Loss of heterozygosity (LOH) involving the long arm of chromosome 13 has been reported to occur in as many as one third of primary prostate cancers. Candidate tumor suppressor genes on 13q that may ...be important in the development of prostate cancer include the retinoblastoma susceptibility gene (RBI) and a gene associated with inherited breast cancer (BRCA2). To define the pattern of allelic loss of 13q in prostate cancer, LOH analysis was performed using nine mapped polymorphic markers spanning the entire chromosomal arm. Nineteen (48%) of 40 prostate cancer cases obtained following radical prostatectomy demonstrated atllelic loss with at least one marker. Furthermore, 13 (33%) of 40 cases had evidence of allelic loss involving a region of 13q14 containing RB1. To test the hypothesis that RB1 is the targeted tumor suppressor gene in this region, 37 of 40 cases were assessed for expression of pRB, the protein product of RB1 using immunohistochemical techniques. By this analysis, 8 (22%) of 37 prostate tumors demonstrated no pRB expression. However, allelic loss at RB1, assessed with an intragenic marker, did not correlate with absent pRB expression (Fisher's exact test, P=0.375). Taken together, these data confirm that allelic loss of a common region of 13q14 occurs in approximately one third of prostate cancers. Lack of correlation of LOH at RB1 with absent pRB expression suggests the existence of another tumor suppressor gene in this region important in prostate cancer.
Acute bleeding after bone marrow transplantation (BMT) was investigated in 1,402 patients receiving transplants at Johns Hopkins Hospital between January 1, 1986 and June 30, 1995. Bleeding ...categorization was based on daily scores of intensity used by the blood transfusion service. Moderate and severe episodes were analyzed for bleeding sites. Analysis of the cause of death and the interval of the bleeding episode to outcome endpoints was recorded. Survival estimates were computed for 1,353 BMT patients. The overall incidence was 34%. Minor bleeding was seen in 10.6%, moderate bleeding was seen in 11.3%, and severe bleeding was seen in 12% of all patients. Fourteen percent of patients had moderate or severe gastrointestinal hemorrhage, 6.4% had moderate or severe hemorrhagic cystitis, 2.8% had pulmonary hemorrhage, and 2% had intracranial hemorrhage. Sixty-one percent had 1 bleeding site and 34.4% had more than 1 site. Moderate and severe bleeding was more prevalent in allogeneic (31%) and unrelated patients (62.5%) compared with autologous patients (18.5%). Significant distribution of incidence was found among the different diagnoses, but not by disease status in acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma. Bleeding was associated with significantly reduced survival in allogeneic, autologous, and unrelated BMT and in each disease category except multiple myeloma. Survival was correlated with the bleeding intensity, bleeding site, and the number of sites. Although close temporal association was evident to mortality, bleeding was recorded as the cause of death in only the minority of cases compared with other toxicities after BMT (graft-versus-host disease, infections, and preparative regimen toxicity). Acute bleeding is a common complication after BMT that is profoundly associated with morbidity and mortality. Although bleeding was not a direct cause of death in the majority of cases, it has a potential prognostic implication as a predictor of poor outcome in clinical assessment of patients after BMT.
Utilizing tissue microdissection and PCR techniques, we have examined 35 prostate tumors paired with normal tissues from the same patients for allelic loss at 24 polymorphic loci spanning chromosome ...10. Twenty-five tumors (71%) were deleted for at least one chromosome 10 locus. Of the total 35 tumors, 6 (17%) were deleted for 10p loci only, 5 (14%) for 10q loci only, and 14 (40%) were deleted for both 10p and 10q loci. The common region of deletion on 10p included loci D10S211-D10S89-D10S111. Fluorescence in situ hybridization of yeast artificial chromosome probes encompassing these loci demonstrated that the 10p region of deletion maps to 10p11.2. Losses involving 10p loci alone were most common in localized (5/14, 36%) and least common in metastatic (0/8) tumors. The common region of deletion on 10q included loci D10S219-D10S215, consistent with the major region of deletion recently defined for prostate tumors on 10q. Losses involving 10q loci alone were lowest in localized and locally invasive tumors (1/14 and 2/12, respectively) and highest in tumors metastatic to regional lymph nodes (2/8). These results suggest that 10p losses may define less invasive tumors, whereas 10q losses may play a role in the progression to more advanced tumor states in the prostate. Furthermore, this is the first report of allelic loss of a defined region on 10p potentially harboring tumor suppressor gene loci in human prostate cancer.
Recent studies have provided epidemiological evidence in support
of a possible prostate cancer susceptibility locus on the X chromosome.
