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| 4. |
- Hudson, Thomas J., et al.
(författare)
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International network of cancer genome projects
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 9. |
- Aine, Mattias, et al.
(författare)
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Molecular analyses of triple-negative breast cancer in the young and elderly
- 2021
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Ingår i: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Breast cancer in young adults has been implicated with a worse outcome. Analyses of genomic traits associated with age have been heterogenous, likely because of an incomplete accounting for underlying molecular subtypes. We aimed to resolve whether triple-negative breast cancer (TNBC) in younger versus older patients represent similar or different molecular diseases in the context of genetic and transcriptional subtypes and immune cell infiltration.PATIENTS AND METHODS: In total, 237 patients from a reported population-based south Swedish TNBC cohort profiled by RNA sequencing and whole-genome sequencing (WGS) were included. Patients were binned in 10-year intervals. Complimentary PD-L1 and CD20 immunohistochemistry and estimation of tumor-infiltrating lymphocytes (TILs) were performed. Cases were analyzed for differences in patient outcome, genomic, transcriptional, and immune landscape features versus age at diagnosis. Additionally, 560 public WGS breast cancer profiles were used for validation.RESULTS: Median age at diagnosis was 62 years (range 26-91). Age was not associated with invasive disease-free survival or overall survival after adjuvant chemotherapy. Among the BRCA1-deficient cases (82/237), 90% were diagnosed before the age of 70 and were predominantly of the basal-like subtype. In the full TNBC cohort, reported associations of patient age with changes in Ki67 expression, PIK3CA mutations, and a luminal androgen receptor subtype were confirmed. Within DNA repair deficiency or gene expression defined molecular subgroups, age-related alterations in, e.g., overall gene expression, immune cell marker gene expression, genetic mutational and rearrangement signatures, amount of copy number alterations, and tumor mutational burden did, however, not appear distinct. Similar non-significant associations for genetic alterations with age were obtained for other breast cancer subgroups in public WGS data. Consistent with age-related immunosenescence, TIL counts decreased linearly with patient age across different genetic TNBC subtypes.CONCLUSIONS: Age-related alterations in TNBC, as well as breast cancer in general, need to be viewed in the context of underlying genomic phenotypes. Based on this notion, age at diagnosis alone does not appear to provide an additional layer of biological complexity above that of proposed genetic and transcriptional phenotypes of TNBC. Consequently, treatment decisions should be less influenced by age and more driven by tumor biology.
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| 10. |
- Akdemir, KC, et al.
(författare)
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Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer
- 2020
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:3, s. 294-
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Tidskriftsartikel (refereegranskat)abstract
- Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.
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| 11. |
- Alexandrov, Ludmil B., et al.
(författare)
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Signatures of mutational processes in human cancer
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 500:7463, s. 415-421
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Tidskriftsartikel (refereegranskat)abstract
- All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
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| 12. |
- Alexandrov, Ludmil B, et al.
(författare)
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The repertoire of mutational signatures in human cancer
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 578:7793, s. 94-101
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Tidskriftsartikel (refereegranskat)abstract
- Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature1. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses3-15, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.
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| 13. |
- 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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| 14. |
- Andersson, Alma, et al.
(författare)
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Spatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions
- 2021
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- In the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra- and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. By integration with single cell data, we spatially map tumor-associated cell types to find tertiary lymphoid-like structures, and a type I interferon response overlapping with regions of T-cell and macrophage subset colocalization. We construct a predictive model to infer presence of tertiary lymphoid-like structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define a high resolution map of cellular interactions in tumors and provide tools generalizing across tissues and diseases. While transcriptomics have enhanced our understanding for cancer, spatial transcriptomics enable the characterisation of cellular interactions. Here, the authors integrate single cell data with spatial information for HER2 + tumours and develop tools for the prediction of interactions between tumour-infiltrating cells.
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| 15. |
- Andersson, Alma, et al.
(författare)
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Spatial Deconvolution of HER2-positive Breast Tumors Reveals Novel Intercellular Relationships
- 2020
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra-and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. We integrate and spatially map tumor-associated types from single cell data to find: segregated epithelial cells, interactions between B and T-cells and myeloid cells, co-localization of macrophage and T-cell subsets. A model is constructed to infer presence of tertiary lymphoid structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define novel interactions between tumor-infiltrating cells in breast cancer and provide tools generalizing across tissues and diseases.
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| 16. |
- Andersson, Ulrika, et al.
(författare)
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Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer
- 2014
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Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 16:10, s. 1333-1340
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. Methods: Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer. The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. Results: We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. Conclusions: Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes.
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| 17. |
- Antoniou, A, et al.
(författare)
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Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies
- 2003
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 72:5, s. 1117-1130
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers ( P trend .0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.
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| 18. |
- 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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| 19. |
- Antoniou, Antonis C., et al.
(författare)
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Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers
- 2011
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:16, s. 3304-3321
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Tidskriftsartikel (refereegranskat)abstract
- Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
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| 20. |
- Antoniou, A. C., et al.
