Ulf S.R. Bergerheim

Karolinska Institutet, Сольна, Stockholm, Sweden

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Publications (49)208.16 Total impact

  • U. Bergerheim · A. Alimov · B. Sundelin · N. Wang · C. Larsson

    No preview · Article · Mar 2005 · European Urology Supplements
  • H Matsuyama · Y Pan · K Oba · S Yoshihiro · K Matsuda · L Hägarth · D Kudren · K Naito · U S R Bergerheim · P Ekman
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    ABSTRACT: The natural course of human prostate cancer is highly variable, and we still lack reliable tools to predict the patient's outcome. Recent publications suggest that the deletion of chromosome 8p22 has an important role for tumor progression in prostate cancer. Totally, 97 patients (41 Japanese and 56 Swedish) were studied to detect the status of chromosome 8p22 deletion by the fluorescence in situ hybridization (FISH) technique. Seventy-seven underwent surgery (59 radical prostatectomies or 18 lymph node dissections), and the specimens were prepared by touch biopsy. Fine-needle aspiration biopsies (FNAB) were obtained from another non-operative 20 cases. Disease progression was evaluated in 57 patients with a median follow-up of 59 months. 8p22 deletions were detected in 58 (60 %) of all cases. The frequency of 8p22 deletion did not significantly differ between different preparations of specimens (touch biopsy vs. FNAB) as well as between different races (Japanese vs. Swedish). Cases with more than pT3 tumors had a significantly higher frequency of 8p22 deletion than those with pT2 (p < 0.01). Multivariate analysis demonstrated that 8p22 deletion was the strongest parameter to predict disease progression (hazard ratio = 5.75; p = 0.0001). Studies on chromosomal deletions of 8p22 by the FISH technique may serve as a universal genetic marker to optimize the treatment strategy in patients with prostate cancer.
    No preview · Article · Jul 2003 · Aktuelle Urologie
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    ABSTRACT: We lack simple and reliable diagnostic tools to predict pathological staging as well as further progression of prostate cancer in individual cases. We studied deletions on 8p (8p22 and 8p23-pter), 10q (10q24-qter), and 16q (16q24) by fluorescence in situ hybridization in 53 specimens from patients with prostate cancer, and compared the status of these deletions with various clinical parameters. Forty-five cases were further evaluated regarding disease progression with a median follow-up period of 62 months. The overall frequencies of deletions for 8p, 10q, and 16q were 74, 55, and 55%, respectively. The frequency of 8p and 16q deletions increased significantly in parallel with tumor grade (P < 0.01 and < 0.05, respectively), while that of 10q deletions did not. Patients whose tumors showed 8p22 deletions had a significantly higher frequency in pT3 or metastatic tumors than in pT2 tumors. Patients whose tumors showed both 8p22 and 16q24 deletions had a significantly higher frequency of nodal metastases than non-metastases. A Cox hazard proportional model revealed 8p22 deletion to be the strongest parameter predictive of disease progression (hazard ratio = 6.624; P = 0.0001). Estimation of 8p22 and 16q24 deletions may serve as a genetic diagnosis for predicting pathological staging as well as disease progression in prostate cancer.
