| 1. |
- Ericson, K, et al.
(författare)
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Defective mismatch-repair in patients with multiple primary tumours including colorectal cancer
- 2003
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Ingår i: European Journal of Cancer. - 1879-0852. ; 39:2, s. 8-240
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Tidskriftsartikel (refereegranskat)abstract
- Individuals with an inherited predisposition to cancer development are at an increased risk of developing multiple tumours. Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common hereditary cancer syndromes and is estimated to account for approximately 2% of colorectal cancers. However, HNPCC individuals are at an increased risk of developing other tumour types such as cancers of the endometrium, urothelium and small intestine. We have utilised a population-based regional cancer registry to identify all patients with double primary colorectal cancers and at least one additional malignancy and characterised the tumour spectrum in this patient group. We subsequently selected those 47 individuals who had developed at least four malignancies, including two colorectal cancers, for studies of the tumour characteristics associated with HNPCC. In total, these individuals developed 209 tumours, 156 of which were successfully retrieved. Microsatellite instability (MSI), a phenomenon caused by defective mismatch-repair (MMR), was identified in 63/154 (41%) evaluable tumours with a MSI-high pattern in 59 and a MSI-low pattern in four tumours. All tumours were immunohistochemically stained for the MMR proteins MLH1 and MSH2, with loss of expression in 55/63 (87%) MSI tumours and in 2/89 (2%) microsatellite stable (MSS) tumours. This loss affected MLH1 in 24 tumours and MSH2 in 33 tumours. A concordant loss of expression for the same MMR protein in several tumours from the same individual, a pattern that strongly suggests an underlying germline MMR gene mutation, was found in 17/45 (38%) patients and affected MLH1 in 8 patients and MSH2 in 9 patients. We conclude that the development of multiple primary tumours, including synchronous or metachronous colorectal cancers, is associated with an increased frequency of MSI and loss of immunohistochemical expression of MLH1 and MSH2.
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| 2. |
- Jönsson, M, et al.
(författare)
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Involvement of adenomatous polyposis coli (APC)/beta-catenin signalling in human breast cancer
- 2000
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Ingår i: European Journal of Cancer. - 0959-8049. ; 36:2, s. 8-242
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Tidskriftsartikel (refereegranskat)abstract
- We studied the relevance of adenomatous polyposis coli (APC)/beta-catenin signalling in the development of breast cancer by analysing the expression of beta-catenin in 54 primary breast tumours (34 ductal and 20 lobular). We showed that 13% of the tumours exhibited upregulated levels of beta-catenin in the cytosol suggesting that defects in APC/beta-catenin signalling components had lowered the rate of beta-catenin degradation. No mutations were observed in the amino-terminal region of beta-catenin, which comprises conserved serine residues important for phosphorylation-dependent degradation of the protein, but the APC protein was altered in 6% of the tumours. Tyrosine phosphorylation of beta-catenin was detected in only one tumour and could, therefore, not have been responsible for the observed increased levels of this protein. Although 9% of the tumours displayed upregulation of c-MYC protein, there was no correlation with beta-catenin overexpression, suggesting that increased beta-catenin expression is not the major cause of c-myc gene activation in breast cancer. It is imperative that elements that selectively drive the oncogenic activity of beta-catenin in breast cancer be identified.
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| 3. |
- Malander, S, et al.
(författare)
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One in 10 ovarian cancer patients carry germ line BRCA1 or BRCA2 mutations : results of a prospective study in Southern Sweden
- 2004
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 40:3, s. 422-428
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Tidskriftsartikel (refereegranskat)abstract
- At least 10% of all ovarian cancers are estimated to have a hereditary background. Hereditary breast-ovarian cancer (HBOC) due to mutations in the BRCA genes is a major cause of hereditary ovarian cancer, although its frequency and relationship to age and family history in unselected series of ovarian cancers is not completely known. We report here the results of a full mutational screening analysis for germ line BRCA1 and BRCA2 mutations in 161 patients with invasive epithelial ovarian carcinomas. Age at diagnosis ranged from 22 to 82 years (mean 59 years). Deleterious (frame-shift, nonsense and missense) mutations were detected in 13/161 (8%) of the patients and affected BRCA1 in 12 cases and BRCA2 in one case. Four additional missense variants (one in BRCA1 and three in BRCA2) with a possible association with an increased risk ovarian cancer were revealed, resulting in a total frequency of BRCA gene alterations of 17/161 (11%). The 13 patients with deleterious mutations had a mean age of 57 years (range 41-76 years) and only three of these patients were below 50 years of age. A family history of at least one breast cancer and/or ovarian cancer was reported in all but 1 of the patients with BRCA mutations compared with only 24% of patients without mutations. Our findings in this prospective study confirm approximately 1 in 10 patients with ovarian cancer carry a germ line BRCA gene mutation associated with HBOC, and also indicate that a large number of these patients are over 50 years of age at diagnosis.
