the affected-only analyses were found at 11q14, where the two-point LOD score was 2.97 (theta = 0.0 at D11S901), GENEHUNTER heterogeneity LOD (HLOD) of 3.36, and a non-parametric-linkage (NPL) score of 2.67 (P = 0.008). A second positive site was at 3p25-26, with a two-point LOD score of 2.57 (theta = 0.01 at D3S1297), HLOD of 2.15, and NPL score of 2.27 (P = 0.02). CONCLUSIONS: The results suggest two HPC regions in the Finnish population, which have not been reported previously and warrant further study.     

Surgical margin and Gleason score as predictors of postoperative recurrence in prostate cancer with or without chromosome 8p allelic imbalance

BACKGROUND: Identification of prostate cancer patients at risk for postoperative disease recurrence is an important clinical issue. Existing pathological markers can predict disease recurrence only to a certain extent, and there is a need for more accurate predictors. METHODS: Using "counting alleles," a novel experimental method, we determined allelic status of chromosome 8p in 107 prostatectomy specimens. Statistical analyses examined the association between pathologic predictors (Gleason score, stage, surgical margin, etc.) and cancer recurrence in patients with and without 8p allelic imbalance (8p AI). RESULTS: 8p AI cancers were more likely to recur in the presence of a positive surgical margin, whereas recurrence of 8p retaining tumors was associated with the Gleason score, but not with the surgical margin. CONCLUSIONS: Our findings suggest that chromosome 8p allelic status affects the predictive value of "traditional" markers of prostate cancer recurrence. If confirmed by larger studies, these results may have important clinical implications.     

Microsatellite analysis of allelic imbalance in tumour and blood from patients with prostate cancer

OBJECTIVE

To investigate whether a high frequency of allelic imbalance (AI) is associated with clinicopathological variables of patients with prostate cancer.

PATIENTS AND METHODS

We analysed loss of heterozygosity (LOH) and microsatellite (MS) instability (MSI) on circulating plasma DNA in a polymerase chain reaction (PCR)‐based MS study of 230 patients with prostate cancer and 43 with benign prostatic hyperplasia (BPH) using a panel of 13 polymorphic MS markers.

RESULTS

The overall incidence of AI was significantly higher in primary tumours (34%) than in blood plasma samples from patients with prostate cancer (11%). Although LOH (2.0%) and MSI (1.5%) were also found in BPH plasma samples, their frequencies were low. AI identified in plasma samples from patients with prostate cancer could be retrieved in 63% of the paired tumour samples. The highest concordance of AI and retention of heterozygosity between tumour and plasma samples was 83% at the marker D8S360. There were high frequencies of LOH at the markers THRB, D7S522 and D8S137 in both types of specimens. The markers D11S898 and D11S1313 on the chromosome arm 11q showed frequent MSI. The comparison with established risk factors showed significant associations of an increase in prostate volume with AI at the combined markers D6S474/D7S522 in tumour tissues and at D7S522 in plasma samples (P < 0.04). In the primary tumours there was a further correlation of LOH at D11S1313 with increasing tPSA value (P = 0.005). The combination of total prostate‐specific antigen (PSA) and % free PSA was associated with LOH at THRB in plasma samples.

CONCLUSIONS

Plasma‐based MS analysis may have clinical value for the molecular staging of prostate cancer.     

A genome-wide association screen identifies regions on chromosomes 1q25 and 7p21 as risk loci for sporadic prostate cancer