    Full-text · Article · Feb 2003 · The Prostate
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    ABSTRACT: An author (H.M.) had a chance to go abroad to Karolinska Institute, Sweden from 1992 to 94, and learnded molecular cytogenetic techniques. The following results had been obtained and published in the literature: Bradder cancer: Numericalalterations on chromosome 7, 9, and 17 by dual-color fruorescence in situ hybridization (FISH) demonstrated that chromosome 7 trisomy and 9 monosomy were the most frequently occurred not only in the tumor, but also in the surrounding intact bladder mucosa, and that 9 monosomy detected by using negative cytology specimen could predict early recurrence of superficial bladder cancer. Chromosome 17p 13.1 region, on which p53 gene was located, was studied by using cosmid probe, and deletion of these regions had a striking impact on the functional loss of tumor suppresor function in invasive bladder cancer. Immunohistochemical staining of p53 showed clinical significance in predicting patient prognosis in bladder cancer. Prostate cancer: Studies on chromosomal deletion of 8p22, 23-pter, 10q24-qter, and 16q24 demonstrated that 8p deletion had close association with tumor stage as well as pathological grade. Further investigation on Japanese prostate cancer suggested that putative tumor suppressor genes are located on 8p 21.1-21.2 and 21.3-22. Collaborative studies with Karolinska Institute were published that 16q 24 deletion had signficant relation to metastatic ability in prostage cancer, and sporadic prostate cancer arose from mutual influence of those genomic alterations with environmental factors. Further follow-up study proved deletion on 8p22 to a universal genetic marker for disease progression in Japanese prostage cancer as well as Swedish. Renal cell carcinoma: FISH studies on 5q22.3-23.2 demonstrated that gain and loss of 5q22.3-23.2 were predictive genetic marker for favorable and unfavorable patient outcome, respectively in renal cell carcinoma. Cases with 3p loss, the most frequent alteration in renal cell carcinoma, in association with 8q24 (c-myc) gain was significantly higher in high stage tumor. Genetic mapping on chromosome 9 using satellite marker showed frequent deletion in PTCH gene located on 9q22.
    No preview · Article · Jan 2003
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    H Matsuyama · Y Pan · K Oba · S Yoshihiro · K Matsuda · L Hägarth · D Kudren · K Naito · U.S.R. Bergerheim · P Ekman
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    ABSTRACT: A recent report demonstrated that the deletion of chromosome 8p22 could predict disease progression in stage III (capsular penetrating) prostate cancer. We studied if the status of chromosomal deletions of 8p22 could reflect pathological stage as well as patient prognosis, thereby serving as a diagnostic tool to optimize the treatment strategy in prostate cancer. A total of 97 patients (41 Japanese and 56 Swedish) were studied by the fluorescence in situ hybridization technique. Seventy-seven patients (23 pT2, 18 pT3, and 36 pN+ tumors) underwent surgery (radical prostatectomy or lymph node dissection). The specimens were prepared by touch biopsy. From another 20 cases, fine-needle aspiration biopsies were obtained. 8p22 deletions were detected in 47 (61%) and 11 (55%) specimens of 77 touch biopsies and 20 fine-needle aspiration biopsies, respectively. No significant difference was found in the frequency of 8p22 deletion between different preparations of specimens, as well as between different races (Japanese versus Swedish). The frequency of 8p22 deletion was statistically higher in patients with pT3 or more than in those with pT2 (P < 0.01). Disease progression was evaluated in 57 patients. The Cox proportional hazards model revealed 8p22 deletion to be the strongest parameter to predict disease progression (hazards ratio = 5.75; P = 0.0001). Studies on chromosomal deletions of 8p22 by fluorescence in situ hybridization technique may serve as a genetic marker to optimize the treatment strategy in patients with prostate cancer to the optimal treatment.
    Full-text · Article · Oct 2001 · Clinical Cancer Research
  • E Mahdy · Y Pan · NN Wang · P U Malmström · P Ekman · U Bergerheim
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    ABSTRACT: Chromosome 8 aberration and c-myc amplification have been suggested as playing important roles in the development of different human cancers. Using fluorescence in situ hybridization (FISH), chromosome 8 polysomy and c-myc amplification can be detected in cells from bladder cancer. We investigated the correlation of chromosome 8 polysomy, c-myc gene alteration and p53 deletion with histopathological parameters. Twenty-four tumors obtained from patients with bladder cancer were analyzed by interphase cytogenetics using FISH with chromosome 8 and 17 centromere probes together with an YAC clone covering the c-myc locus and three cosmid DNA probes covering the p53 locus. Chromosome 8 polysomy was found in 12 tumors. The average copy number of chromosome 8 centromere signals were significantly higher in high grade and stage, cancers. Also the c-myc copy gain and p53 deletion were significantly correlated with grade as well as stage (p<0.05, in both cases). Both polysomy 8 and c-myc copy gain were significantly correlated with p53 deletions (p<0.01) and DNA ploidy (p<0.001). On the contrary there was no significant correlation between c-myc protein over-expression and c-myc gene amplification. These results may indicate that alteration of chromosomal regions on 8q and 17p, including c-myc and p53 genes, may be linked to progression of bladder cancer.