The androgen receptor ( AR ) gene, located at Xq11–12,
has ...been implicated as a risk factor for the development of prostate
cancer. To examine the potential role of the AR locus in
prostate cancer susceptibility, the AR CAG repeat length
was measured in 270 Caucasian men with prostate cancer from 133
unrelated families. Each of these families has two or more confirmed
cases of prostate cancer occurring in first- and/or second-degree
relatives. No evidence for linkage of the AR gene to
prostate cancer was observed. We tested for the previously reported
association of short CAG alleles with prostate cancer using
t tests, Pearson’s χ 2 tests, and logistic
regression; analyses were subsequently repeated to incorporate only men
with moderate- to high-grade prostate cancer. No association between
AR CAG allele length and prostate cancer was detected
when either a subset of unrelated patients or a subset of unrelated
patients with moderate- to high-grade cancer was compared with a set of
unrelated controls. We failed to detect an association between short
AR CAG alleles and early age of prostate cancer
diagnosis. Once specific hereditary prostate cancer genes have been
identified, future studies can more carefully delineate the potential
role of this AR polymorphism as a modifier locus in
high-risk families.
Membrane-bound complement regulatory proteins (mCRPs) are ubiquitously expressed throughout the cells of the hematopoietic system and protect host cells from complement-mediated lysis. The expression ...and functionality of mCRPs have been demonstrated in several types of cancers; however, no clear correlation has been appreciated between tumor stage and mCRP expression.
We investigated the expression pattern of CD46, CD55, CD59, and CD97 (a receptor for CD55) in prostate cancer by tissue microarray analysis using high-density tissue microarrays spotted with tissue cores from biopsy and autopsy specimens. Real-time polymerase chain reaction was used to confirm the tissue microarray data by quantifying mRNA expression in clinically identified tissue specimens.
CD55 and CD97 demonstrated increased expression in prostatic intraepithelial neoplasia, localized prostate cancer, and metastatic prostate cancer specimens compared with normal tissue specimens. No appreciable difference was seen in CD46 or CD59 expression. These data were confirmed by real-time polymerase chain reaction of mRNA expression levels in grossly identified specimens.
These data suggest that mCRPs are differentially expressed in prostate cancer, with CD55 the predominant mCRP upregulated in malignant prostate epithelial cells. Additionally, CD97 expression correlated with the malignant phenotype and may contribute to the tumorigenic and metastatic potential of prostate cancer.
Allelic loss of 8p, 10q, 13q, 16q, and 18q has been frequently demonstrated in prostate cancer, implying the existence of putative tumor suppressor genes in these regions. However, there are likely a ...number of additional genetic events that define the progression from normal prostatic epithelium to prostate cancer that have yet to be identified. To characterize a novel region of deletion in sporadic prostate cancers, 52 tumors obtained from radical prostatectomy cases were analyzed for loss of heterozygosity (LOH) using 10 polymorphic markers spanning chromosome 6 including one marker on 6p and nine markers on 6q. Markers were selected from available databases, and a comprehensive linkage map was constructed. By this analysis, LOH for one or more polymorphic markers was detected in 17 of 52 sporadic prostate cancer cases (33%). Thirteen of 17 tumors were shown to have a common region of allelic loss extending from D6S286 to D6S283 or 6q14-21, with a minimum region of loss containing markers D6S1082 and D6S501. A second separate region of deletion centered around marker D6S404. LOH of one or more 6q markers did not correlate with Gleason grade or pathological stage of the cancer. In summary, this is the first comprehensive analysis of 6q deletions in prostate cancer, and we conclude that 6q14-21 may harbor a tumor suppressor gene important in prostate carcinogenesis.
The diagnosis of prostate cancer is dependent on histologic confirmation in biopsy core tissues. The biopsy procedure is invasive, puts the patient at risk for complications, and is subject to ...significant sampling errors. An epigenetic test that uses methylation-specific polymerase chain reaction to determine the epigenetic status of the prostate cancer-associated genes GSTP1, APC, and RASSF1 has been clinically validated and is used in clinical practice to increase the negative predictive value in men with no history of prostate cancer compared with standard histopathology. Such information can help to avoid unnecessary repeat biopsies. The repeat biopsy rate may provide preliminary clinical utility evidence in relation to this assay's potential impact on the number of unnecessary repeat prostate biopsies performed in US urology practices.
The purpose of this preliminary study was to quantify the number of repeat prostate biopsy procedures to demonstrate a low repeat biopsy rate for men with a history of negative histopathology who received a negative epigenetic assay result on testing of the residual prostate tissue.
In this recently completed field observation study, practicing urologists used the epigenetic test called ConfirmMDx for Prostate Cancer (MDxHealth, Inc, Irvine, CA) to evaluate cancer-negative men considered at risk for prostate cancer. This test has been previously validated in 2 blinded multicenter studies that showed the superior negative predictive value of the epigenetic test over standard histopathology for cancer detection in prostate biopsies. A total of 5 clinical urology practices that had ordered a minimum of 40 commercial epigenetic test requisitions for patients with previous, cancer-negative biopsies over the course of the previous 18 months were contacted to assess their interest to participate in the study. Select demographic and prostate-screening parameter information, as well as the incidence of repeat biopsy, specifically for patients with a negative test result, was collected and merged into 1 collective database. All men from each of the 5 sites who had negative assay results were included in the analysis.
