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Träfflista för sökning "WFRF:(Borg Åke) srt2:(1995-1999)"

Sökning: WFRF:(Borg Åke) > (1995-1999)

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1.
  • Kainu, Tommi, et al. (författare)
  • Detection of Germline BRCA1 Mutations in Breast Cancer Patients by Quantitative Messenger RNA in situ Hybridization
  • 1996
  • Ingår i: Cancer Research. - American Association for Cancer Research Inc.. - 1538-7445. ; s. 2912-2915
  • Tidskriftsartikel (refereegranskat)abstract
    • Mutations in the breast cancer susceptibility gene 1 (BRCA1) may account for one half of all familial breast cancers. Because of the wide spectrum of different germline mutations, identification of BRCA1 mutation carriers using current techniques is laborious and difficult. The majority of the identified mutations, however, lead to aberrant expression of the gene product in tumor tissue, potentially allowing the detection of BRCA1-linked breast cancers using simple histochemical techniques. We performed quantitative mRNA in situ hybridization analysis on archival paraffin-embedded tumor specimens from 25 patients with characterized germline BRCA1 mutations or linkage and from 29 patients with sporadic breast cancers. BRCA1 mRNA levels were invariably low in tumors from BRCA1 mutation carriers. Normal breast epithelium surrounding the BRCA1 tumors showed higher mRNA levels than the tumor tissue, indicating that the low mRNA levels were due to somatic inactivation of the wild-type BRCA1 allele in the tumor tissue. The expression levels in the sporadic tumors were, on average, six times higher than in the BRCA1 tumors (P < 0.0001). The difference allowed identification of BRCA1-mutated and sporadic tumors with more than 95% specificity and sensitivity. We conclude that the analysis of BRCA1 gene expression by mRNA in situ hybridization may be useful in screening for patients with BRCA1-linked breast cancer.
2.
  • Borg, Åke, et al. (författare)
  • Novel germline p16 mutation in familial malignant melanoma in southern Sweden
  • 1996
  • Ingår i: Cancer Research. - American Association for Cancer Research Inc.. - 0008-5472. ; 56:11, s. 500-2497
  • Tidskriftsartikel (refereegranskat)abstract
    • The p16 (CDKN2/MTS1/INK4a) malignant melanoma susceptibility gene was analyzed in 10 melanoma kindreds from southern Sweden using single-stranded conformation polymorphism analysis of all three exons and flanking intron regions followed by sequence analysis. A novel germline mutation, constituting an in-frame 3-bp duplication at nucleotide 332 in exon 2, was identified in two families (Lund M2 and M9). The mutation results in an insertion of Arg at codon 105, which interrupts the last of the four ankyrin repeats of the p16 protein, motifs which have been demonstrated as important in binding and inhibiting the activity of cyclin D-dependent kinases 4 and 6 in cell cycle G1 phase regulation. All five tested individuals of Lund M2 and M9 affected by melanoma were mutation carriers, as were five melanoma-free individuals. Other malignancies observed in gene carriers or obligate carriers included cervical, breast, and pancreatic carcinomas and a non-Hodgkin's lymphoma. Analysis of microsatellite markers adjacent to the p16 gene at chromosomal region 9p21 revealed that both families share a common haplotype, in keeping with a common ancestor.
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3.
  • Bratt, O, et al. (författare)
  • CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk
  • 1999
  • Ingår i: British Journal of Cancer. - Nature Publishing Group. - 0007-0920. ; 81:4, s. 6-672
  • Tidskriftsartikel (refereegranskat)abstract
    • The length of the polymorphic CAG repeat in the N-terminal of the androgen receptor (AR) gene is inversely correlated with the transactivation function of the AR. Some studies have indicated that short CAG repeats are related to higher risk of prostate cancer. We performed a case-control study to investigate relations between CAG repeat length and prostate cancer risk, tumour grade, tumour stage, age at diagnosis and response to endocrine therapy. The study included 190 AR alleles from prostate cancer patients and 186 AR alleles from female control subjects. All were whites from southern Sweden. The frequency distribution of CAG repeat length was strikingly similar for cases and controls, and no significant correlation between CAG repeat length and prostate cancer risk was detected. However, for men with non-hereditary prostate cancer (n = 160), shorter CAG repeats correlated with younger age at diagnosis (P = 0.03). There were also trends toward associations between short CAG repeats and high grade (P = 0.07) and high stage (P = 0.07) disease. Furthermore, we found that patients with long CAG repeats responded better to endocrine therapy, even after adjusting for pretreatment level of prostate-specific antigen and tumour grade and stage (P = 0.05). We conclude that short CAG repeats in the AR gene correlate with young age at diagnosis of prostate cancer, but not with higher risk of the disease. Selection of patients with early onset prostate cancer in case-control studies could therefore lead to an over-estimation of the risk of prostate cancer for men with short CAG repeats. An association between long CAG repeats and good response to endocrine therapy was also found, but the mechanism and clinical relevance are unclear.