    No preview · Article · Sep 2001 · Anticancer research
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    ABSTRACT: Chromosome analysis by G-banding, spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) was performed on 24 short-term cultured transitional cell bladder carcinomas and 5 cell lines established from bladder carcinomas. Except for one tumor with an apparently normal chromosomal constitution, clonal chromosome abnormalities were detected in all examined cases by the combined approach. The application of SKY and FISH techniques improved the karyotypic descriptions, originally based on G-banding only, by identifying 32 additional numerical changes, by establishing the chromosomal origin of 27 markers and 2 ring chromosomes, by redefining 53 aberrations and by detecting 15 hidden chromosomal rearrangements. No recurrent translocation, however, was detected. The most prominent karyotypic feature was thus the occurrence of deletions and losses of whole chromosome copies indicating the importance of tumor suppressor genes in transitional cell carcinoma pathogenesis. Invasive carcinomas were karyotypically more complex than were low grade superficial tumors. Specific losses of material from chromosome 9 and from chromosome arms 11p and 8p, and gains of 8q and 1q seem to be early changes appearing in superficial tumors, whereas losses from 4p and 17p and the formation of an isochromosome for 5p were associated with more aggressive tumor phenotypes.
    Full-text · Article · Jul 2001 · International Journal of Cancer
  • Y Pan · W O Lui · N Nupponen · C Larsson · J Isola · T Visakorpi · U.S.R. Bergerheim · S Kytölä
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    ABSTRACT: Prostate cancer cell lines have been widely used as model systems characterizing pathogenetic, functional, and therapeutic aspects of prostate cancer development. However, their chromosomal compositions are poorly characterized. In this study, five prostate cancer cell lines-TSU-Pr1, JCA-1, NCI-H660, ALVA-31, and PPC-1-were investigated by G-banding, comparative genomic hybridization (CGH), and spectral karyotyping. The results were combined with our previous findings in the prostate cancer cell lines PC-3, DU145, and LNCaP. By comparative genomic hybridization (CGH), the most frequent losses were observed at 13q, 8p, 9p, and 4q, whereas gains were most commonly seen at 8q, 10q, and 18p. The composite karyotypes were characterized by multiple numerical and structural chromosomal aberrations. Recurrent breakpoints at 5q11, 8p11, and 10q22 were observed to participate in deletion and translocation events in five of the cell lines, suggesting the importance of tumor suppressor and/or oncogenes in these regions. ALVA-31 and PPC-1 shared nine identical derivative chromosomes, two of which have also been detected in PC-3. In addition, the identification of the same homozygous deletion at D10S541 and of an identical TP53 gene mutation in all three cell lines suggests a common origin of these cell lines.
    No preview · Article · Mar 2001 · Genes Chromosomes and Cancer
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    ABSTRACT: Prostate cancer cell lines have been widely used as model systems characterizing pathogenetic, functional, and therapeutic aspects of prostate cancer development. However, their chromosomal compositions are poorly characterized. In this study, five prostate cancer cell lines—TSU-Pr1, JCA-1, NCI-H660, ALVA-31, and PPC-1—were investigated by G-banding, comparative genomic hybridization (CGH), and spectral karyotyping. The results were combined with our previous findings in the prostate cancer cell lines PC-3, DU145, and LNCaP. By comparative genomic hybridization (CGH), the most frequent losses were observed at 13q, 8p, 9p, and 4q, whereas gains were most commonly seen at 8q, 10q, and 18p. The composite karyotypes were characterized by multiple numerical and structural chromosomal aberrations. Recurrent breakpoints at 5q11, 8p11, and 10q22 were observed to participate in deletion and translocation events in five of the cell lines, suggesting the importance of tumor suppressor and/or oncogenes in these regions. ALVA-31 and PPC-1 shared nine identical derivative chromosomes, two of which have also been detected in PC-3. In addition, the identification of the same homozygous deletion at D10S541 and of an identical TP53 gene mutation in all three cell lines suggests a common origin of these cell lines. © 2000 Wiley-Liss, Inc.