A total of 138 patients were identified in these urology practices and were included in the analysis. The median age of the men was 63 years, and the current median serum prostate-specific antigen level was 4.7 ng/mL. Repeat biopsies had been performed in 6 of the 138 (4.3%) men with a negative epigenetic assay result, in whom no evidence of cancer was found on histopathology.
In this study, a low rate of repeat prostatic biopsies was observed in the group of men with previous histopathologically negative biopsies who were considered to be at risk for harboring cancer. The data suggest that patients managed using the ConfirmMDx for Prostate Cancer negative results had a low rate of repeat prostate biopsies. These results warrant a large, controlled, prospective study to further evaluate the clinical utility of the epigenetic test to lower the unnecessary repeat biopsy rate.
Objectives. Previous studies have observed higher age-specific serum prostate-specific antigen (PSA) values in African-American (AA) men without prostate cancer compared to white men, leading some to ...recommend race-specific PSA reference ranges for the early detection of prostate cancer. The primary objective of the Flint Men’s Health Study was to determine age-specific PSA reference values in a community-based sample of AA men, aged 40 to 79 years.
Methods. A probability sample of 943 AA men was selected from households in Genesee County, Michigan. Men without a prior history of prostate cancer/surgery were invited to participate in a prostate cancer screening protocol, consisting of measurement of serum total PSA, free/total PSA ratio, and digital rectal examination. Sextant biopsies were recommended, based on total PSA greater than 4.0 ng/mL and/or an abnormal digital rectal examination.
Results. From the sample of 943 men, 732 were eligible, 432 had blood drawn for PSA testing, and 374 completed all phases of the clinical examination. The 95th percentile PSA values were estimated to range from 2.36 ng/mL for men in the fifth decade to 5.59 ng/mL for men in the eighth decade. The 95th percentile values for age-specific PSA were comparable to those observed in a similar study of white men in Olmsted County, Minnesota. The median and 5th percentile values for free/total PSA did not vary significantly across age.
Conclusions. The minor differences in PSA reference ranges between AA and white men may not be of sufficient magnitude to recommend the use of race-specific PSA reference ranges for screening.
To evaluate active surveillance (AS) selection, safety and durability among men with low-risk prostate cancer assessed using the clinical cell cycle risk (CCR) score, a combined clinical and ...molecular score.
Initial treatment selection (AS vs treatment) and duration of AS were evaluated for men with low-risk prostate cancer according to the CCR score and National Comprehensive Cancer Network guidelines. Adverse events included biochemical recurrence and metastasis.
82.4% (547/664) of men initially selected AS (median follow-up: 2.2 years), 0.4% (2/547) of whom experienced an adverse event. Two-thirds of patients remained on AS for more than 3 years; patient choice was the most common reason for leaving AS.
The CCR score may aid in the identification of men who can safely defer prostate cancer treatment.
To determine whether the use of biopsy kits with 6 to 12 containers in which biopsies of the prostate are individually submitted and processed reduces the monthly rates of equivocal diagnoses.
We ...searched our computer records for prostate needle biopsies submitted in 1 to 2 containers between July 1998 and June 2000 (group 1, 515 patients) and biopsies submitted individually in 6 to 12 containers between January 2001 and December 2002 (group 2, 933 patients). We analyzed the patient demographics and pathologic diagnoses between the two groups, including the rates of equivocal diagnoses, which included atypical gland suspicious for adenocarcinoma (ATYP) and high-grade prostatic intraepithelial neoplasia (PIN) with adjacent ATYP.
Group 2 had statistically significant reductions in the monthly rates of equivocal diagnosis (2.8% versus 6.0%,
P = 0.003), ATYP diagnosis (1.8% versus 3.5%,
P = 0.042), and PIN with adjacent ATYP diagnosis (1.0% versus 2.5%,
P = 0.038). The differences in the monthly prostatic adenocarcinoma rates (36.9% versus 35.9%,
P = 0.388) and high-grade PIN rates (13.5% versus 12.3%,
P = 0.311) between the two study groups were not statistically significant.
Multiple needle biopsies submitted in 1 to 2 containers tend to entangle and fragment and are difficult to embed in a single plane during processing. The resulting loss of tissue surface area makes a definitive diagnosis difficult on small foci of atypical glands, resulting in equivocal pathology reports. The results of our study indicate that individual submission and processing of prostate biopsies in 6 to 12 container kits reduces the monthly rates of equivocal diagnoses.
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