(författare)
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The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions
- 2008
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 98:8, s. 1457-1466
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Tidskriftsartikel (refereegranskat)abstract
- Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes ( polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families ( 301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920 - 1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in userfriendly Web-based program(http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home. html).
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| 21. |
- Aoude, Lauren G., et al.
(författare)
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A BAP1 Mutation in a Danish Family Predisposes to Uveal Melanoma and Other Cancers
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Truncating germline mutations in the tumor suppressor gene BRCA-1 associated protein-1 (BAP1) have been reported in families predisposed to developing a wide range of different cancer types including uveal melanoma and cutaneous melanoma. There has also been an association between amelanotic tumor development and germline BAP1 mutation suggesting a possible phenotypic characteristic of BAP1 mutation carriers. Though there have been many types of cancer associated with germline BAP1 mutation, the full spectrum of disease association is yet to be ascertained. Here we describe a Danish family with predominantly uveal melanoma but also a range of other tumor types including lung, neuroendocrine, stomach, and breast cancer; as well as pigmented skin lesions. Whole-exome sequencing identified a BAP1 splice mutation located at c.581-2A>G, which leads to a premature truncation of BAP1 in an individual with uveal melanoma. This mutation was carried by several other family members with melanoma or various cancers. The finding expands on the growing profile of BAP1 as an important uveal and cutaneous melanoma tumor suppressor gene and implicates its involvement in the development of lung, and stomach cancer.
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| 22. |
- Aoude, Lauren G, et al.
(författare)
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Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma.
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:2, s. 408-408
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Tidskriftsartikel (refereegranskat)abstract
- The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.
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| 23. |
- Arason, Adalgeir, et al.
(författare)
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Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families
- 2010
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 12:4, s. R50-
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Tidskriftsartikel (refereegranskat)abstract
- Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.
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| 24. |
- Archey, WB, et al.
(författare)
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Increased CpG methylation of the estrogen receptor gene in BRCA1-linked estrogen receptor-negative breast cancers
- 2002
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 21:46, s. 7034-7041
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Tidskriftsartikel (refereegranskat)abstract
- A distinctive feature of BRCA1-linked breast cancers is that they typically do not express estrogen receptor-alpha (ERalpha). Previous investigation suggests that methylation of CpGs within the ERa promoter mediates repression of gene expression in some ERalpha-negative breast cancers. To determine if methylation of CpGs within the ERalpha promoter is associated with BRCA1-linked breast cancers, we evaluated methylation in exon 1 of the ERalpha gene in 40 ERalpha-negative breast cancers, 20 of which were non BRCA1-linked and 20 BRCA1-linked. CpG methylation was evaluated by either methylation-sensitive restriction digest (HpaII), methylation-sensitive PCR (MSP), or direct sequencing of bisulfite-treated genomic DNA. Results from HpaII digests and MSP documented a high degree of methylation, the MSP data showing slightly higher methylation in the BRCA1-linked group. CpGs analysed by direct sequencing showed an overall average methylation of 25% among non BRCA1-linked cancers and 40% among BRCA1-linked cancers (P=0.0031). The most notable difference was found at five particular CpGs, each of which exhibited a greater than twofold increase in methylation in the BRCA1-linked group compared to the non BRCA1-linked group (P < 0.03 for each CpG). Methylation of certain critical CpGs may represent an important factor in transcriptional repression of the ERa gene in BRCA1-linked breast cancers.
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| 25. |
- Arver, Brita, et al.
(författare)
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First BRCA1 and BRCA2 gene testing implemented in the health care system of Stockholm
- 2001
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Ingår i: Genetic Testing. - : Mary Ann Liebert Inc. - 1557-7473 .- 1090-6576. ; 5:1, s. 41282-41282
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to optimize the criteria for the BRCA1 and BRCA2 gene testing and to improve oncogenetic counseling in the Stockholm region. Screening for inherited breast cancer genes is laborious and a majority of tested samples turn out to be negative. The frequencies of mutations in the BRCA1 and BRCA2 genes differ across populations. Between 1997 and 2000, 160 families with breast and/or ovarian cancer were counseled and screened for mutations in the two genes. Twenty-five BRCA1 and two BRCA2 disease-causing mutations were found. Various factors associated with the probability of finding a BRCA1 mutation in the families were estimated. Age of onset in different generations and other malignancies were also studied. Families from our region in which both breast and ovarian cancer occur were likely to carry a BRCA1 mutation (34%). In breast-only cancer families, mutations were found only in those with very early onset. All breast-only cancer families with a mutation had at least one case of onset before 36 years of age and a young median age of onset (< 43 years). Other malignancies than breast and ovarian cancers did not segregate in the BRCA1 families and surveillance for other malignancies is not needed, in general. Decreasing age of onset with successive generations was common and must be taken into account when surveillance options are considered.
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| 26. |
- Augsten, Martin, et al.