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| 4. |
- Nilbert, Mef, et al.
(författare)
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Lessons from genetic profiling in soft tissue sarcomas
- 2004
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Ingår i: Acta Orthopaedica Scandinavica. Supplementum. - : Medical Journals Sweden AB. - 0300-8827 .- 0001-6470. ; 75:Supplement 311, s. 35-50
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Planck, M, et al.
(författare)
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Somatic frameshift alterations in mononucleotide repeat-containing genes in different tumor types from an HNPCC family with germline MSH2 mutation
- 2000
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Ingår i: Genes, Chromosomes and Cancer. - 1045-2257. ; 29:1, s. 33-39
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by a germline mutation in one of several DNA repair genes, which in the tumors is reflected as microsatellite instability (MSI). MSI+ tumors have been found to carry somatic frameshift mutations in mononucleotide repeats within the coding regions of several genes involved in growth control, apoptosis, and DNA repair, e.g., TGFBRII, BAX, IGFIIR, TCF4, MSH3, and MSH6. We have studied the occurrence of somatic frameshift alterations in these mononucleotide repeat-containing genes in 24 tumors (15 colorectal cancers, 1 colon adenoma, 4 endometrial cancers, 1 ovarian cancer, 1 gastric cancer, 1 urothelial cancer, and 1 duodenal cancer) from 14 individuals in an HNPCC family with germline hMSH2 mutation. Such somatic frameshift mutations occurred at a variable frequency; the long mononucleotide repeats that characterize intronic MSI markers were mutated in the majority of tumors, 13 of the tumors displayed alterations in the (A)(10) tract of TGFBII, eight tumors (all of gastrointestinal origin) had alterations in the (A)(9) repeat of TCF4, and one to five tumors had somatic frameshift alterations in the shorter mononucleotide repeats of IGFIIR, BAX, MSH3, and MSH6. Thus, longer mononucleotide repeats were more frequently affected by somatic frameshift mutations. The pattern of alterations varied between the tumors from different family members as well as between different tumors from the same individual. To what extent this variable pattern depends on the widespread mismatch repair deficiency induced by the underlying MSH2 mutation, or represents alternative ways whereby the tumors can achieve a tumorigenic phenotype, is unknown. We suggest, however, that the accumulation of somatic frameshifts, rather than the specific loci in which these occur, drives the development of the tumorigenic phenotype in HNPCC.
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| 6. |
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| 7. |
- Holten-Andersen, M, et al.
(författare)
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Association between preoperative plasma levels of tissue inhibitor of metalloproteinases 1 and rectal cancer patient survival: a validation study
- 2004
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 40:1, s. 64-72
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Tidskriftsartikel (refereegranskat)abstract
- The level of the tissue inhibitor of metalloproteinases 1 (TIMP-1) has previously been demonstrated to predict the survival of early stage colorectal cancer patients. The present study was undertaken to further validate plasma TIMP-1 as a prognostic marker in rectal cancer. Preoperative plasma from 352 rectal cancer patients were analysed using an immunoassay for TIMP-1. The TIMP-1 immunoassay demonstrated robustness and good reproducibility with low interassay coefficients of variation (CV). The rectal cancer patients had a mean plasma TIMP-1 level of 184 mug/l (standard deviation (SD): 70 mug/l). There were no significant differences in TIMP-1 levels between patients with Dukes' stage A, B or C disease, whereas Dukes' stage D patients had significantly increased TIMP-1 levels (P < 0.000 1); however, high levels of TIMP-1 were not restricted to those with advanced disease. Univariate analysis demonstrated an increasing risk of mortality with increasing TIMP-1 levels Hazard Ratio (HR)=2.9; 95% Confidence Interval (CI): 1.7-5.0; P<0.0001). Including additional covariates, multivariate analysis identified plasma T1MP-1 as an independent prognostic marker (HR=2.2; 95% CI: 1.2-4.1 (P 0.01). This study showed a highly significant and independent association between preoperative plasma TIMP-I levels and survival in rectal cancer patients, thus confirming our previous findings. Furthermore, the TIMP-1 immunoassay proved to be stable and reproducible in this confirmatory study. © 2003 Elsevier Ltd. All rights reserved.
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