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4.
  • Fernö, Mårten, et al. (författare)
  • Recurrence-free survival in breast cancer improved by adjuvant tamoxifen--especially for progesterone receptor positive tumors with a high proliferation
  • 1995
  • Ingår i: Breast Cancer Research and Treatment. - Springer. - 1573-7217. ; 36:1, s. 23-34
  • Tidskriftsartikel (refereegranskat)abstract
    • Although the beneficial effect on breast cancer of adjuvant tamoxifen (TAM) is well established, in the series studied by our group this effect seems to have been restricted to patients with steroid receptor (especially progesterone receptor (PgR)) positive tumors. However, as some patients with PgR-positive tumors manifested recurrence despite adjuvant TAM treatment, the question arose whether some other biological factor(s) could be used to identify these non-responding cases. The level of the S-phase fraction (SPF), as measured by flow cytometry, has been shown to be a useful prognostic marker, prognosis being better in cases where the SPF is low than in those where it is high. The aim of the present study was to relate the prognosis after adjuvant TAM to SPF among patients with PgR-positive tumors. In the PgR-positive group as a whole, the effect of TAM on prognosis was more pronounced in the high SPF group than in the low SPF group (p = 0.005) the respective decrease in 3 year recurrence rate was from 19 to 43% and from 17 to 9%. Multivariate analysis of the data for the TAM-treated group showed the level of PgR concentration (low positive vs. high positive), lymph node status, and tumor size to be independent predictive factors, but not the level of SPF (i.e. high vs. low). By contrast, among patients not treated with TAM, the SPF was a strong independent prognostic factor. To sum up, SPF was a strong independent predictor of outcome only for patients receiving no systemic adjuvant therapy, but not in patients receiving adjuvant TAM. Patients with PgR-positive and high S-phase tumors derived more benefit from TAM than patients with PgR-positive and low SPF tumors.
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5.
  • Fernö, Mårten, et al. (författare)
  • Urokinase plasminogen activator, a strong independent prognostic factor in breast cancer, analysed in steroid receptor cytosols with a luminometric immunoassay
  • 1996
  • Ingår i: European Journal of Cancer. - IFAC & Elsevier Ltd.. - 1879-0852. ; 32a:5, s. 793-801
  • Tidskriftsartikel (refereegranskat)abstract
    • Urokinase plasminogen activator (uPA) is involved in the activation of different proteases which participate in the degradation of extracellular matrix, thereby enhancing the invasive capacity of tumour cells. uPA has been shown to be of prognostic importance in breast cancer. We have analysed uPA with a new luminometric immunoassay (LIA), applicable in cytosol samples routinely used for oestrogen-receptor (ER) and progesterone-receptor (PgR) analyses. At a cut-off value of 0.62 ng uPA/mg protein, 33% (230/688) samples were classified as representing high uPA tumours. High uPA content was found to be associated with shorter recurrence-free survival (median observation time: 42 months), ER and PgR negativity, increased p53 expression, DNA non-diploidy and a high S-phase fraction (SPF), but not with lymph node involvement or tumour size (< or = 20 mm versus > 20 mm). In the subgroup of patients not treated with systemic adjuvant therapy, multivariate analysis showed uPA to be an independent prognostic factor together with lymph node status and SPF. If these results can be reproduced, uPA may be a factor suitable for inclusion in a prognostic index.
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6.