    No preview · Article · Feb 2001 · Genes Chromosomes and Cancer
  • H. Matsuyama · K. Oba · S. Yoshihiro · K. Naito · Y. Pan · U.S.R. Bergerheim · P. Ekman
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    ABSTRACT: Although radical prostatectomy is recognized to be the best modality for localized prostate cancer, preoperative clinical assessment is critical to identify those patients who will benefit from surgical treatment. To date, nomograms using the clinical parameters of stage, grade, and PSA have proved to be the best tools for predicting advanced disease at the time of diagnosis. Sato et al. reported that the deletion of chromosome 8p22 detected by the FISH technique could predict disease progression in stage C (capsular-penetrating) prostate cancer (JNCI 91 : 1574-1580, 1999)2). We have also reported that the deletions of 8p22 and 16q24 had a close correlation to pathological stage as well as tumor grade. Thus, we studied whether the status of chromosomal deletions of 8p22 and 16q24 could have a striking impact on pathological stage as well as patient prognosis, thereby allowing the optimal treatment modality to be chosen for prostate cancer patients. In total, 97 patients (41 Japanese and 56 Swedish) with prostate cancer were studied. Seventy-seven patients were surgically treated by radical prostatectomy and specimens were prepared by touch biopsy. Twenty were non-operative patients and specimens were prepared by fine-needle aspiration biopsy technique. The pathological stage of the 77 operated cases was pT2 in 23, pT3 in 18 and pN + in 36 cases. The mean age of the patients was 67 years. The patient prognosis was based on disease progression including biological failure in 45 patients, with a median follow-up of 53 months. Deletion on 8p22 and 16q24 was studied by the dual-color FISH technique in 97 and 44 cases, respectively. In total, 47 of the 77 specimens (61%) obtained by touch biopsy (prostatectomized patients) and 11 of the 20 specimens (55%) obtained by aspiration biopsy (non-operated patients) had chromosomal deletion of 8p22. There was no significant difference in the frequency of 8p22 deletion, pathological grade and numerical aberrations between the different slide preparations, or races (Japanese and Swedish). The frequency of 8p22 deletion was statistically higher in patients with pT3 or more than in those with pT2 (p<0.05, Fisher's tes). In the 30 cases who had 8p22 deletion and in whom the status of 16q24 was studied, the 16q24 deletion was statistically higher in patients with nodal metastasis (pN+) than in those without (pT2 or T3) (p<0.05, Fisher's test). Out of the 45 cases (14 pT2, 10 pT3 and 21 pN1 tumors) with follow-up, patients whose tumors had 8p22 (LPL) deletions had a significantly shorter period from surgery to disease progression than those whose tumors retained 8p22 (Log-rank test, p<0.01). A Cox's hazard proportional multivariate regression analysis revealed 8p22 deletion to be the strongest parameter for predicting disease progression as well as tumor stage (hazard ratio=3.94; 95% confidence interval=1.50-13.53; p=0.0039). These data suggest patients whose tumors have 8p22 deletion are likely to be suffering from advanced (beyond capsular penetration) prostate cancer, and to be at a higher risk of disease progression. The data also suggest that these genetic data can be preoperatively acquired by applying aspiration biopsy materials in combination with the FISH technique. Additionally, patients who had both 8p22 and 16q24 deletions had a higher risk of distant metastasis. Those patients may choose hormonal therapy rather than radiation therapy. In conclusion, the detection of 8p22 and 16q24 deletions may be a useful genetic marker for deciding the treatment modality in prostate cancer.
