| 1. |
- Johannsson, Oskar, et al.
(författare)
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Incidence of malignant tumours in relatives of BRCA1 and BRCA2 germline mutation carriers
- 1999
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Ingår i: European Journal of Cancer. - 1879-0852. ; 35:8, s. 1248-1257
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Tidskriftsartikel (refereegranskat)abstract
- We investigated cancer incidence between 1958 and 1995 in 1873 individuals belonging to 29 consecutively identified BRCA1 and 20 BRCA2 associated families from Southern Sweden using data from parish and local tax authorities, as well as the Swedish Cancer Registry, Cause of Death Registry and Census Registry. 150 malignant tumours were analysed from 1145 relatives in the BRCA1 families and 87 tumours were analysed from 728 relatives in the BRCA2 families. After excluding index cases which led to the mutation analysis, the incidence for all malignant tumours was significantly increased for both BRCA1- standardised morbidity rate, SMR, 1.98, 95% confidence interval (CI) 1.59-2.45; P < 0.0001 and BRCA2- (SMR 1.79, 95% CI 1.35-2.31; P < 0.0001) associated family members. For women in BRCA1-associated families, the incidence of breast cancer (SMR 3.76, 95% CI 2.29-5.80, P < 0.0001), ovarian cancer (SMR 15.49, 95% CI 9.46-23.92, P < 0.0001), stomach cancer (SMR 5.86, 95% CI 1.60-15.01, P = 0.005) were significantly increased. Amongst men only invasive squamous cell cancer of the skin was significantly increased (SMR 6.02, 95% CI 1.96-14.05, P = 0.002). In BRCA2 associated families, female breast cancer (SMR 3.03, 95% CI 1.61-5.18, P = 0.0005) was increased after exclusion of index cases. If these were included, ovarian cancer (SMR 5.16, 95% CI 1.89-11.24, P = 0.001), invasive cervical cancer (SMR 4.21, 95% CI 1.15-10.79, P = 0.016), male breast cancer (SMR 290.52, 95% CI 125.42-572.43, P < 0.0001), and prostate cancer (SMR 2.21, 95% CI 0.89-4.56, P = 0.042) were significantly increased. The increased risk for ovarian cancer in BRCA2 related families were limited to the cases leading to mutation analysis. Our data suggest that apart from breast and ovarian cancer, the incidence of other cancer types do not appear to be greatly increased in BRCA1- and BRCA2-associated families and does not warrant specific clinical follow-up in carriers.
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| 2. |
- Koul, Anjila, et al.
(författare)
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Identification of TP53 gene mutations in uterine corpus cancer with short follow-up
- 1997
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 1095-6859 .- 0090-8258. ; 67:3, s. 295-302
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Tidskriftsartikel (refereegranskat)abstract
- The involvement of the TP53 tumor suppressor gene in uterine corpus cancer was investigated by single-stranded conformation polymorphism and sequence analysis of its exons 4 to 10. Mutations were found in 12 (18.5%) of 65 cases. Ten of these 12 were single-base substitutions (8 missense and 2 nonsense mutations), whereas 2 were frame-shifting mutations. TP53 gene mutations correlated significantly with advanced surgical stage of disease (P = 0.006) and unfavorable tumor histology types (P = 0.003), whereas the association to myometrial wall invasion did not reach statistical significance (P = 0.054). TP53 gene mutations also correlated significantly with allelic loss at TP53 locus (P = 0.024), absence of estrogen (P = 0.045) and progesterone receptors (P = 0.001), DNA nondiploidy (P = 0.002), and high S-phase fraction values (P = 0.002). Our results suggest that inactivation of the TP53 checkpoint function is associated with disease transition into a stage of rapid progression and spread.
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| 3. |
- Fernö, Mårten, et al.
(författare)
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Recurrence-free survival in breast cancer improved by adjuvant tamoxifen--especially for progesterone receptor positive tumors with a high proliferation
- 1995
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Ingår i: Breast Cancer Research and Treatment. - 1573-7217. ; 36:1, s. 23-34
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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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| 4. |
- Jernström, Helena, et al.