  • Fioretos, Thoas, et al. (författare)
  • Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations
  • 1999
  • Ingår i: Blood. - American Society of Hematology. - 1528-0020. ; 94:1, s. 225-232
  • Tidskriftsartikel (refereegranskat)abstract
    • An isochromosome of the long arm of chromosome 17, i(17q), is the most frequent genetic abnormality observed during the disease progression of Philadelphia chromosome-positive chronic myeloid leukemia (CML), and has been described as the sole anomaly in various other hematologic malignancies. The i(17q) hence plays a presumably important pathogenetic role both in leukemia development and progression. This notwithstanding, the molecular consequences of this abnormality have not been investigated in detail. We have analyzed 21 hematologic malignancies (8 CML in blast crisis, 8 myelodysplastic syndromes [MDS], 2 acute myeloid leukemias, 2 chronic lymphocytic leukemias, and 1 acute lymphoblastic leukemia) with i(17q) by fluorescence in situ hybridization (FISH). Using a yeast artificial chromosome (YAC) contig, derived from the short arm of chromosome 17, all cases were shown to have a breakpoint in 17p. In 12 cases, the breaks occurred within the Smith-Magenis Syndrome (SMS) common deletion region in 17p11, a gene-rich region which is genetically unstable. In 10 of these 12 cases, we were able to further map the breakpoints to specific markers localized within a single YAC clone. Six other cases showed breakpoints located proximally to the SMS common deletion region, but still within 17p11, and yet another case had a breakpoint distal to this region. Furthermore, using chromosome 17 centromere-specific probes, it could be shown that the majority of the i(17q) chromosomes (11 of 15 investigated cases) were dicentric, ie, they contained two centromeres, strongly suggesting that i(17q) is formed through an intrachromosomal recombination event, and also implicating that the i(17q), in a formal sense, should be designated idic(17)(p11). Because i(17q) formation results in loss of 17p material, potentially uncovering the effect of a tumor suppressor on the remaining 17p, the occurrence of TP53 mutations was studied in 17 cases by sequencing the entire coding region. In 16 cases, no TP53 mutations were found, whereas one MDS displayed a homozygous deletion of TP53. Thus, our data suggest that there is no association between i(17q) and coding TP53 mutations, and that another tumor suppressor gene(s), located in proximity of the SMS common deletion region, or in a more distal location, is of pathogenetic importance in i(17q)-associated leukemia.
7.
  • Hakansson, Sara, et al. (författare)
  • Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer
  • 1997
  • Ingår i: American Journal of Human Genetics. - Cell Press. - 0002-9297. ; 60:5, s. 1068-1078
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous studies of high-risk breast cancer families have proposed that two major breast cancer-susceptibility genes, BRCA1 and BRCA2, may account for at least two-thirds of all hereditary breast cancer. We have screened index cases from 106 Scandinavian (mainly southern Swedish) breast cancer and breast-ovarian cancer families for germ-line mutations in all coding exons of the BRCA1 and BRCA2 genes, using the protein-truncation test, SSCP analysis, or direct sequencing. A total of 24 families exhibited 11 different BRCA1 mutations, whereas 11 different BRCA2 mutations were detected in 12 families, of which 3 contained cases of male breast cancer. One BRCA2 mutation, 4486delG, was found in two families of the present study and, in a separate study, also in breast tumors from three unrelated males with unknown family history, suggesting that at least one BRCA2 founder mutation exists in the Scandinavian population. We report 1 novel BRCA1 mutation, eight additional cases of 4 BRCA1 mutations described elsewhere, and 11 novel BRCA2 mutations (9 frameshift deletions and 2 nonsense mutations), of which all are predicted to cause premature truncation of the translated products. The relatively low frequency of BRCA1 and BRCA2 mutations in the present study could be explained by insufficient screening sensitivity to the location of mutations in uncharacterized regulatory regions, the analysis of phenocopies, or, most likely, within predisposed families, additional uncharacterized BRCA genes.
8.