    No preview · Article · Jan 2001 · Nishinihon Journal of Urology
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    ABSTRACT: We have recently developed an allele titration assay (ATA) to assess the sensitivity and influence of normal cell admixture in loss of heterozygosity (LOH) studies based on CA-repeat. The assay showed that these studies are biased by the size-dependent differential sensitivity of allele detection. Based on these data, we have set up new criteria for evaluation of LOH. By combining these new rules with comparative genome hybridization (CGH) we have shown the presence of interstitial deletions in renal cell carcinoma (RCC) biopsies and cell lines. At least three out of 11 analysed RCC cell lines and three out of 37 biopsies contain interstitial deletions on chromosome 3. Our study suggests the presence of several regions on human chromosome 3 that might contribute to tumor development by their loss: (i) 3p25-p26, around the VHL gene (D3S1317); (ii) 3p21. 3-p22 (between D3S1260 and D3S1611); (iii) 3p21.2 (around D3S1235 and D3S1289); (iv) 3p13-p14 (around D3S1312 and D3S1285). For the first time, AP20 region (3p21.3-p22) was carefully tested for LOH in RCC. It was found that the AP20 region is the most frequently affected area. Our data also suggest that another tumor suppressor gene is located near the VHL gene in 3p25-p26.
    Full-text · Article · Apr 2000 · Oncogene
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    ABSTRACT: Previous studies on touch biopsy specimens have determined numerical or structural changes involving many different chromosomes in bladder cancer. The aim of this study was to evaluate the use of fluorescence in situ hybridization (FISH) assay in bladder washings as an objective technique to detect chromosomal numerical aberrations in bladder cancer. The main advantages of bladder washings are that they can be easily collected during the clinical follow-up of patients with superficial bladder cancer and they do not contain so many degenerate cells as urine samples. We collected specimens from 25 patients who underwent transurethral resection of bladder tumors. Double target FISH assays with centromeric labeled probes for chromosomes 7, 8, 9 and 11 were used on the bladder washings and on the touch biopsy slides. The results were compared to flow cytometry and tumor grade and stage. We found monosomy 9 and trisomy 7, 8, 9 and 11 in 28, 32, 36, 28 and 25% respectively of the patients. FISH analysis of bladder washing versus touch biopsy specimens were concordant in approximately 90% of the slides. Total DNA aneuploidy correlated well with numerical aberrations of chromosomes 7, 8 and 11, but not with chromosome 9. Although better hybridization efficiency was obtained on touch biopsy slides, the results in bladder washings were in high concordance. FISH analysis on bladder washing samples may become a simple tool to improve the accuracy of cytology.
    No preview · Article · Apr 2000 · European Urology
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    ABSTRACT: Renal cell carcinoma (RCC), although occurring less frequently than prostate and bladder cancer, is actually the most malignant urologic disease, killing >35% of affected patients. Therefore, investigation of the nature of premalignant lesions of the kidney is a relevant issue. Following the most recent histological classification RCC can be subdivided into four categories: conventional RCC; papillary RCC; chromophobe RCC; and collecting duct carcinoma. In contrast to many genitourinary malignancies, premalignant alterations in the kidney are scarcely described. Intratubular epithelial dysplasia has been recognized as the most common precursor of RCC. In analogy to prostatic intraepithelial neoplasia (PIN), the premalignant lesions of the kidney are described as high or low-grade renal intratubular neoplasia. In contrast, precancerous lesions have been described as part of the von Hippel-Lindau syndrome (VHL) where the evolution from a simple cyst to an atypical cyst with epithelial hyperplasia to cystic or solid conventional-type RCC is well documented. Finally, in the genesis of papillary RCC an adenoma-carcinoma sequence has been recognized with specific genetic changes. There are no data on the epidemiology of premalignant lesions of the kidney, but research into the etiology of RCC has been extended substantially. Familial and genetic factors are well documented in VHL disease, in hereditary papillary RCC, in the tuberous sclerosis complex and in familial RCC. Cigarette smoking and obesity are established risk factors for RCC. Hypertension or its medication has also been associated with an increased risk. Among dietary factors an inverse relation between risk and consumption of vegetables and fruit has been found. Occupational exposure to substances such as asbestos and solvents has been linked to an increased risk of RCC. Specific RCC variants have