(författare)
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Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties
- 2014
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Ingår i: Cancer Research. - 1538-7445. ; 74:11, s. 2999-3010
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Tidskriftsartikel (refereegranskat)abstract
- Cancer-associated fibroblasts (CAF) stimulate tumor growth and metastasis. Signals supporting CAF function are thus emerging as candidate therapeutic targets in the tumor microenvironment. The chemokine CXCL14 is a potent inducer of CAF protumorigenic functions. This study is aimed at learning how the protumoral functions of CXCL14-expressing CAF are maintained. We found that the nitric oxide synthase NOS1 is upregulated in CXCL14-expressing CAF and in fibroblasts stimulated with CXCL14. Induction of Nos1 was associated with oxidative stress and occurred together with activation of NRF2 and HIF1 alpha signaling in CXCL14-expressing CAF. Genetic or pharmacologic inhibition of NOS1 reduced the growth of CXCL14-expressing fibroblasts along with their ability to promote tumor formation following coinjection with prostate or breast cancer cells. Tumor analysis revealed reduced macrophage infiltration, with NOS1 downregulation in CXCL14-expressing CAF and lymphangiogenesis as a novel component of CXCL14-promoted tumor growth. Collectively, our findings defined key components of a signaling network that maintains the protumoral functions of CXCL14-stimulated CAF, and they identified NOS1 as intervention target for CAF-directed cancer therapy. (C) 2014 AACR.
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| 27. |
- Augsten, Martin, et al.
(författare)
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CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:9, s. 3414-3419
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Tidskriftsartikel (refereegranskat)abstract
- This study explored the role of secreted fibroblast-derived factors in prostate cancer growth. Analyses of matched normal and tumor tissue revealed up-regulation of CXCL14 in cancer-associated fibroblasts of a majority of prostate cancer. Fibroblasts over-expressing CXCL14 promoted the growth of prostate cancer xenografts, and increased tumor angiogenesis and macrophage infiltration. Mechanistic studies demonstrated that autocrine CXCL14-stimulation of fibroblasts stimulate migration and ERK-dependent proliferation of fibroblasts. CXCL14-stimulation of monocyte migration was also demonstrated. Furthermore, CXCL14-producing fibroblasts, but not recombinant CXCL14, enhanced in vitro proliferation and migration of prostate cancer cells and in vivo angiogenesis. These studies thus identify CXCL14 as a novel autocrine stimulator of fibroblast growth and migration, with multi-modal tumor-stimulatory activities. In more general terms, our findings suggest autocrine stimulation of fibroblasts as a previously unrecognized mechanism for chemokine-mediated stimulation of tumor growth, and suggest a novel mechanism whereby cancer-associated fibroblasts achieve their pro-tumorigenic phenotype.
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| 28. |
- Augustinsson, Annelie, et al.
(författare)
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Accuracy of self-reported family history of cancer, mutation status and tumor characteristics in patients with early onset breast cancer
- 2018
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Ingår i: Acta Oncologica. - 0284-186X. ; 57:5, s. 595-603
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Tidskriftsartikel (refereegranskat)abstract
- Background: The main objectives of this study were to evaluate the concordance between self-reported and registry-reported information regarding family history of breast cancer (BC), ovarian cancer (OvC) and other types of cancer in first-degree relatives of patients with early onset BC, and to determine the frequency of mutation carriers and non-mutation carriers. The secondary objective was to describe tumor characteristics for each mutation group. Material and methods: Between 1993 and 2013, 231 women who were ≤35 years old when diagnosed with BC were registered at the Oncogenetic Clinic at Skåne University Hospital in Lund, Sweden. Self-reported and registry-reported information regarding first-degree family history of cancer was collected together with information regarding tumor characteristics. Results: Almost perfect agreement was observed between self-reported and registry-reported information regarding first-degree family history of BC (κ = 0.92) and OvC (κ = 0.86). Lesser agreement was observed between reports regarding family history of other types of cancer (κ = 0.51). Mutation screening revealed pathogenic germline mutations in 30.4%; 18.8% in BRCA1, 7.1% in BRCA2 and 4.5% in other genes. Compared with other mutation groups, BRCA1 mutation carriers were more likely to be diagnosed with high-grade, ER-, PR- and triple-negative tumors. Conclusions: Our results demonstrate that physicians and genetic counselors can rely on self-reported information regarding BC and OvC in first-degree relatives. However, self-reported information regarding other types of cancer is not communicated as effectively, and there should be more focus on retrieving the correct information regarding family history of all tumor types. Furthermore, we observed that even though all BC patients fulfilled the criteria for genetic counseling and testing, a large number of patients diagnosed at ≤35 years of age did not receive genetic counseling at the Oncogenetic Clinic. This finding merits further elucidation.
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| 29. |
- Balciuniene, Jorune, et al.
