| 31. |
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| 32. |
- Hietala, M, et al.
(författare)
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Testosterone levels in relation to oral contraceptive use and the androgen receptor CAG and GGC length polymorphisms in healthy young women
- 2007
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Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 22:1, s. 83-91
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The combined effect from the androgen receptor (AR) CAG and GGC length polymorphisms on testosterone levels has not been studied in young women. METHODS: Testosterone levels were measured in blood drawn on both menstrual cycle days 5-10 and 18-23 in 258 healthy women, aged <= 40 years, from high-risk breast cancer families. CAG and GGC length polymorphisms were analysed by PCR and fragment analyses. All women completed a questionnaire including information on oral contraceptive (OC) use and reproductive factors. RESULTS: OC users had lower median testosterone levels than non-users during cycle days 5-10 and 18-23 (P <= 0.005 for both). The BRCA mutation status was associated neither with testosterone levels nor with CAG or GGC length polymorphism. The CAG length polymorphism was not associated with testosterone levels. The cumulative number of long GGC alleles (>= 17 repeats) was significantly associated with lower testosterone levels in OC users during cycle days 5-10 (P-trend =0.014), but not during cycle days 18-23 or in non-users. The interaction between the GGC length polymorphism and OC status was highly significant during cycle days 5-10 (P = 0.002) and near-significant during days 18-23 (P = 0.07). Incident breast cancer was more common in women with two short GGC alleles (log-rank P = 0.003). CONCLUSION: The GGC repeat length was the only significant genetic factor modifying the testosterone levels in current OC users from high-risk families. Homozygosity for the short GGC allele may be linked to the increased risk of early-onset breast cancer after OC exposure in high-risk women.
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| 33. |
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| 34. |
- Honeth, Gabriella, et al.
(författare)
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The CD44(+)/CD24(-) phenotype is enriched in basal-like breast tumors
- 2008
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Human breast tumors are heterogeneous and consist of phenotypically diverse cells. Breast cancer cells with a CD44(+)/CD24(-) phenotype have been suggested to have tumor-initiating properties with stem cell-like and invasive features, although it is unclear whether their presence within a tumor has clinical implications. There is also a large heterogeneity between tumors, illustrated by reproducible stratification into various subtypes based on gene expression profiles or histopathological features. We have explored the prevalence of cells with different CD44/CD24 phenotypes within breast cancer subtypes. Methods Double-staining immunohistochemistry was used to quantify CD44 and CD24 expression in 240 human breast tumors for which information on other tumor markers and clinical characteristics was available. Gene expression data were also accessible for a cohort of the material. Results A considerable heterogeneity in CD44 and CD24 expression was seen both between and within tumors. A complete lack of both proteins was evident in 35% of the tumors, while 13% contained cells of more than one of the CD44(+)/CD24(-), CD44(-)/CD24(+) and CD44(+)/CD24(+) phenotypes. CD44(+)/CD24(-) cells were detected in 31% of the tumors, ranging in proportion from only a few to close to 100% of tumor cells. The CD44(+)/CD24(-) phenotype was most common in the basal-like subgroup-characterized as negative for the estrogen and progesterone receptors as well as for HER2, and as positive for cytokeratin 5/14 and/or epidermal growth factor receptor, and particularly common in BRCA1 hereditary tumors, of which 94% contained CD44(+)/CD24(-) cells. The CD44(+)/CD24(-) phenotype was surprisingly scarce in HER2+ tumors, which had a predominantly CD24(+) status. A CD44(+)/CD24(-) gene expression signature was generated, which included CD44 and alpha(6)-integrin (CD49f) among the top-ranked overexpressed genes. Conclusion We demonstrate an association between basal-like and particularly BRCA1 hereditary breast cancer and the presence of CD44(+)/CD24(-) cells. Not all basal-like tumors and very few HER2+ tumors, however, contain CD44(+)/CD24(-) cells, emphasizing that a putative tumorigenic ability may not be confined to cells of this phenotype and that other breast cancer stem cell markers remain to be identified.
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| 35. |
- Huang, J, et al.
(författare)
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Robust smooth segmentation approach for array CGH data analysis
- 2007
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1460-2059 .- 1367-4811. ; 23:18, s. 2463-2469
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Tidskriftsartikel (refereegranskat)abstract
- Motivation: Array comparative genomic hybridization (aCGH) provides a genome- wide technique to screen for copy number alteration. The existing segmentation approaches for analyzing aCGH data are based on modeling data as a series of discrete segments with unknown boundaries and unknown heights. Although the biological process of copy number alteration is discrete, in reality a variety of biological and experimental factors can cause the signal to deviate from a stepwise function. To take this into account, we propose a smooth segmentation (smoothseg) approach. Methods: To achieve a robust segmentation, we use a doubly heavy-tailed random-effect model. The first heavy-tailed structure on the errors deals with outliers in the observations, and the second deals with possible jumps in the underlying pattern associated with different segments. We develop a fast and reliable computational procedure based on the iterative weighted least- squares algorithm with band-limited matrix inversion. Results: Using simulated and real data sets, we demonstrate how smoothseg can aid in identification of regions with genomic alteration and in classification of samples. For the real data sets, smoothseg leads to smaller false discovery rate and classification error rate than the circular binary segmentation (CBS) algorithm. In a realistic simulation setting, smoothseg is better than wavelet smoothing and CBS in identification of regions with genomic alterations and better than CBS in classification of samples. For comparative analyses, we demonstrate that segmenting the t- statistics performs better than segmenting the data.
