| 31. |
- Moller, P., et al.
(författare)
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Genetic epidemiology of BRCA1 mutations in Norway
- 2001
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Ingår i: European Journal of Cancer. - 1879-0852. ; 37:18, s. 2428-2434
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Tidskriftsartikel (refereegranskat)abstract
- Familial breast-ovarian cancer has been demonstrated to be frequent but unevenly distributed in Norway. This was assumed to be caused by the reduced population size created by the medieval Bubonic plague, 25 generations ago, and by the following rapid expansion. We have previously reported that four mutations account for 68% of the BRCA1 mutation carriers. Subsequent analysis has resulted in a total of 100 separate families carrying one of these founder mutations. The four mutations occurred on one specific BRCA1 haplotype each. The 1675delA, 816delGT and 3347detAG families originated from the South-West coast of Norway with a few Families in the north, while the traceable ancestors of the 1135insA families clustered along the historical inland road from the South-East to mid-Norway. The carriers of each of the four mutations today are descendants of one or a few individuals surviving the plagues. We may identify the majority of BRCA1 mutation carriers in Norway by screening for local founder mutations.
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| 32. |
- Moller, P, et al.
(författare)
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Survival in prospectively ascertained familial breast cancer: Analysis of a series stratified by tumour characteristics, BRCA mutations and oophorectomy
- 2002
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 101:6, s. 555-559
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Tidskriftsartikel (refereegranskat)abstract
- Dedicated clinics have been established for the early diagnosis and treatment of women at risk for inherited breast cancer, but the effects of such interventions are currently unproven. This second report on prospectively diagnosed inherited breast cancer from the European collaborating centres supports the previous conclusions and adds information on genetic heterogeneity and the effect of oophorectomy. Of 249 patients, 20% had carcinoma in situ (CIS), 54% had infiltrating cancer without spread (CaNO) and 26% had cancer with spread (CaN+). Five-year survival was 100% for CIS, 94% for CaNO and 72% for CaN+ (p = 0.007). Thirty-six patients had BRCA1 mutations, and 8 had BRCA2 mutations. Presence of BRCA1 mutation was associated with infiltrating cancer, high grade and lack of oestrogen receptor (p < 0.05 for all 3 characteristics). For BRCA1 mutation carriers, 5-year survival was 63% vs. 91% for noncarriers (p = 0.04). For CaNO patients, mutation carriers had 75% S-year disease-free survival vs. 96% for noncarriers (p = 0.01). Twenty-one of the mutation carriers had undergone prophylactic oophorectomy, prior to or within 6 months of diagnosis in 13 cases. All but I relapse occurred in the I S who had kept their ovaries, (p < 0.01); no relapse occurred in those who had removed the ovaries within 6 months (p = 0.04) Contralateral cancer was more frequently observed in mutation noncarriers, but this finding did not reach statistical significance. Our findings support the concept that BRCA1 cancer is biologically different from other inherited breast cancers. While current screening protocols appear satisfactory for the majority of women at risk of familial breast cancer, this may not be the case for BRCA1 mutation carriers. The observed effect of oophorectomy was striking.
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| 33. |
- Måsbäck, Anna, et al.