  • Haraldsson, K, et al. (författare)
  • BRCA2 germ-line mutations are frequent in male breast cancer patients without a family history of the disease
  • 1998
  • Ingår i: Cancer Research. - American Association for Cancer Research Inc.. - 1538-7445. ; 58:7, s. 71-1367
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast cancer is a rare disease in men, affecting less than 0.1% of the male population. Two heritable gene defects have been associated with a predisposition to male breast cancer development, ie., germ-line mutations in the breast cancer susceptibility gene BRCA2 and the androgen receptor (AR) gene. In this study, the entire coding regions of BRCA2 and AR were screened for mutations in 34 consecutive male breast cancer patients. Five different truncating BRCA2 mutations were identified in 7 (21%) of the 34 cases, with all mutations being of germ-line origin. Three of the mutated cases carried the same mutation (4186delG), which has been found earlier in two Swedish families with multiple female breast cancer cases. Haplotype analysis supported a common ancestry of 4186delG. One mutation, 6503delTT, was found in a male carrying also a previously identified COOH-terminal polymorphic stop codon (Lys3326ter). No differences were seen between mutation carriers and noncarriers with respect to clinical stage and estrogen or progesterone receptor status. Mutation carriers tended to be younger at diagnosis. No germ-line AR mutations were found in the present material, but the number of AR polyglutamine repeats tended to be lower among mutation carriers. Most surprisingly, only one of the seven BRCA2 mutation carriers had a positive family history of breast cancer, suggesting a lower penetrance of some BRCA2 mutations or an influence of modifying factors for disease development in males and females. The present study implies that approximately one-fifth of all male breast cancer cases in the Swedish population are due to germ-line BRCA2 mutations.
9.
  • Hedenfalk, Ingrid, et al. (författare)
  • Activated cell cycle checkpoints in epirubicin-treated breast cancer cells studied by BrdUrd-flow cytometry
  • 1997
  • Ingår i: Cytometry. - John Wiley & Sons. - 0196-4763. ; 29:4, s. 321-327
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic alterations, such as p53 mutations, may affect a tumour's response to chemotherapy. We have treated two human breast cancer cell lines that differ in p53 status with epirubicin in order to study if there are differences in cell cycle kinetic response. MCF-7 cells express wild-type p53, while SK-BR-3 cells express only a mutated form of p53. The transition of cells from one cell cycle stage to another was studied by a bromodeoxyuridine (BrdUrd)-flow cytometry (FCM) method. MCF-7 cells showed a block in the G1 phase after treatment with 50 nM epirubicin for 24 hours, in agreement with the actions of p53 at the G1 checkpoint. SK-BR-3 cells, on the other hand, progressed through the G1 checkpoint and were blocked in late S and G2 phases, presumably due to the activation of a later checkpoint. In addition, studies of the mRNA levels of p53 and its effector gene p21 revealed that although both cell lines expressed p53 mRNA, a marked difference in the mRNA levels of p21 was seen. A dramatic increase in the level of p21 mRNA was seen in epirubicin-treated MCF-7 cells, while no such increase was seen in SK-BR-3 cells.
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10.
  • Jernström, Helena, et al. (författare)
  • Do BRCA1 mutations affect the ability to breast feed? Significantly shorter length of breast feeding among BRCA1 mutation carriers compared with their unaffected relatives.
  • 1998
  • Ingår i: Breast. - Churchill Livingstone. - 1532-3080. ; 7:6, s. 320-324
  • Tidskriftsartikel (refereegranskat)abstract
    • The difference in length of breast feeding between women with a BRCA 1 mutation and their unaffected relatives was investigated. Fifty women belonging to a family with a known BRCA1 mutation had themselves undergone testing and each had given birth to at least one child. Women with BRCA1 mutation breast-fed their first infant for a significantly shorter period (P = 0.048) and the second and third infants for a non-significantly shorter time than their unaffected relatives. Computing a mean breast-feeding time per child based on the first three infants and also taking birth year of the mother and smoking into account, having a BRCA1 mutation was associated with a significantly shorter time of breast-feeding (P = 0.034), and so was smoking (P = 0.001), but birth year of the woman did not significantly influence length of breast-feeding. Seventy-five per cent of the assessable women with a BRCA1 mutation stopped breast-feeding owing to little or no milk production compared with 36% of the non-carriers OR = 5.3 (CI 95% 1.1–22.1) and (P = 0.02). Our finding may reflect a disturbed differentiation of the breast tissue in women with BRCA1 mutations.
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