distinctive chromosome alterations and several genes have been implicated in the development of RCC. Loss of material from the 3p chromosome characterizes conventional RCC and the deletion of the VHL suppressor gene plays an important role in the genesis of this RCC variant. In contrast, numerical changes with trisomy of chromosomes 7 and 17 and loss of the sex chromosome are typical changes in papillary tumors, whereas papillary RCC have additional trisomies. Chromophobe RCC is characterized by loss of chromosomes with a combination of monosomies. Less consistent genetic alterations are associated with collecting duct carcinoma. The traditional treatment of RCC is surgery by radical or partial nephrectomy. The latter approach carries a risk of tumor recurrence as a result of unrecognized satellite lesions or premalignant lesions that might have been present at the time of surgery. However, the reported recurrence rates after partial nephrectomy are <1% and therefore the possible presence of premalignant disease does not alter the actual treatment strategy advocated. Although multifocality and bilateral occurrence of RCC are much more likely in cases of papillary RCC, biopsy of the renal remnant or contralateral kidney is not justified even in patients with this tumor type. Conversely, patients with RIN in a partial or radical nephrectomy specimen or in a renal biopsy taken for whatever reason should be subjected to closer follow-up with regularly repeated ultrasound. When an effective chemopreventive regimen becomes available it might be useful for patients with an inherited risk of RCC as well as in those who are at risk of tumor recurrence after intervention. Mass screening with the purpose of detecting RCC at its earliest stage is not recommended at the present time, but screening focused on certain risk groups can be advocated. Further research is needed to identify avoidable risks, develop effective chemoprevention and recognize patients at risk.
    Full-text · Article · Feb 2000 · Scandinavian journal of urology and nephrology. Supplementum
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    ABSTRACT: We studied chromosome 10q loss of heterozygosity and PTEN/MMAC1 gene inactivation in renal cell carcinoma (RCC). Fifty-four cases of RCCs were analysed by three 10q RFLP markers. Forty one of them were heterozygous for at least one of the markers, of which fourteen showed LOH (34%). Six tumors which showed 10q deletion for RFLP markers and six randomly selected tumors without RFLP LOH were included in an extended study of 10q by eight microsatellite markers. Eight of these cases showed LOH with two smallest deleted regions (SRO) at 10q23 delineated by markers D10S541 and D10S579 while the other distal SRO is between markers D10S587 and D10S212 at 10q25-26. The five tumors with LOH covering 10q23 were selected for mutation analysis of PTEN/MMAC1 gene. One tumor without LOH of 10q23 was selected as a control. Using direct sequencing of nine exons, we found three different base pair changes in three tumors with LOH. Nine RCC cell lines were analysed for PTEN/MMAC1 gene inactivation. One homozygous deletion was detected in the cell line UOK147. No expression of PTEN/MMAC1 gene was detect by RT-PCR in the cell line UOK 147.
    No preview · Article · Sep 1999 · Anticancer research
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    ABSTRACT: Genetic polymorphisms and expression of steroid receptors may explain why some individuals are more at risk of developing prostate cancer. Some risk factors often discussed are androgen stimulation, and vitamin A and D deficiency. Long CAG-repeats in exon 1 of the androgen receptor (AR) gene on the X chromosome seem to have a protective role against androgen overstimulation. Likewise, long vitamin D receptor alleles in the poly-A tract may prevent vitamin D stimulation. Blood samples from 59 Swedish patients with sporadic prostate cancers, 59 with hereditary prostate cancer, and 34 Japanese prostate cancer patients were compared with benign controls. Tissue specimens from 37 Swedish and 23 Japanese prostate cancer patients with matching blood samples were investigated by immunohistochemical techniques. The number of CAG-repeats was identical in sporadic and hereditary prostate cancer patients, but the repeats were significantly shorter than in benign controls. Benign Japanese controls were similar to Swedish controls, but Japanese prostate cancers had longer repeats than did controls. Both the vitamin D and A receptor staining was stronger in Japanese than in Swedish prostate cancer specimens. Prostate cancer occurs approximately 5 years later in Japanese compared with Swedish men. Varying lengths of CAG-repeats of the androgen receptor cannot fully explain racial differences in clinical prostate cancer incidence. A larger content of vitamin A and D receptors may be linked to a delayed onset of clinical prostate cancer in Japanese men.
