Jan-Erik Damber

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.

Evidence for a prostate cancer susceptibility locus on the X chromosome.

Over 200,000 new prostate cancer cases are diagnosed in the United States each year, accounting for more than 35% of all cancer cases affecting men, and resulting in 40,000 deaths annually1. Attempts to characterize genes predisposing to prostate cancer have been hampered by a high phenocopy rate, the late age of onset of the disease and, in the absence of distinguishing clinical features, the inability to stratify patients into subgroups relative to suspected genetic locus heterogeneity. We previously performed a genome-wide search for hereditary prostate cancer (HPC) genes, finding evidence of a prostate cancer susceptibility locus on chromosome 1 (termed HPC1; ref. 2). Here we present evidence for the location of a second prostate cancer susceptibility gene, which by heterogeneity estimates accounts for approximately 16% of HPC cases. This HPC locus resides on the X chromosome (Xq27-28), a finding consistent with results of previous population-based studies suggesting an X-linked mode of HPC inheritance. Linkage to Xq27-28 was observed in a combined study population of 360 prostate cancer families collected at four independent sites in North America, Finland and Sweden. A maximum two-point lod score of 4.60 was observed at DXS1113, θ=0.26, in the combined data set. Parametric multipoint and non-parametric analyses provided results consistent with the two-point analysis. evidence for genetic locus heterogeneity was observed, with similar estimates of the proportion of linked families in each separate family collection. Genetic mapping of the locus represents an important initial step in the identification of an X-linked gene implicated in the aetiology of HPC.

Transforming growth factor β1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer

Prostate tumors express high levels of transforming growth factor‐β1 (TGF‐β1) and seem to acquire resistance to its antiproliferative effects with tumor progression. Moreover, TGF‐β1 could be involved in tumor‐promoting processes such as angiogenesis, cell migration, and immunosuppression.

COMBINED ORCHIECTOMY AND EXTERNAL RADIOTHERAPY VERSUS RADIOTHERAPY ALONE FOR NONMETASTATIC PROSTATE CANCER WITH OR WITHOUT PELVIC LYMPH NODE INVOLVEMENT: A PROSPECTIVE RANDOMIZED STUDY

PURPOSE We compare the combination of orchiectomy and radiotherapy to radiotherapy alone as treatment for pelvic confined prostate cancer, that is T1-4, pN0-3, M0 (TNM classification). MATERIALS AND METHODS In this prospective study 91 patients with clinically localized prostate cancer were, after surgical lymph node staging, randomized to receive definitive external beam radiotherapy (46) or combined orchiectomy and radiotherapy (45). Patients treated with radiotherapy alone had androgen ablation at clinical disease progression. The effects on progression-free, disease specific and overall survival rates were calculated. RESULTS After a median followup of 9.3 years (range 6.0 to 11.4) clinical progression was seen in 61% of the radiotherapy only patients (group 1) and in 31% of the combined treatment patients (group 2) (p = 0.005). The mortality was 61 and 38% (p = 0.02), and cause specific mortality was 44 and 27%, respectively (p = 0.06), in groups 1 and 2. The differences in favor of combined treatment were mainly caused by lymph node positive tumors. For node negative tumors there was no significant difference in survival rates. CONCLUSIONS The progression-free, disease specific and overall survival rates for patients with prostate cancer and pelvic lymph node involvement are significantly better after combined androgen ablation and radiotherapy than after radiotherapy alone. These results strongly suggest that early androgen deprivation is better than deferred endocrine treatment for these patients.

TESTOSTERONE STIMULATES ANGIOGENESIS AND VASCULAR REGROWTH IN THE VENTRAL PROSTATE IN CASTRATED ADULT RATS

The castration-induced regression and testosterone stimulated regrowth of the vasculature in the rat ventral prostate lobe were studied using stereological techniques. Seven days after castration, the endothelial cell proliferation rate (bromodeoxyuridine labeling index); the total weights of blood vessel walls, blood vessel lumina, endothelial cells, glandular epithelial cells; and total organ weight were all decreased. Within 2 days after sc treatment with testosterone, the total weights of blood vessel walls, endothelial cells, and vascular lumina, as well as the endothelial cell proliferation rate, were all normalized. In contrast to the rapid response of the vasculature, the total weight of glandular epithelium and total organ weight were not normalized during the 4 days of testosterone treatment. Growth of the vasculature apparently precedes growth of the glandular epithelium. The testosterone- dependent factors stimulating the vasculature are unknown, but factors derived from epithelial cells, mast cells (which accumulate in the prostate during the first day of testosterone treatment), and tissue macrophages could all be involved. Castration-induced regression and testosterone-stimulated regrowth of the prostatic vasculature can be used as an experimental model to study factors regulating angiogenesis and organ growth in the prostate.

Rye Bran and Soy Protein Delay Growth and Increase Apoptosis of Human LNCaP Prostate Adenocarcinoma in Nude Mice

In this study, we investigated whether dietary intervention could inhibit tumor growth of an androgen‐sensitive human prostatic cancer.

Familial prostate cancer in sweden: A nationwide register cohort study

Although prostate carcinoma is not widely recognized as a familial cancer, familial aggregation of this disease has been shown in some retrospective case–control studies. To study familial prostate cancer in Sweden, a population‐based cohort study was performed, that attempted to avoid possible bias connected with some earlier studies of familial prostate cancer.

Vascular density is a predictor of cancer‐specific survival in prostatic carcinoma

Microvessel density has been shown to give prognostic information in a variety of solid tumors, but its role in prostatic carcinoma needs further elucidation.

Inhibitory effects of soy and rye diets on the development of Dunning R3327 prostate adenocarcinoma in rats

Dunning R3327 PAP prostate tumors were transplanted in 125 rats, the rats were divided into five groups, and tumor development was examined for 24 weeks during treatment with diets containing 33% of soy flour (SD), rye bran (RB), heat‐treated rye bran (HRB), or rye endosperm (RE).

Studies of genetic factors in prostate cancer in a twin population

It has been suggested that positive family history constitutes a risk factor for the development of prostate cancer. Familial clustering of prostate cancer might suggest that genetic factors are of importance in the etiology of this disease. To elucidate further the relative importance of genetic factors, we studied prostate cancer among an unselected Swedish twin population. Information from the Swedish Twin Registry and the Swedish Cancer Registry was used. In 4,840 male twin pairs 458 prostate cancers were identified between 1959 and 1989. Among these 16 monozygotic and 6 dizygotic twin pairs were concordant for prostate cancer. Proband concordance rates of 0.192 and 0.043, and a correlation of liability of 0.40 and -0.05 were found for monozygotic and dizygotic pairs, respectively. These differences in proband concordance rates and correlations of liability for monozygotic pairs compared to dizygotic pairs are pronounced. The results indicate that genetic factors might be of importance for the development of prostate cancer. The results of this study indicate the need for further investigations of genetic factors in prostate cancer, including large scale epidemiological studies and investigations of molecular genetics of risk families.