(författare)
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Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities
- 2007
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 80:5, s. 938-947
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Tidskriftsartikel (refereegranskat)abstract
- Low-copy repeats (LCRs) are genomic features that affect chromosome stability and can produce disease-associated rearrangements. We describe members of three families with deletions in 10q22.3-q23.31, a region harboring a complex set of LCRs, and demonstrate that rearrangements in this region are associated with behavioral and neurodevelopmental abnormalities, including cognitive impairment, autism, hyperactivity, and possibly psychiatric disease. Fine mapping of the deletions in members of all three families by use of a custom 10q oligonucleotide array-based comparative genomic hybridization (NimbleGen) and polymerase chain reaction - based methods demonstrated a different deletion in each family. In one proband, the deletion breakpoints are associated with DNA fragments containing noncontiguous sequences of chromosome 10, whereas, in the other two families, the breakpoints are within paralogous LCRs, removing similar to 7.2 Mb and 32 genes. Our data provide evidence that the 10q22-q23 genomic region harbors one or more genes important for cognitive and behavioral development and that recurrent deletions affecting this interval define a novel genomic disorder.
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| 30. |
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| 31. |
- Bartuma, Katarina, et al.
(författare)
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Genetic profiles distinguish different types of hereditary ovarian cancer.
- 2010
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Ingår i: Oncology Reports. - : Spandidos Publications. - 1791-2431 .- 1021-335X. ; 24:4, s. 885-895
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Tidskriftsartikel (refereegranskat)abstract
- Heredity represents the strongest risk factor for ovarian cancer with disease predisposing mutations identified in 15% of the tumors. With the aim to identify genetic classifiers for hereditary ovarian cancer, we profiled hereditary ovarian cancers linked to the hereditary breast and ovarian cancer (HBOC) syndrome and the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Genome-wide array comparative genomic hybridization was applied to 12 HBOC associated tumors with BRCA1 mutations and 8 HNPCC associated tumors with mismatch repair gene mutations with 24 sporadic ovarian cancers as a control group. Unsupervised cluster analysis identified two distinct subgroups related to genetic complexity. Sporadic and HBOC associated tumors had complex genetic profiles with an average 41% of the genome altered, whereas the mismatch repair defective tumors had stable genetic profiles, with an average 18% of the genome altered. Losses of 4q34, 13q12-q32 and 19p13 were overrepresented in the HBOC subset. Discriminating genes within these regions include BRCA2, FOXO1A and RB1. Gains on chromosomes 17 and 19 characterized the HNPCC tumors, but target genes herein are unknown. The results indicate that HBOC and HNPCC associated ovarian cancer develop along distinct genetic pathways and genetic profiles can thus be applied to distinguish between different types of hereditary ovarian cancer.
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| 32. |
- Begg, Colin B, et al.
(författare)
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Variation of breast cancer risk among BRCA1/2 carriers
- 2008
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Ingår i: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 299:2, s. 194-201
-
Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: The risk of breast cancer in BRCA1 and BRCA2 mutation carriers has been examined in many studies, but relatively little attention has been paid to the degree to which the risk may vary among carriers. OBJECTIVES: To determine the extent to which risks for BRCA1 and BRCA2 carriers vary with respect to observable and unobservable characteristics. DESIGN, SETTING, AND PARTICIPANTS: Probands were identified from a population-based, case-control study (Women's Environmental Cancer and Radiation Epidemiology [WECARE]) of asynchronous contralateral breast cancer conducted during the period of January 2000 to July 2004. Participants previously diagnosed with contralateral breast cancer or unilateral breast cancer were genotyped for mutations in BRCA1 and BRCA2. All participants had their initial breast cancer diagnosed during the period of January 1985 to December 2000, before the age of 55 years. MAIN OUTCOME MEASURE: Incidence of breast cancer in first-degree female relatives of the probands was examined and compared on the basis of proband characteristics and on the basis of variation between families. RESULTS: Among the 1394 participants with unilateral breast cancer, 73 (5.2%) were identified as carriers of deleterious mutations (42 with BRCA1 and 31 with BRCA2). Among the 704 participants with contralateral breast cancer, 108 (15.3%) were identified as carriers of deleterious mutations (67 with BRCA1 and 41 with BRCA2). Among relatives of carriers, risk was significantly associated with younger age at diagnosis in the proband (P = .04), and there was a trend toward higher risk for relatives of contralateral breast cancer vs unilateral breast cancer participants (odds ratio, 1.4 [95% confidence interval, 0.8-2.4]; P = .28). In addition, there were significant differences in risk between carrier families after adjusting for these observed characteristics. CONCLUSION: There exists broad variation in breast cancer risk among carriers of BRCA1 and BRCA2 mutations.
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| 33. |
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| 34. |
- Bengtsson, Ylva, et al.