(författare)
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Reproductive factors in hereditary breast cancer
- 1999
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Ingår i: Breast Cancer Research and Treatment. - 1573-7217. ; 58:3, s. 295-301
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: An early age at menarche, a short menstrual cycle length, and a high age at first full term pregnancy or nulliparity are known risk factors for breast cancer. These risk factors have previously been reported to differ between breast cancer patients with and without a family history of breast cancer and also between breast cancer patients and controls. METHODS: Self-administered questionnaires were filled out by 95 women belonging to 24 families with known BRCA1 mutations, 16 women belonging to nine families with known BRCA2 mutations, and 95 women belonging to 65 families with hereditary breast cancer where no BRCA1 or BRCA2 mutations could be detected. Thirty-nine women were BRCA1 mutation carriers and 56 women were BRCA1 negative, 11 women were BRCA2 carriers and five BRCA2 negative. All women were born between 1905 and 1979. RESULTS: Age at menarche, physiological menstrual cycle length at age 30 or at current age in younger women (when not using oral contraceptives), age at first full term pregnancy, and nulliparity did not significantly differ between BRCA1 mutation carriers and BRCA1 negative women. Too few women were BRCA2 negative to serve as a control group. BRCA2 mutation carriers were therefore compared with BRCA1 negative and BRCA2 negative women. None of the above reproductive factors did significantly differ between BRCA2 mutation carriers and from BRCA1 and BRCA2 families. Women from non-BRCA1/BRCA2 hereditary breast cancer families had a higher age at menarche, but this was no longer significant after adjustment for other factors in a multivariate model. CONCLUSION: Our results suggest that reproductive risk factors of breast cancer are not related to BRCA1 or BRCA2 carrier status. There was also no indication that these factors differ in carriers of unknown susceptibility genes compared with non-carriers from BRCA1 and BRCA2 families.
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| 5. |
- Hakansson, Sara, et al.
(författare)
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Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer
- 1997
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Ingår i: American Journal of Human Genetics. - 0002-9297. ; 60:5, s. 1068-1078
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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.
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| 6. |
- Persson, Karin, et al.
(författare)
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Chromosomal aberrations in breast cancer: a comparison between cytogenetics and comparative genomic hybridization
- 1999
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Ingår i: Genes, Chromosomes and Cancer. - 1045-2257. ; 25:2, s. 115-122
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Tidskriftsartikel (refereegranskat)abstract
- The analysis of chromosomal imbalances in solid tumors using comparative genetic hybridization (CGH) has gained much attention. A survey of the literature suggests that CGH is more sensitive in detecting copy number aberrations than is karyotyping, although careful comparisons between CGH and cytogenetics have not been performed. Here, we compared cytogenetics and CGH in 29 invasive breast cancers after converting the karyotypes into net copy number gains and losses. We found 15 tumors (56%) with a significant agreement between the two methods and 12 tumors (44%) where the methods were in disagreement (two cases failed CGH analysis). Interestingly, in 13 of the 15 tumors where the two methods were concordant, there was also a strong correlation between chromosome index and DNA index by flow cytometry. In the opposite situation, i.e., when chromosome and DNA indices were not matching, there was disagreement between cytogenetics and CGH in 10 of the 12 tumors. Of the discordant cases, all except one had a "simple" abnormal karyotype. Unresolved chromosomal aberrations (marker chromosomes, homogeneously staining regions, double minutes) could not completely explain the differences between CGH and karyotyping. A likely explanation for the discrepancies is that the methods analyzed different cell populations. Gains and losses found by CGH represented the predominant (often aneuploid) clone, whereas the abnormal, near-diploid karyotypes represented minor cell clone(s), which, for unknown reasons, had a growth advantage in vitro.
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| 7. |
- 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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| 8. |
- Bratt, O, et al.
(författare)
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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
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 81:4, s. 6-672
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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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| 9. |
- 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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| 10. |
- Haraldsson, K, et al.
(författare)
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BRCA2 germ-line mutations are frequent in male breast cancer patients without a family history of the disease
- 1998
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Ingår i: Cancer Research. - 1538-7445. ; 58:7, s. 71-1367
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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.
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