    No preview · Article · Jul 1999 · The Prostate
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    ABSTRACT: BACKGROUND Genetic polymorphisms and expression of steroid receptors may explain why some individuals are more at risk of developing prostate cancer. Some risk factors often discussed are androgen stimulation, and vitamin A and D deficiency. Long CAG-repeats in exon 1 of the androgen receptor (AR) gene on the X chromosome seem to have a protective role against androgen overstimulation. Likewise, long vitamin D receptor alleles in the poly-A tract may prevent vitamin D stimulation.METHODS Blood samples from 59 Swedish patients with sporadic prostate cancers, 59 with hereditary prostate cancer, and 34 Japanese prostate cancer patients were compared with benign controls. Tissue specimens from 37 Swedish and 23 Japanese prostate cancer patients with matching blood samples were investigated by immunohistochemical techniques.RESULTSThe number of CAG-repeats was identical in sporadic and hereditary prostate cancer patients, but the repeats were significantly shorter than in benign controls. Benign Japanese controls were similar to Swedish controls, but Japanese prostate cancers had longer repeats than did controls. Both the vitamin D and A receptor staining was stronger in Japanese than in Swedish prostate cancer specimens. Prostate cancer occurs approximately 5 years later in Japanese compared with Swedish men.CONCLUSIONS Varying lengths of CAG-repeats of the androgen receptor cannot fully explain racial differences in clinical prostate cancer incidence. A larger content of vitamin A and D receptors may be linked to a delayed onset of clinical prostate cancer in Japanese men. Prostate 39:262–268, 1999. © 1999 Wiley-Liss, Inc.
    Full-text · Article · Jun 1999 · The Prostate
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    ABSTRACT: Hereditary papillary renal carcinoma (HPRC) is characterized by multiple, bilateral papillary renal carcinomas. Previously, we demonstrated missense mutations in the tyrosine kinase domain of the MET proto-oncogene in HPRC and a subset of sporadic papillary renal carcinomas. In this study, we screened a large panel of sporadic papillary renal carcinomas and various solid tumors for mutations in the MET proto-oncogene. Summarizing these and previous results, mutations of the MET proto-oncogene were detected in 17/129 sporadic papillary renal carcinomas but not in other solid tumors. We detected five novel missense mutations; three of five mutations were located in the ATP-binding region of the tyrosine kinase domain of MET. One novel mutation in MET, V1110I, was located at a codon homologous to an activating mutation in the c-erbB proto-oncogene. These mutations caused constitutive phosphorylation of MET when transfected into NIH3T3 cells. Molecular modeling studies suggest that these activating mutations interfere with the intrasteric mechanism of tyrosine kinase autoinhibition and facilitate transition to the active form of the MET kinase. The low frequency of MET mutations in noninherited papillary renal carcinomas (PRC) suggests that noninherited PRC may develop by a different mechanism than hereditary papillary renal carcinoma.
    Full-text · Article · May 1999 · Oncogene
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    ABSTRACT: Cadherins (CDH) are cell adhesion molecules and their dysfunctions have been implicated in the development of cancer metastases. Several cadherin genes are tandemly located on 16q, which is frequently deleted in prostate cancer. We therefore used 22 markers on 16q to localize important deleted regions in metastases of this tumor. We found 16q deletions in 24/32 (75%) tumors. All lymph node and brain metastases showed extensive deletions, while 52% of primary tumors displayed limited deletions. Commonly deleted regions (CDRs) on 16q23-24, CDR2 (D16S515-D16S516) and CDR4 (D16S520-D13S3028), were strongly associated with metastases and increased Gleason score. Reduced CDH1 (E-cadherin) expression was seen in 16/32 (50%) tumors, but the CDH1 gene is not within either of these two regions. Sequencing analysis for all 16 exons of the CDH1 gene did not reveal any mutations in 10 tumors, including three brain metastases with both 16q22.1 deletion and absent E-cadherin expression. Our results implicate other, yet unidentified genes on 16q23-24 to be the frequent targets of mutations and deletions in prostate cancer metastases.