We conducted a genome-wide association study of 3090 sporadic prostate cancer patients and controls using the Affymetrix 10 000 SNP GeneChip. Initial screening of 40 prostate cancer cases and 40 non-cancer controls revealed 237 SNPs to be associated with prostate cancer (P<0.05). Among these SNPs, 33 were selected for further association analysis of 2069 men who had undergone a cancer-screening prostate biopsy. Results identified five loci as being significantly associated with increased prostate cancer risk in this larger sample (rs 1930293, OR=1.7, P=0.03; rs 717809-2p12, OR=1.3, P=0.03; rs 494770-4q34, OR=1.3, P=0.01; rs 2348763-7p21, OR=1.5, P=0.01; rs 1552895-9p22, OR=1.5, P=0.002). To validate these association data, 61 additional HapMap tagSNPs spanning the latter five loci were genotyped in this subject cohort and an additional 1021 men (total subject number=3090). This analysis revealed tag SNP rs 4568789 (chromosome 1q25) and tag SNP rs 13225697 (chromosome 7p21) to be significantly associated with prostate cancer (P-values 0.009 and 0.008, respectively). Haplotype analysis revealed significant associations of prostate cancer with two allele risk haplotypes on both chromosome 1q25 (adjusted OR of 2.7 for prostate cancer, P=0.0003) and chromosome 7p21 (adjusted OR of 1.3, P=0.0004). As linkage data have identified a putative prostate cancer gene on chromosome 1q25 (HPC1), and microarray data have revealed the ETV1 oncogene to be overexpressed in prostate cancer tissue, it appears that chromosome 1q25 and 7p21 may be sites of gene variants conferring risk for sporadic and inherited forms of prostate cancer.     

Association between sequence variants at 17q12 and 17q24.3 and prostate cancer risk in European and African Americans

BACKGROUND: Three SNPs at 17q12 and four SNPs at 17q24.3 were recently identified to be associated with prostate cancer risk using a genome-wide association study. METHODS: We evaluated these 7 SNPs in two hospital-based case-control study populations, including European Americans (EA; 1,563 cases and 576 controls) and African Americans (AA; 364 cases and 353 controls). RESULTS: Each of the reported risk alleles of these seven SNPs were more common in cases than in controls among EA and AA. The differences were highly significant in EA (P = 10(-4)) and marginally significant in AA (P = 0.04) for SNPs at 17q12. In contrast, the differences were not statistically significant in EA or AA for SNPs at 17q24.3, but were marginally significant for two SNPs (P = 0.04-0.06) when EA and AA subjects were combined. Similar results were obtained when genotype and haplotype frequencies between cases and controls were analyzed. These risk variants were not associated with more aggressive prostate cancer or other clinical variables such as TNM stage, pre-operative PSA, or age at diagnosis. CONCLUSIONS: Results from our study provide the first confirmation of these 17q SNPs as novel prostate cancer susceptibility loci in EA and the first indication that these two loci may also play roles in prostate cancer risk among AA.     

A candidate gene approach within the susceptibility region PCaP on 1q42.2-43 excludes deleterious mutations of the PCTA-1 gene to be responsible for hereditary prostate cancer

OBJECTIVE: The Prostate Carcinoma Tumor Antigen-1 (PCTA-1) is located at the prostate cancer susceptibility locus on chromosome 1q42.2-43 (PCaP). In this candidate gene approach, we searched for deleterious mutations within the PCTA-1 gene and its promoter. MATERIALS AND METHODS: Seventy-seven familial prostate cancer cases from 36 German and French pedigrees were screened for germline mutations in the PCTA-1 gene using enzymatic mutation detection (EMD). Putative missense mutations were genotyped by RPLP and ddNTP primer extension assays in 88 controls to assess allele frequencies and haplotypes. RESULTS: Several sequence variants were found but none of the findings indicated a deleterious mutation. Three affected brothers showed an intronic variation, which may interfere with correct splicing. Four non-conservative SNPs were characterized, coding for the amino acid alterations Y19F, C36R, V56M and S184R. All exchanges were found in controls with common allelic frequencies of at least 28%. Haplotype definition including six SNPs within the PCTA-1 gene revealed a complete linkage disequilibrium. Low haplotype diversity leads to a predominance of only two peptide variants of the PCTA-1 protein, coded by 95% of all chromosomes. CONCLUSIONS: PCTA-1 is not a classical high risk gene with deleterious mutations predisposing to hereditary prostate cancer. Its contribution to prostate cancer susceptibility as a low risk factor in sporadic disease has to be assessed in larger samples by association studies.