| 1. |
- Borg, Åke, et al.
(författare)
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Novel germline p16 mutation in familial malignant melanoma in southern Sweden
- 1996
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Ingår i: Cancer Research. - 0008-5472. ; 56:11, s. 500-2497
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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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| 2. |
- Fernö, Mårten, et al.
(författare)
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Urokinase plasminogen activator, a strong independent prognostic factor in breast cancer, analysed in steroid receptor cytosols with a luminometric immunoassay
- 1996
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 32a:5, s. 793-801
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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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| 3. |
- Kainu, Tommi, et al.
(författare)
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Detection of Germline BRCA1 Mutations in Breast Cancer Patients by Quantitative Messenger RNA in situ Hybridization
- 1996
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Ingår i: Cancer Research. - 1538-7445. ; , s. 2912-2915
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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.
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| 4. |
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| 5. |
- van den Berg, J, et al.
(författare)
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Allelic loss at chromosome 13q12-q13 is associated with poor prognosis in familial and sporadic breast cancer
- 1996
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Ingår i: British Journal of Cancer. - 0007-0920. ; 74:10, s. 1615-1619
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Tidskriftsartikel (refereegranskat)abstract
- Loss of heterozygosity (LOH) was analysed in 84 primary tumours from sporadic, familial and hereditary breast cancer using five microsatellite markers spanning the chromosomal region 13q12-q13 which harbours the BRCA2 breast cancer susceptibility gene, and using one other marker located within the RBI tumour-suppressor gene at 13q14. LOH at the BRCA2 region was found in 34% and at RBI in 27% of the tumours. Selective LOH at BRCA2 occurred in 7% of the tumours, whereas selective LOH at RBI was observed in another 7%. Moreover, a few tumours demonstrated a restricted deletion pattern, suggesting the presence of additional tumour-suppressor genes both proximal and distal of BRCA2. LOH at BRCA2 was significantly correlated to high S-phase values, low oestrogen and progesterone receptor content and DNA non-diploidy. LOH at BRCA2 was also associated, albeit non-significantly, with large tumour size and the ductal and medullar histological types. No correlation was found with lymph node status, patient age or a family history of breast cancer. A highly significant and independent correlation existed between LOH at BRCA2 and early recurrence and death. LOH at RBI was not associated with the above mentioned factors or prognosis. The present study does not provide conclusive evidence that BRCA2 is the sole target for deletions at 13q12-q13 in breast tumours. However, the results suggest that inactivation of one or several tumour-suppressor genes in the 13q12-q13 region confer a strong tumour growth potential and poor prognosis in both familial and sporadic breast cancer.
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