    No preview · Article · Apr 1999 · Genes Chromosomes and Cancer
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    ABSTRACT: Cadherins (CDH) are cell adhesion molecules and their dysfunctions have been implicated in the development of cancer metastases. Several cadherin genes are tandemly located on 16q, which is frequently deleted in prostate cancer. We therefore used 22 markers on 16q to localize important deleted regions in metastases of this tumor. We found 16q deletions in 24/32 (75%) tumors. All lymph node and brain metastases showed extensive deletions, while 52% of primary tumors displayed limited deletions. Commonly deleted regions (CDRs) on 16q23–24, CDR2 (D16S515-D16S516) and CDR4 (D16S520-D13S3028), were strongly associated with metastases and increased Gleason score. Reduced CDH1 (E-cadherin) expression was seen in 16/32 (50%) tumors, but the CDH1 gene is not within either of these two regions. Sequencing analysis for all 16 exons of the CDH1 gene did not reveal any mutations in 10 tumors, including three brain metastases with both 16q22.1 deletion and absent E-cadherin expression. Our results implicate other, yet unidentified genes on 16q23–24 to be the frequent targets of mutations and deletions in prostate cancer metastases. Genes Chromosomes Cancer 24:175–182, 1999. © 1999 Wiley-Liss, Inc.
    No preview · Article · Mar 1999 · Genes Chromosomes and Cancer
  • H. Matsuyama · S. Yoshihiro · K. Naito · Y. Pan · B. Tribukait · P. Ekman · U.S.R. Bergerheim
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    ABSTRACT: In spite of the general agreement that cancer is the disease of gene, little is known about the genetic background regarding oncogenesis and disease progression in prostate cancer. Deletions of chromosomes 8p, 10q and 16q frequently occur in prostate cancer, while the role of these chromosomal deletions has not yet been clarified. Thus, the FISH technique was applied to detect these deletions, and a comparison was made with clinical parameters including tumor differentiation, grade and stage in 53 cases of prostate cancer. Both the region-specific cosmid probes for 8p22, 8p23-pter, 10q24- qter, 16q22-qter and the corresponding centromere probes were co-hybridized, respectively, and detected by the dual-color FISH technique. Forty-five case (14 pT2, 10 pT3 and 21 pN1 tumors) were further evaluated regarding the disease progression of individual cases, with a median follow-up period of 53 months. In total, 74% of chromosome 8p, in particular 66% of 8p22, were deleted. The overall frequencies of deletions for 10q and 16q were both 55%. The 8p and 16q deletions were significantly correlated to tumor de- differentiation (p<0.01 and <0.05, respectively), while 10q deletions were not. Patients with 8p22 deletions had a significantly shorter progression- free survival than those who retained 8p22 (Log-rank test, P<0.05). A multivariate analysis by Cox's hazard proportional model showed 8p22 deletion to be an independent prognostic indicator for disease progression together with tumor stage. We concluded that an estimation of 8p22 deletion may serve as a prognostic marker for disease progression in prostate cancer.
    No preview · Article · Mar 1999

Publication Stats

3k Citations
208.16 Total Impact Points

Institutions

  • 1999-2001
    • Karolinska Institutet
      • Department of Microbiology, Tumor and Cell Biology (MTC)
      Сольна, Stockholm, Sweden
  • 1989-2001
    • Karolinska University Hospital
      • Department of Urology
      Tukholma, Stockholm, Sweden
  • 2000
    • Universitair Ziekenhuis Leuven
      • Department of Urology
      Louvain, Flanders, Belgium
  • 1990-1991
    • Ludwig Institute for Cancer Research Sweden
      Uppsala, Uppsala, Sweden