(författare)
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Serum copper, zinc and copper/zinc ratio in relation to survival after breast cancer diagnosis: A prospective multicenter cohort study
- 2023
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Ingår i: Redox Biology. - 2213-2317. ; 63
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe essential trace elements copper and zinc, and their ratio (copper/zinc), are important for maintaining redox homeostasis. Previous studies suggest that these elements may impact breast cancer survival. However, no epidemiological study has so far been conducted on the potential association between copper and copper/zinc levels and survival after breast cancer diagnosis. In this study, we aimed to examine the relationship between serum copper, zinc and copper/zinc levels and survival following breast cancer diagnosis.Patients and methodsThe Sweden Cancerome Analysis Network – Breast Initiative (SCAN-B) is a population-based cohort study including multiple participating hospitals in Sweden. A total of 1998 patients diagnosed with primary invasive breast cancer were followed for approximately nine years. Serum levels of copper and zinc and their ratio at the time of diagnosis was analyzed in relation to breast cancer survival using multivariate Cox regression, yielding hazard ratios (HR) with 95% confidence intervals.ResultsA higher copper/zinc ratio was associated with lower overall survival after breast cancer diagnosis. Comparing patients with a copper/zinc ratio in quartile 4 vs 1, the crude HR was 2.29 (1.65–3.19) (Ptrend ConclusionThere is evidence that the serum copper/zinc ratio provides an independent predictive value for overall survival following breast cancer diagnosis.
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| 35. |
- Bergthorsson, J.T., et al.
(författare)
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BRCA1 and BRCA2 mutation status and cancer family history of Danish women affected with multifocal or bilateral breast cancer at a young age
- 2001
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 38:6, s. 361-368
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Tidskriftsartikel (refereegranskat)abstract
- Introduction - A small fraction of breast cancer is the result of germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes. Mutation carriers frequently have a positive family history of breast and ovarian cancer, are often diagnosed at a young age, and may have a higher incidence of double or multiple primary breast tumours than breast cancer patients in general. Objectives - To estimate the prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish patients affected with bilateral or multifocal breast cancer and to determine the relationship of mutation status to family history of cancer. Subjects - From the files of the Danish Breast Cancer Cooperative Group (DBCG), we selected 119 breast cancer patients diagnosed before the age of 46 years with either bilateral (n=59) or multifocal (n=61) disease. Methods - DNA from the subjects was screened for BRCA1 and BRCA2 mutations using single strand conformation analysis (SSCA) and the protein truncation test (PTT). Observed and expected cancer incidence in first degree relatives of the patients was estimated using data from the Danish Cancer Registry. Results - Twenty four mutation carriers were identified (20%), of whom 13 had a BRCA1 mutation and 11 carried a BRCA2 mutation. Two mutations in BRCA1 were found repeatedly in the material and accounted for seven of the 24 (29%) mutation carriers. The mutation frequency was about equal in patients with bilateral (22%) and multifocal breast cancer (18%). The incidence of breast and ovarian cancer was greatly increased in first degree relatives of BRCA1 and BRCA2 mutation carriers, but to a much lesser degree in relatives of non-carriers. An increased risk of cancer was also noted in brothers of non-carriers. Conclusions - A relatively broad spectrum of germline mutations was observed in BRCA1 and BRCA2 and most of the mutations are present in other populations. Our results indicate that a diagnosis of bilateral and multifocal breast cancer is predictive of BRCA1 and BRCA2 mutation status, particularly when combined with information on the patients' age at diagnosis and family history of breast/ovarian cancer.
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| 36. |
- Bernstein, Jonine L., et al.
(författare)
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Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers: A WECARE Study Report
- 2013
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 49:14, s. 2979-2985
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Tidskriftsartikel (refereegranskat)abstract
- Background: Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers. Methods: A population-based, nested case-control study was conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC). Cases were 603 women with CBC and controls were 1199 women with UBC individually matched on age at diagnosis, race, year of first diagnosis and cancer registry. All women were tested for BRCA1 and BRCA2 mutations. Radiation absorbed dose from the initial radiotherapy (RT) to the CBC location within the contralateral breast was reconstructed from measurements in a tissue-equivalent phantom and details available in the therapy records. Findings: Among women treated with radiation, the mean radiation dose was 1.1 Gy (range = 0.02-6.2 Gy). Risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR = 4.5, confidence interval, CI = 3.0-6.8), and also among those treated with RT (RR = 1.2, CI = 1.0-1.6). However, among mutation carriers, an incremental increase in risk associated with radiation dose was not statistically significant. Interpretation: Multiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers, but this was not apparent. Accordingly, there was no clear indication that carriers of deleterious BRCA/BRCA2 mutations were more susceptible to the carcinogenic effects of radiation than non-carriers. These findings are reassuring and have important clinical implications for treatment decisions and the clinical management of patients harbouring deleterious BRCA1/BRCA2 mutations. Funding: All work associated with this study was supported by the U.S. National Cancer Institute [R01CA097397, U01CA083178]. (C) 2013 Elsevier Ltd. All rights reserved.
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| 37. |
- Bhandari, Vinayak, et al.
(författare)
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Divergent mutational processes distinguish hypoxic and normoxic tumours
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.
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| 38. |
- Bogdanska, Jasna, et al.