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| 36. |
- Isinger Ekstrand, Anna, et al.
(författare)
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CHEK2 1100delC in patients with metachronous cancers of the breast and the colorectum
- 2006
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Development of multiple primary tumors is a hallmark of hereditary cancer. At least 1/10 of breast cancers and colorectal cancers occur because of heredity and recently the cell cycle kinase 2, CHEK2 1100delC allele has been identified at a particularly high frequency in families with hereditary breast and colorectal cancer. Methods: We utilized the Southern Sweden population-based cancer registry to identify women with double primary breast and colorectal cancer and sequenced tumor material in order to assess the contribution of the CHEK2 1100delC to the development of such metachronous tumors. Results: Among the 75 patients successfully analyzed, 2 (2.5%) carried the CHEK2 1100delC allele. which was not significantly different (p = 0.26) from the 1% (3/300) carriers identified in the control group. Conclusion: In summary, our data suggest that the CHEK2 1100delC is not a major cause of double primary breast and colorectal cancer in Sweden, which suggests that this patient group should not routinely be screened for the CHEK2 1100delC variant.
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| 37. |
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| 38. |
- Jernström, Helena, et al.
(författare)
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High follicular phase luteinizing hormone levels in young healthy BRCA1 mutation carriers: Implications for breast and ovarian cancer risk.
- 2005
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Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192. ; 86:1-2, s. 320-327
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Tidskriftsartikel (refereegranskat)abstract
- BRCA1 mutation carriers have up to 80% life-time risk of developing breast cancer and 20-40% risk of developing ovarian cancer. High LH levels have been linked to increased risks of both breast and ovarian cancers in some studies and it is unknown whether gonadotropin levels are associated with BRCA1 mutation status. The aim of the study was to explore whether gonadotropin levels were associated with BRCA1 mutation status among healthy <= 40-year-old-women from hereditary breast cancer families. All women completed a questionnaire including information on reproductive factors and OC use. We measured height, weight, breast volumes, and plasma levels of LH, FSH, and estradiol (E2) once during menstrual cycle days 5-10 and once again during cycle days 18-23 in 43 non-carriers from BRCA1 families, 20 BRCA1 mutation carriers, and 101 women from non-BRCA1/2 families. The strongest predictors of high LH levels among BRCA1 mutation carriers and non-carriers during cycle days 5-10 were being a BRCA1 mutation carrier (p = 0.002), lack of current OC use (p = 0.003), and being nulliparous (p = 0.01), adjusted for age and menstrual cycle day when the samples were obtained. This association was seen both in non-OC users and current OC users but was only significant in the former group (p = 0.005). Because of multiple analyses it is possible that our finding is a result of a Type 1 statistical error. After a permutation test the new adjusted p value in non-OC users was 0.05. FSH and E2 were similar in non-carriers, BRCA1 mutation carriers and women from non-BRCA1/2 families. We found significantly elevated LH levels in the follicular phase among young healthy BRCA1 mutation carriers compared with non-carriers from BRCA1 families. This is a small study and confirmatory studies are warranted to establish whether elevated LH levels are part of the BRCA1 phenotype and may be manipulated in order to reduce cancer risks in BRCA1 mutation carriers.
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| 39. |
- Jernström, Helena, et al.
(författare)
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Impact of teenage oral contraceptive use in a population-based series of early-onset breast cancer cases who have undergone BRCA mutation testing
- 2005
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 41:15, s. 2312-2320
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Tidskriftsartikel (refereegranskat)abstract
- Oral contraceptive (OC) use in young women has been associated with an increased risk of breast cancer. This matched case-control study aims to elucidate the combined effects of OC use and genetic factors in a population-based series of BRCA1/2 mutation-tested early-onset breast cancers. A first invasive breast cancer was diagnosed in 259 women aged <= 40 years between 1990 and 1995 in the South Swedish Health Care Region. A total of 245 women were included in this study. Information on family history of cancer, reproductive factors, smoking and OC use was obtained from questionnaires or patient charts. Three age-matched controls per case were chosen from a prospective South Swedish cohort. Ever OC use and current OC use were not associated with breast cancer. Cases were more likely to have used OCs before age 20 years (adjusted odds ratio (OR) 2.10 (95% CI 1.32-3.33)) and before their first child (adjusted OR 1.63 (95% CI 1.02-2.62)). When stratified by age, the effect of early OC use was limited to women diagnosed prior to age 36 years (OR 1.53 (1.17-1.99) per year of OC use prior to age 20 years). The risks were similar for low-dose and high-dose OCs. The probability of being a BRCA1/2 mutation carrier was three times higher among cases who started OC use prior to age 20 years compared with cases who started at age 20 years or older or who had never used OCs. However, the duration of OC use was similar among cases with and without BRCA1/2 mutations. No association was seen with a first-degree family history of breast cancer. Each year of OC use prior to age 20 years conferred a significantly increased risk for early-onset breast cancer, while there was no risk associated with use after age 20 years.
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| 40. |
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