(författare)
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Clinical and histopathological features of malignant melanoma in germline CDKN2A mutation families
- 2002
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Ingår i: Melanoma Research. - 0960-8931. ; 12:6, s. 549-557
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Tidskriftsartikel (refereegranskat)abstract
- Primary cutaneous malignant melanomas (CMMs) from 26 individuals belonging to nine families with an identified CDKN2A mutation were clinically and histopathologically compared with 78 matched CMM controls and with a population-based series of CMMs (n=667). All tumours were histopathologically re-examined. CDKN2A-associated cases were significantly less invasive compared with the matched controls, with an adjusted odds ratio (adjOR) of 2.9 and a 95% confidence interval (CI) of 1.0-8.1 (P=0.04). According to the odds ratio (OR) values, CDKN2A-associated cases seemed to have tumours more often located on the head and neck (adjOR 2.9, 95% CI 0.6-13.7), with less inflammation (adjOR 0.7, 95% CI 0.3-1.8) and regression (adjOR 0.6, 95% CI 0.2-1.8) but more frequent histological ulceration (adjOR 1.9, 95% CI 0.6-5.8). In comparison with the population-based material, CDKN2A-associated cases were significantly younger at diagnosis (crude OR 3.5, 95% CI 1.6-7.5, divided at 50 years) and had less regressive reaction in their tumours (crude OR 0.355 95% CI 0.2-0.8). No significant differences were seen for tumour thickness between the different groups. On multivariate analysis, the overall survival was significantly worse for thicker tumours and older age (P=0.04 for both). To our knowledge this is the first description of the histopathological features of CMMs from families with mutations in the CDKN2A gene.
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| 34. |
- Möller, P, et al.
(författare)
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The BRCA1 syndrome and other inherited breast or breast-ovarian cancers in a Norwegian prospective series
- 2001
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Ingår i: European Journal of Cancer. - 1879-0852. ; 37:8, s. 1027-1032
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Tidskriftsartikel (refereegranskat)abstract
- Inherited breast cancer is a heterogenous group of diseases. We examined this heterogeneity in a prospective series of inherited breast and ovarian cancers, previously demonstrated to include 84% of inherited cancers. Ninety-two tumours (65 breast and 27 ovarian) in 82 patients from 70 kindreds were prospectively diagnosed. Fifteen of the breast cancers were in situ, 50 were infiltrating. 40 (49%) of the 82 women carried a BRCA1 mutation, whereas no mutation in BRCA2 was found. Approximately, two-thirds of the BRCA1 mutation carriers had one of the four most frequent Norwegian founder mutations. Ninety-five per cent of the epithelial ovarian cancers occurred in BRCA1 mutation carrying women versus 38% of infiltrating breast cancers and 7% of carcinoma in situ of the breast. The BRCA1 syndrome was phenotypically distinct with invasive, high grade, oestrogen receptor-negative breast cancers and epithelial ovarian cancers. Non-BRCA1/2 inherited breast cancers included carcinoma in situ and lobular carcinoma and were frequently bilateral. Non-BRCA1/2 inherited breast cancer is not associated with epithelial ovarian cancer and in breast cancers has distinct biological characteristics, indicating that the different subgroups of inherited breast cancer may need different healthcare services.
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| 35. |
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| 36. |
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| 37. |
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| 38. |
- Perkowska, Magdalena, et al.
(författare)
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BRCA1 and BRCA2 mutation analysis in breast-ovarian cancer families from northeastern Poland
- 2003
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 21:5, s. 553-554
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Tidskriftsartikel (refereegranskat)abstract
- Sixty high-risk breast and/or ovarian cancer families from North-Eastern Poland were screened for germline mutations in BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185), using a combination of protein truncation test, denaturing high-performance liquid chromatography and direct sequencing. Sixteen (27%) of the families were found to carry nine different BRCA mutations, including 14 families with BRCA1 mutation and two families with BRCA2 mutation. The results suggest the presence of two strong BRCA1 founder mutations in the Polish population - 5382insC (6 families) and 300T>G (Cys61Gly; 3 families). The remaining seven mutations were found in single families and included three previously reported BRCA1 mutations (185delAG, 2682C>T [Gln855Ter] and 3819del5), a novel BRCA1 mutation (IVS14+1G>A), as well as two BRCA2 mutations (4088delA and 7985G>A [Trp2586Ter]) not previously observed in Polish families. We confirm the strong influence of two Central-Eastern European BRCA1 founder mutations in familial breast and/or ovarian cancer in Poland. We also conclude that the Polish population has a more dispersed BRCA mutation spectrum than had been earlier thought. This warrants further careful BRCA mutation screening in order to optimise genetic counselling and disease prevention in affected families.
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| 39. |
- 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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| 40. |
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