(författare)
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Tissue distribution of (35)S-labelled perfluorooctane sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high experimental dose
- 2011
-
Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 284:1-3, s. 54-62
-
Tidskriftsartikel (refereegranskat)abstract
- The widespread environmental pollutant perfluorooctane sulfonate (PFOS), detected in most animal species including the general human population, exerts several effects on experimental animals, e.g., hepatotoxicity, immunotoxicity and developmental toxicity. However, detailed information on the tissue distribution of PFOS in mammals is scarce and, in particular, the lack of available information regarding environmentally relevant exposure levels limits our understanding of how mammals (including humans) may be affected. Accordingly, we characterized the tissue distribution of this compound in mice, an important experimental animal for studying PFOS toxicity. Following dietary exposure of adult male C57/BL6 mice for 1-5 days to an environmentally relevant (0.031 mg/kg/day) or a 750-fold higher experimentally relevant dose (23 mg/kg/day) of (35)S-PFOS, most of the radioactivity administered was recovered in liver, bone (bone marrow), blood, skin and muscle, with the highest levels detected in liver, lung, blood, kidney and bone (bone marrow). Following high daily dose exposure, PFOS exhibited a different distribution profile than with low daily dose exposure, which indicated a shift in distribution from the blood to the tissues with increasing dose. Both scintillation counting (with correction for the blood present in the tissues) and whole-body autoradiography revealed the presence of PFOS in all 19 tissues examined, with identification of thymus as a novel site for localization for PFOS and bone (bone marrow), skin and muscle as significant body compartments for PFOS. These findings demonstrate that PFOS leaves the bloodstream and enters most tissues in a dose-dependent manner.
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| 39. |
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| 40. |
- Bogdanska, Jasna, et al.
(författare)
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Tissue distribution of C-14-labelled perfluorooctanoic acid in adult mice after 1-5 days of dietary exposure to an experimental dose or a lower dose that resulted in blood levels similar to those detected in exposed humans
- 2020
-
Ingår i: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 239
-
Tidskriftsartikel (refereegranskat)abstract
- Perfluorooctanoic acid (PFOA), a global environmental pollutant detected in both wildlife and human populations, has several pathophysiological effects in experimental animals, including hepatotoxicity, immunotoxicity, and developmental toxicity. However, details concerning the tissue distribution of PFOA, in particular at levels relevant to humans, are lacking, which limits our understanding of how humans, and other mammals, may be affected by this compound. Therefore, we characterized the tissue distribution of C-14-PFOA in mice in the same manner as we earlier examined its analogues perfluorooctanesulfonate (PFOS) and perfluorobutanesulfonate (PFBS) in order to allow direct comparisons. Following dietary exposure of adult male C57/BL6 mice for 1, 3 or 5 days to a low dose (0.06 mg/kg/day) or a higher experimental dose (22 mg/kg/day) of C-14-PFOA, both scintillation counting and whole-body autoradiography revealed the presence of PFOA in most of the 19 different tissues examined, demonstrating its ability to leave the bloodstream and enter tissues. There were no differences in the pattern of tissue distribution with the low and high dose and the tissue-to-blood ratios were similar. At both doses, PFOA levels were highest in the liver, followed by blood, lungs and kidneys. The body compartments estimated to contain the largest amounts of PFOA were the liver, blood, skin and muscle. In comparison with our identical studies on PFOS and PFBS, PFOA reached considerably higher tissue levels than PFBS, but lower than PFOS. Furthermore, the distribution of PFOA differed notably from that of PFOS, with lower tissue-to-blood ratios in the liver, lungs, kidneys and skin.
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| 41. |
- Bogdanska, Jasna, et al.
(författare)
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Tissue distribution of S-35-labelled perfluorobutanesulfonic acid in adult mice following dietary exposure for 1-5 days
- 2014
-
Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 98, s. 28-36
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Tidskriftsartikel (refereegranskat)abstract
- Perfluorobutanesulfonyl fluoride (PBSF) has been introduced as a replacement for its eight-carbon homolog perfluorooctanesulfonyl fluoride (POSF) in the manufacturing of fluorochemicals. Fluorochemicals derived from PBSF may give rise to perfluorobutanesulfonic acid (PFBS) as a terminal degradation product. Although basic mammalian toxicokinetic data exist for PFBS, information on its tissue distribution has only been reported in one study focused on rat liver. Therefore, here we characterized the tissue distribution of PFBS in mice in the same manner as we earlier examined its eight-carbon homolog perfluorooctanesulfonate (PFOS) to allow direct comparisons. Following dietary exposure of adult male C57/BL6 mice for 1,3 or 5 d to 16 mg S-35-PFBS kg(-1) d(-1), both scintillation counting and whole-body autoradiography (WBA) revealed the presence of PFBS in all of the 20 different tissues examined, demonstrating its ability to leave the bloodstream and enter tissues. After 5 d of treatment the highest levels were detected in liver, gastrointestinal tract, blood, kidney, cartilage, whole bone, lungs and thyroid gland. WBA revealed relatively high levels of PFBS in male genital organs as well, with the exception of the testis. The tissue levels increased from 1 to 3 d of exposure but appeared thereafter to level-off in most cases. The estimated major body compartments were whole bone, liver, blood, skin and muscle. This exposure to PFBS resulted in 5-40-fold lower tissue levels than did similar exposure to PFOS, as well as in a different pattern of tissue distribution, including lower levels in liver and lungs relative to blood.
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| 42. |
- Bolton, Kelly L., et al.
