8p22 loss concurrent with 8c gain is associated with poor outcome in prostate cancer

OBJECTIVES: A critical issue in the management of prostate cancer is the ability to distinguish patients at risk of disease recurrence. The aim of this study was to determine whether specific physical alterations of chromosome 8 may be associated with disease recurrence and poor outcome using postoperative prostate-specific antigen (PSA) values as surrogate end points. METHODS: To test this hypothesis, we examined paired normal and tumor radical prostatectomy tissues from 25 patients with prostate cancer for chromosome 8 alterations using dual fluorescence in situ hybridization with a fluorescein-labeled 8p22-specific (8p) cosmid probe and a rhodamine-labeled 8-centromere-specific (8c) probe. The probes were enumerated in 200 nuclei per tissue. RESULTS: Of the 25 tumors examined, 22 demonstrated distinct classes of genetic alterations, or nuclear types, including disomy for 8p and 8c (1 tumor), loss of 8p and disomy for 8c (10 tumors), or loss of 8p concurrent with gain of 8c (11 tumors). The presence of even a small population of tumor nuclei characterized by the loss of 8p concurrent with the gain of 8c was correlated with poor tumor grade (P = 0.009), preoperative PSA values 11 ng/mL or higher (P = 0.022), high tumor stage (P = 0.086), and detectable, rising postoperative PSA values (P = 0.086). These observations are consistent with the hypothesis that a gain of chromosome 8 is associated with poor outcome in prostate cancer. CONCLUSIONS: 8p loss concurrent with 8c gain may successfully predict disease recurrence and poor clinical outcome before the observation of detectable postoperative PSA values in patients with prostate cancer.     

TGFBR3 loss and consequences in prostate cancer

BACKGROUND: Resistance to transforming growth factor-beta (TGF-beta) is important in tumorigenesis. TGF-beta resistance mechanisms in prostate cancer are not well understood. METHODS: We have conducted a systematic analysis of TGF-beta pathway components with a meta-analysis of seven microarray studies using Oncomine and evaluated the results of TGFBR3 expression in prostate cell lines. Furthermore, we knocked down TGFBR3 in prostate epithelial cells and analyzed the consequences of TGFBR3 knockdown. RESULTS: We found that TGFBR3 is the TGF-beta component most commonly downregulated among localized human prostate cancer studies. TGFBR3 knockdown led to focus formation and enhanced expression of CD133, a marker found on prostate cancer stem cells. DNA microarray analysis of TGFBR3 knockdown cells identified 101 genes regulated by TGFBR3. Seven of these genes show a corresponding decrease in clinical prostate cancer specimens, which include genes involved in prostate mass and vasculature. CONCLUSIONS: TGFBR3 downregulation is an important step in prostate tumorigenesis.     

Chromosome 16 allelic loss analysis of a large set of microdissected prostate carcinomas.

PURPOSE: To perform loss of heterozygosity (LOH) analysis on chromosome 16 in 102 highly purified DNA samples isolated from one or more adenocarcinomas, prostatic intraepithelial neoplasia (PIN), and matched benign prostatic epithelium from 95 radical prostatectomy patients. MATERIALS AND METHODS: Specimens were procured by microdissection of frozen tissue samples, thus ensuring that highly select pure populations of cells were obtained for DNA extraction and LOH analysis. Multiple microsatellite markers were used to determine allelic loss on chromosome 16q. RESULTS: Overall loss on 16q was seen in 31% of the cancers, and occurred more frequently in high stage cancers than low stage cancers. In contrast, allelic loss in PIN failed to exceed 6% at any of the loci that were examined. CONCLUSIONS: These results suggest that inactivation of a putative tumor suppressor gene on 16q may be involved in the progression of some prostate cancers.     

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.     

Review: prostate cancer epidemiology

Prostate cancer is common among men in the United States. Factors of possible importance in the etiology of prostate cancer include diet, primarily implicated by ecologic studies of national, regional, and ethnic variation in rates; endocrine function, implicated by the importance of endocrine function in normal prostatic growth and in the treatment of prostate cancer; genetic susceptibility, supported by familial aggregation; some aspect of sexual behavior, suggested by case-control differences in sexual behavior; and occupational exposure, particularly cadmium exposure. Despite the public health importance of prostate cancer, it has received only moderate epidemiologic study; thus the etiologic importance of these and other possible determinants of prostate cancer risk is uncertain [55].     

