| 1. |
- Andersson, Anna, et al.
(författare)
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Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations
- 2005
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 19:6, s. 1042-1050
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Tidskriftsartikel (refereegranskat)abstract
- Hematologic malignancies are characterized by fusion genes of biological/clinical importance. Immortalized cell lines with such aberrations are today widely used to model different aspects of leukemogenesis. Using cDNA microarrays, we determined the gene expression profiles of 40 cell lines as well as of primary leukemias harboring 11q23/MLL rearrangements, t(1;19)[TCF3/PBX1], t(12;21)[ETV6/RUNX1], t(8;21)[RUNX1/CBFA2T1], t(8;14) [IGH@/MYC], t(8;14)[TRA@/MYC], t(9;22)[BCR/ABL1], t(10;11) [PICALM/MLLT10], t(15;17)[PML/RARA], or inv(16)[CBFB/MYH11]. Unsupervised classification revealed that hematopoietic cell lines of diverse origin, but with the same primary genetic changes, segregated together, suggesting that pathogenetically important regulatory networks remain conserved despite numerous passages. Moreover, primary leukemias cosegregated with cell lines carrying identical genetic rearrangements, further supporting that critical regulatory pathways remain intact in hematopoietic cell lines. Transcriptional signatures correlating with clinical subtypes/primary genetic changes were identified and annotated based on their biological/molecular properties and chromosomal localization. Furthermore, the expression profile of tyrosine kinase-encoding genes was investigated, identifying several differentially expressed members, segregating with primary genetic changes, which may be targeted with tyrosine kinase inhibitors. The identified conserved signatures are likely to reflect regulatory networks of importance for the transforming abilities of the primary genetic changes and offer important pathogenetic insights as well as a number of targets for future rational drug design.
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| 2. |
- Antoniou, A C, et al.
(författare)
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Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies
- 2005
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 42:7, s. 602-603
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Tidskriftsartikel (refereegranskat)abstract
- A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.
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| 3. |
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| 4. |
- 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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| 5. |
- 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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| 8. |
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| 9. |
- Kvist, Anders, et al.
(författare)
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Promoter usage of BRCA1-IRIS
- 2005
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Ingår i: Nature Cell Biology. - : Springer Science and Business Media LLC. - 1465-7392 .- 1476-4679. ; 7:4, s. 325-326
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Laakso, M, et al.
(författare)
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Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors
- 2005
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Ingår i: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 18:10, s. 1321-1328
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Tidskriftsartikel (refereegranskat)abstract
- Breast ducts contain two types of epithelial cells, inner luminal cells and outer basal/ myoepithelial cells. These cells can be distinguished by their immunophenotype. Cytokeratins ( CKs) 8 and 18 are expressed in the luminal layer, whereas CK5/ 14 and the transcription factor p63 characterize the basal epithelial layer. We studied a population- based cohort of 288 sporadic ductal invasive cancers and found 9% positive for CK5/ 14 and 4% positive for p63. Using a highly sensitive polymer- based immunohistochemical staining, all sporadic tumors were positive for the luminal CK8/ 18, including those positive for CK5/ 14. Pairs of primary tumors and metastases ( n = 38) were always concordant for CK5/ 14 expression. The majority of the CK5/ 14- positive cases were of histologic grade III ( P = 0.0007) and steroid hormone receptor negative ( P < 0.0001). CK5/ 14 expression was inversely associated with HER- 2 oncogene amplification, but only in the subgroup of estrogen receptor-negative tumors ( P = 0.007). In a separate set of 42 hereditary breast cancers, the majority ( 78%) of the BRCA1-associated tumors, but only one of 15 BRCA2- associated tumors was positive for CK5/ 14. In contrast to sporadic CK5/ 14- positive tumors, BRCA1- associated tumors displayed less intense CK8/ 18 staining, including some truly CK5/ 14- positive CK8/ 18- negative cases. These results suggest that CK5/ 14- positive sporadic breast cancers arise from glandularly committed progenitor cells rather than true CK8/ 18- negative basal cells.
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