(författare)
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Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer
- 2012
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Ingår i: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 307:4, s. 382-390
-
Tidskriftsartikel (refereegranskat)abstract
- Context Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. Objective To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. Design, Setting, and Participants A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n=909) or BRCA2 (n=304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). Main Outcome Measure Five-year overall mortality. Results The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P<.001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P<.001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P<.001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P<.001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity=.003). Conclusion Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis. JAMA. 2012;307(4):382-390
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| 43. |
- Borg, Daniel, et al.
(författare)
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Perinatal tissue distribution of perfluorooctane sulphonate (PFOS) in mice.
- 2009
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Ingår i: Abstracts of the 46th Congress of the European Societies of Toxicology. - : Elsevier BV. ; 189:SI, s. S147-S147
-
Konferensbidrag (refereegranskat)abstract
- Perfluorooctane sulfonate (PFOS) is an industrial chemical that has been used as a surfactant and surface protector for more than fifty years. It has during the last decade emerged as an environmental contaminant due to its widespread presence in humans and wildlife and its persistant, bioaccumulative and toxic properties. PFOS is developmentally toxic and late in utero exposure in rodents affects neonatal survival and growth. Observed symptoms suggest impaired pulmonary function, but the cause of the mortality has not been clarified. The purpose of this study was to determine the perinatal tissue distribution of S35-labelled PFOS in mice using whole-body autoradiography (WBA) combined with liquid scintillation counting (LSC). Pregnant C57Bl/6 mice were dosed orally on gestation day (GD) 16 and sampled on GD18, GD20 and postnatal day (PND) 1 (dams + pups). The results from the WBA and the LSC were unequivocal. In dams, PFOS accumulated primarily in the liver, but also the lungs contained levels higher than the blood. PFOS was readily transferred to the fetus. At GD18 general PFOS levels were higher in the fetus than in the blood of the corresponding dam with accumulation in the liver. At GD20, general PFOS levels remained higher in the fetus than in the dam, with substantial accumulation also in the lung. The accumulation in the lung persisted at PND1. Our results show that the fetus is exposed to higher levels of PFOS than the dam and point towards the lung being the main perinatal target organ of PFOS.
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| 44. |
- Borg, D., et al.
(författare)
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Tissue distribution of S-35-labelled perfluorooctane sulfonate (PFOS) in C57Bl/6 mice following late gestational exposure
- 2010
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Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 30:4, s. 558-565
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Tidskriftsartikel (refereegranskat)abstract
- Exposure of rodents in utero to perfluorooctane sulfonate (PFOS) impairs perinatal development and survival Following intravenous or gavage exposure of C57Bl/6 mouse dams on gestational day (GD) 16 to S-35-PFOS (12 5 mg/kg) we determined the distribution in dams fetuses (GD18 and GD20) and pups (postnatal day 1 PND1) employing whole-body autoradiography and liquid scintillation counting In dams levels were highest in liver and lungs After placental transfer S-35-PFOS was present on GD18 at 2-3 times higher levels in lungs liver and kidneys than in maternal blood In PND1 pups levels in lungs were significantly higher than in GD18 fetuses A heterogeneous distribution of S-35-PFOS was observed in brains of fetuses and pups with levels higher than in maternal brain This first demonstration of substantial localization of PFOS to both perinatal and adult lungs is consistent with evidence describing the lung as a target for the toxicity of PFOS at these ages.
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| 45. |
- Borg, O., et al.
(författare)
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Expansion of spatial and host range of Puumala virus in Sweden : an increasing threat for humans?
- 2017
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Ingår i: Epidemiology and Infection. - : Cambridge University Press. - 0950-2688 .- 1469-4409. ; 145:8, s. 1642-1648
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Tidskriftsartikel (refereegranskat)abstract
- Hantaviruses are globally distributed and cause severe human disease. Puumala hantavirus (PUUV) is the most common species in Northern Europe, and the only hantavirus confirmed to circulate in Sweden, restricted to the northern regions of the country. In this study, we aimed to further add to the natural ecology of PUUV in Sweden by investigating prevalence, and spatial and host species infection patterns. Specifically, we wanted to ascertain whether PUUV was present in the natural reservoir, the bank vole (Myodes glareolus) further south than Dalälven river, in south-central Sweden, and whether PUUV can be detected in other rodent species in addition to the natural reservoir. In total, 559 animals were collected at Grimsö (59°43'N; 15°28'E), Sala (59°55'N; 16°36'E) and Bogesund (59°24'N; 18°14'E) in south-central Sweden between May 2013 and November 2014. PUUV ELISA-reactive antibodies were found both in 2013 (22/295) and in 2014 (18/264), and nine samples were confirmed as PUUV-specific by focus reduction neutralization test. Most of the PUUV-specific samples were from the natural host, the bank vole, but also from other rodent hosts, indicating viral spill-over. Finally, we showed that PUUV is present in more highly populated central Sweden.
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| 46. |
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| 47. |
- Borg, Åke, et al.