Loss and gain of chromosomes 1, 18, and Y in prostate cancer

Nuclear suspensions of 42 prostate carcinoma specimens obtained at surgery were used to investigate loss and gain of chromosomes 1, 18, and Y by fluorescence in situ hybridization (FISH) with centromere-specific probes. The outcome of FISH analysis was correlated with clinical parameters and the relationship between DNA-FCM (ploidy at cellular level) and FISH (ploidy of individual chromosomes) was assessed. Significant loss of chromosomes 1 and 18 was infrequent (respectively, three and five cases), but 53% of the tested specimens showed loss of Y. Loss was not correlated with DNA ploidy. Significant gain occurred in 36% (chromosome 1), 63% (chromosome 18), and 28% (Y) of the specimens. Gain of chromosome 18 was shown in DNA diploid (7/14) and aneuploid tumors (18/26), while gain of chromosomes 1 and Y was nearly restricted to DNA aneuploid specimens. Significant unbalance between these chromosomes occurred in 11 cases. Most cases which had significant gain of chromosome 1 or 18 showed trisomic as well as tetrasomic cells. Simultaneous loss of some and gain of other investigated chromosomes is suggestive of clonal heterogeneity and/or multiclonality. This was observed in eight tumors. Correlation between DNA-FCM and FISH was best for the Y chromosome. DNA-FCM showed more aberrant histograms with increasing stage and grade of tumors. The presence of numerical aberrations of the investigated chromosomes however, seemed independent of clinical grade or stage. © 1994 Wiley-Liss, Inc.     

Bone loss in patients with breast or prostate cancer

Cancers of the breast and prostate are very common in the general population, with breast cancer accounting worldwide for 23% of cancer cases in women and prostate cancer accounting for 12% of cases in men. During the past decade, the survival rates of patients with estrogen-dependent breast cancer and testoster-one-dependent prostate cancer have improved. This improvement has been possible thanks to the introduction of hormone treatments that suppress the synthesis or antagonize the actions of gonadal steroids. However, estrogen and testosterone deficiencies are associated with excessive bone resorption that translates into damage of the bone microarchitecture, loss of bone mineral density, and predisposition to osteoporosis and fractures. Herein, we review the mechanisms of bone loss in breast and prostate cancer survivors, their clinical implications, and different available therapeutic modalities that may help to correct the damage of bone and prevent the development of fractures.     

前列腺癌雄激素剥夺治疗与骨质丢失

目的前列腺癌是男性泌尿系统常见的恶性肿瘤之一。我国前列腺癌的发病率在迅速上升。 目前绝大多数患者采取雄激素剥夺治疗,与化疗相比,雄激素剥夺治疗的毒副作用较轻,更容易被患 者接受,但仍会引起一系列的不良反应,本文将对前列腺癌雄激素剥夺治疗后骨质丢失的情况及防治 策略进行综述。     

Clinical significance of mutator phenotype and chromosome 17p and 18q allelic loss in gastric cancer

BACKGROUND: Tumour stage is the only reliable prognostic factor for gastric cancer. The molecular anomalies involved in this process have the potential to serve as additional prognostic markers. METHODS: Forty-four gastric cancers, treated by surgery alone, have been analysed for chromosome 17p and 18q allelic loss and for the presence of microsatellite instability (MSI), using microsatellite markers and DNA from paraffin-embedded tumours. RESULTS: Eight cancers showed a MSI-positive (MSI+) phenotype. Among the 36 MSI-negative cancers, chromosome 17p and 18q allelic losses were found in 22 of 34 and 19 of 33 informative cases respectively. Multivariate survival analysis indicated MSI status to be an independent prognostic factor along with the tumour stage. MSI+ cancers were associated with longer patient survival, whereas MSI-negative cancers had a significantly poorer prognosis (P = 0.007), with a median actuarial survival of 24 months. CONCLUSION: MSI status is an independent prognostic factor among gastric cancers at the same stage. Chromosome 17p and 18q status added no additional prognostic information to that of tumour stage. The combined use of tumour stage and MSI status may help in deciding whether patients with advanced gastric cancer require additional therapy other than surgery alone.     

Bone loss and the evolving role of bisphosphonate therapy in prostate cancer

Androgen deprivation therapy (ADT) can result in significant loss of bone mineral density (BMD) but to date, there are no prospective studies that document the true severity of bone loss and resulting fracture rates. In the general population, however, the incidence of low BMD is increasing in elderly men. Men suffer more morbidity and mortality from fractures associated with low BMD than women. Problems of underdiagnosis and undertreatment in men can be addressed with enhanced awareness of the risk factors for bone loss in men and the available treatment options. Guidelines for diagnosis of low BMD in women can probably be applied to men. Treatment options have not been studied as extensively in men. For men treated with ADT for prostate cancer, however, use of intravenous zoledronic acid at the initiation of ADT has been shown to prevent and even reverse bone loss. Although the routine use of bisphosphonates to prevent bone loss is not yet recommended, zoledronic acid is a logical choice of therapy in men who have low BMD at baseline or who develop bone loss during the course of therapy. In addition to its effects on BMD, zoledronic acid has also been shown to decrease skeletal morbidity in men with metastatic hormone-refractory prostate cancer. Whether zoledronic acid or other bisphosphonates might actually prevent or delay the development of bone metastases remains to be studied in randomized clinical trials.     