(författare)
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c-myc amplification is an independent prognostic factor in postmenopausal breast cancer
- 1992
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 51:5, s. 687-691
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Tidskriftsartikel (refereegranskat)abstract
- The c-myc proto-oncogene was analyzed in 311 cases of primary breast cancer, in 8% of which it was found to be amplified, usually at moderately increased copy number (2-5 copies). The adjacent pvt gene was co-amplified with c-myc in all tumors analyzed. C-myc amplification was significantly correlated to a high S-phase fraction and to amplification of the c-erbB-2 proto-oncogene. Weak relationships were found between c-myc amplification and the presence of lymph-node metastasis, advanced stage, DNA non-diploidy and premenopausal status, but not tumor size, estrogen receptor or progesterone receptor status, or int-2 amplification. C-myc amplification, and especially a high gene copy number (greater than 5 copies), was significantly related to early recurrence and death in breast cancer, a relationship seen in both the lymph-node-negative and node-positive subcategories. A particularly strong correlation with poor clinical outcome was seen in postmenopausal patients (p greater than 0.0005), an association which persisted in multivariate survival analysis. We conclude that the activation of c-myc is indeed associated with rapidly growing and progressive breast cancer. Gene amplification, on the other hand, is relatively infrequent and occurs mostly at low copy number, implying that tumors are heterogeneous with respect to cell clones harboring c-myc amplification. An immunohistochemical assessment would more accurately illustrate the importance of c-myc activation in human breast cancer. However, the obvious instability of the c-myc transcript and translate suggests that c-myc is not a suitable prognostic marker for routine purposes.
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| 48. |
- Borg, Åke, et al.
(författare)
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Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
- 2010
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 31, s. 1200-1240
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Tidskriftsartikel (refereegranskat)abstract
- BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC. (c) 2010 Wiley-Liss, Inc.
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| 49. |
- Borg, Åke, et al.
(författare)
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Chromosome I alterations in breast cancer : Allelic loss on Ip and Iq Is related to lymphogenic metastases and poor prognosis
- 1992
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 5:4, s. 311-320
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Tidskriftsartikel (refereegranskat)abstract
- The development of human breast cancer is characterized by a variety of genetic alterations, and cytogenetic analyses have documented the consistent involvement of both arms of chromosome I. In the present study, molecular markers detecting restriction fragment length polymorphisms were used in pairwise screening of normal and tumor DNA to determine the frequency of allelic imbalance in breast tumors. Loss of heterozygosity (LOH) in the polymorphic epithelial mucin (PEM or MUCI) gene at 1q21 was found in 16% of 89 informative (constitutionally heterozygous) cases, whereas gain in intensity of one allelic band was more frequent (37%), a total of 47% of cases manifesting either allelic loss or gain. Three additional tumors manifested a structural alteration. Allelic loss or gain in the PEM gene was not associated with other prognostic factors, e.g., tumor size, lymph node status, steroid receptors, DNA ploidy, S phase fraction, protooncogene amplification, histological type, or patient age. However, LOH in the PEM gene was significantly correlated with early disease recurrence (P = 0.006). LOH on 1p was found in 27% of 117 informative cases, using probes for either DIS57 or DIZ2 located at 1p33‐p35 and 1p36, respectively. Somatic allelic imbalance on 1p and 1q seemed to be independent events and not the effect of loss of a whole chromosome 1. LOH on 1 p was significantly correlated to the presence of lymph node metastasis, to larger tumor size, and to DNA nondiploidy, but no correlation was found to disease outcome at this limited duration of follow‐up (median 29 months). ©1992 Wiley‐Liss, Inc.
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- Borg, Åke, et al.
(författare)
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ERBB2 amplification in breast cancer with a high rate of proliferation
- 1991
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Ingår i: Oncogene. - 1476-5594. ; 6:1, s. 137-143
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Tidskriftsartikel (refereegranskat)abstract
- The ERBB2 proto-oncogene was studied in 539 invasive primary breast tumors and was found amplified (2- greater than 30 copies) in 19%. Amplification was correlated to most known risk factors, including; large tumor size, lymph node positivity and many tumor involved nodes, advanced stage, low patient age (less than 40 years), non-diploidy and hypertetraploidy, and most significantly (P less than 0.00001) to the absence of steroid receptors and to a high rate of proliferation (flow cytometric determined S phase fraction). ERBB2 amplification was strongly associated (P less than 0.0001) with early recurrence and death in breast cancer among node-positive patients. This connection did not, however, remain in multivariate analyses. No correlations to clinical outcome were seen among node-negative patients. Similarly, non-diploid, but not diploid, amplified tumors were particularly aggressive. Furthermore, ERBB2 amplification was associated with a high rate of proliferation and poor prognosis in steroid receptor positive, but not receptor negative tumors. In progesterone receptor positive breast cancer, amplification was an independent and with node status equally powerful (P less than 0.0001) predictor of poor survival. It is concluded that ERBB2 activity is related to an increased tumor growth rate but not directly to metastasizing ability. Its clinical relevance as a prognostic factor may be in selecting a high risk subgroup of breast cancer, in general considered as being of good prognosis.
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