High frequency of allelic losses in high-grade prostate cancer is associated with biochemical progression after radical prostatectomy

Loss of heterozygosity (LOH) is the most consistent genetic change in prostate cancer (CaP). We aimed, to correlate specific LOH and the overall LOH frequency, to disease progression after radical prostatectomy (RP) in high-grade CaP. Between January 1990 through December 1998, 126 patients who underwent RP (cT1-T2), Gleason 8-10, were pT3, or pN1, or SM(+) (surgical margins). Nine were lost of follow-up, 39/117 (33%) had no biochemical progression (mean follow-up: 45 months). After exclusion for preoperative PSA >50 ng/mL, a case-control study was designed by matching 26 of these cases with 26 similar patients without biochemical progression (criteria: pT, pN, year of surgery). Using microsatellite markers, LOH were assessed on six chromosomal regions (7q31, 8p22, 12p13, 13q14, 16q23.2, 18q21). No prognostic value was associated with LOH at any one specific locus. However, the overall LOH frequency (five classes, cutoff of 60%), was significantly higher if progression (P = 0.02; P = 0.03) in SM(+) patients, and was near statistical significance (P = 0.08; P = 0.07) for the overall case-control population. In multivariate analysis (overall population), the overall LOH rate > or =60% was independently associated with progression [P = 0.035; Odds Ratio (OR) = 5.54]. An overall LOH rate > or =60% predicted poor outcome in 85% of SM(+) patients and 69% of the whole population. Our results suggest that the overall rate of LOH at chromosomal "hot spots" is more likely to be predictive of recurrence than the presence of LOH at any one particular locus. Moreover, the identification of a threshold of LOH could help in predicting patients with poor outcome who may be candidates for local or systemic adjuvant therapies.     

Bone loss associated with the use of LHRH agonists in prostate cancer

Hypogonadism is a recognised cause of osteoporosis in men. When patients with advanced prostate cancer are treated with luteinising hormone releasing hormone (LHRH) agonist analogues their circulating testosterone levels decline and these patients may develop fractures.We have undertaken a cross-sectional study on a cohort of patients treated with goserelin (n=41) and compared their bone density and bone turnover with patients with prostate cancer not on goserelin and elderly patients living in the community.There was no difference in bone density between the patients on treatment and those living in the community and there was a similar incidence of osteoporosis (50 and 42%, respectively). The bone marker measurements were higher in the treated patients: urine N-telopeptide (NTX) 80.1 (9) (mean (s.e.)) BCE/mmol, compared to 30.1 (2.9), P<0.001 in elderly patients; and bone alkaline phosphatase 41.9 (6.1) u/l in treated patients and 20.7 (1.5) in untreated prostate cancer patients, P<0.002. Patients on treatment with radionuclide scan evidence of metastases did not have higher bone marker values than those with negative scans.As increased bone turnover and low bone density are associated with enhanced risk of osteoporotic fractures, we suggest that patients on LHRH agonist analogues should receive advice and possibly anti-bone resorptive treatment with bisphosphonates to prevent further bone loss and fractures.Prostate Cancer and Prostatic Diseases (2001) 4, 161-166.     

Review of clinical manifestations of biochemically-advanced prostate cancer cases

OBJECTIVE: To review the pattern of initial clinical manifestation of patients who present with biochemically-advanced prostate carcinoma. METHODS: A review of 39 prostate cancer patients with initial prostate specific antigen (PSA) levels of more than 400 ng/mL (study group) and 40 patients whose initial PSA levels were between 20 and 399 ng/mL (control group) was done. RESULTS: The epidemiological profile and median Gleason score were similar in both groups. In the study and control groups, the median initial PSA levels were 1,000 ng/mL (range, 400-20,000 ng/mL) and 83 ng/mL (range, 21.8-337 ng/mL) respectively. Patients in the study group had statistically significantly higher incidences of bone pain, weight loss, loss of appetite, weakness in the lower limbs, and findings of abnormal prostate on digital rectal examination than patients in the control group. Significantly higher morbidity, including spinal cord compression, systemic lymphadenopathy, chronic urinary retention, elevated serum creatinine levels, anaemia and bone metastases, were also seen in the study group compared to the control group. Similar proportions of patients in the two groups developed hormone escape after treatment (50% in the study group, 45% in the control group). The cancer-specific mortality rate was 39.5% in the study group and 17.5% in the control group. CONCLUSION: There is a high incidence of excess morbidity in patients who present with biochemically-advanced prostate carcinoma.