| 1. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 2. |
- Osorio, A., et al.
(författare)
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Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2 (CIMBA)
- 2009
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Ingår i: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 101:12, s. 2048-2054
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Tidskriftsartikel (refereegranskat)abstract
- Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P0.5) mutation carriers. Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.
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| 3. |
- Jakubowska, A, et al.
(författare)
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Association of PHB 1630 C andgt; T and MTHFR 677 C andgt; T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study
- 2012
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Ingår i: British Journal of Cancer. - : Cancer Research UK / Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 106:12, s. 2016-2024
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. less thanbrgreater than less thanbrgreater thanMETHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 Candgt;T (rs6917) polymorphism and the MTHFR 677 Candgt;T (rs1801133) polymorphism, respectively. less thanbrgreater than less thanbrgreater thanRESULTS: There was no evidence of association between the PHB 1630 Candgt;T and MTHFR 677 Candgt;T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 Candgt;T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. less thanbrgreater than less thanbrgreater thanCONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.
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| 6. |
- Martrat, Griselda, et al.
(författare)
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Exploring the link between MORF4L1 and risk of breast cancer
- 2011
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P-trend = 0.45 and 0.05, P-2df = 0.51 and 0.14, respectively; and rs10519219, P-trend = 0.92 and 0.72, P-2df = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.
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| 7. |
- Maxwell, Christopher A., et al.
(författare)
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Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer
- 2011
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885 .- 1544-9173. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
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| 8. |
- Look, M, et al.
(författare)
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Pooled analysis of prognostic impact of uPA and PAI-I in breast cancer patients
- 2003
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 90:3, s. 538-548
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Tidskriftsartikel (refereegranskat)abstract
- In this report we present an extension of the pooled analysis of the prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I in breast cancer patients. We analyzed a different endpoint, metastasis-free survival (MFS). We checked the consistency of the estimates for uPA and PAI-I for relapse-free survival (RFS) and MFS exploring possible sources of heterogeneity. Nodal status, the most important prognostic factor for breast cancer, introduced heterogeneity in the uPA/PAI-I survival analyses, reflecting the interaction between nodal status and uPA/PAI-I. The estimates for uPA and PAI-I were found to be consistent, even when a different transformation of their values was used. The heterogeneity of the separate data sets decreased if the levels of uPA and PAI-I were ranked, data sets were pooled, and the analyses corrected for the base model that included all traditional prognostic factors, and stratified by data set. We conclude that uPA and PAI-I are ready to be used in the clinic to help classify breast cancer patients into high and low risk groups.
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| 9. |
- Plasman, M., et al.
(författare)
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Lithospheric low-velocity zones associated with a magmatic segment of the Tanzanian Rift, East Africa
- 2017
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Ingår i: Geophysical Journal International. - : OXFORD UNIV PRESS. - 0956-540X .- 1365-246X. ; 210:1, s. 465-481
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Tidskriftsartikel (refereegranskat)abstract
- Rifting in a cratonic lithosphere is strongly controlled by several interacting processes including crust/mantle rheology, magmatism, inherited structure and stress regime. In order to better understand how these physical parameters interact, a 2 yr long seismological experiment has been carried out in the North Tanzanian Divergence (NTD), at the southern tip of the eastern magmatic branch of the East African rift, where the southward-propagating continental rift is at its earliest stage. We analyse teleseismic data from 38 broad-band stations ca. 25 km spaced and present here results from their receiver function (RF) analysis. The crustal thickness and Vp/Vs ratio are retrieved over a ca. 200 x 200 km(2) area encompassing the South Kenya magmatic rift, the NTD and the Ngorongoro-Kilimanjaro transverse volcanic chain. Cratonic nature of the lithosphere is clearly evinced through thick (up to ca. 40 km) homogeneous crust beneath the rift shoulders. Where rifting is present, Moho rises up to 27 km depth and the crust is strongly layered with clear velocity contrasts in the RF signal. The Vp/Vs ratio reaches its highest values (ca. 1.9) beneath volcanic edifices location and thinner crust, advocating for melting within the crust. We also clearly identify two major low-velocity zones (LVZs) within the NTD, one in the lower crust and the second in the upper part of the mantle. The first one starts at 15-18 km depth and correlates well with recent tomographic models. This LVZ does not always coexist with high Vp/Vs ratio, pleading for a supplementary source of velocity decrease, such as temperature or composition. At a greater depth of ca. 60 km, a midlithospheric discontinuity roughly mimics the step-like and symmetrically outward-dipping geometry of the Moho butwith a more slanting direction (NE-SW) compared to theNS rift. By comparison with synthetic RF, we estimate the associated velocity reduction to be 8-9 per cent. We relate this interface to melt ponding, possibly favouring here deformation process such as grain-boundary sliding (EAGBS) due to lithospheric strain. Its geometry might have been controlled by inherited lithospheric fabrics and heterogeneous upper mantle structure. We evidence that crustal and mantle magmatic processes represent first order mechanisms to ease and locate the deformation during the first stage of a cratonic lithospheric breakup.
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| 11. |
- Tiberi, C., et al.
(författare)
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Lithospheric modification by extension and magmatism at the craton-orogenic boundary : North Tanzania Divergence, East Africa
- 2019
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Ingår i: Geophysical Journal International. - : OXFORD UNIV PRESS. - 0956-540X .- 1365-246X. ; 216:3, s. 1693-1710
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Tidskriftsartikel (refereegranskat)abstract
- We present a joint analysis of newly acquired gravity and teleseismic data in the North Tanzanian Divergence, where the lithospheric break-up is at its earliest stage. The impact of a mantle upwelling in more mature branches of the East African Rift has been extensively studied at a lithospheric scale. However, few studies have been completed that relate the deep-seated mantle anomaly detected in broad regional seismic tomography with the surface deformation observed in the thick Archaean Pan-African suture zone located in North Tanzania. Our joint inversion closes the gap between local and regional geophysical studies, providing velocity and density structures from the surface down to ca. 250 km depth with new details. Our results support the idea of a broad mantle upwelling rising up to the lithosphere and creating a thermal modification along its path. However, our study clearly presents an increasing amplitude of the associated anomaly both in velocity and density above 200 km depth, which cannot be solely explained by a temperature rise. We infer from our images the combined impact of melt (2-3 per cent), composition and hydration that accompany the modification of a thick heterogenous cratonic lithosphere are a response to the hot mantle rising. The detailed images we obtained in density and velocity assert that Archaean and Proterozoic units interact with the mantle upwelling to restrict the lithosphere modifications within the Magadi-Natron-Manyara rift arm. The composition and hydration variations associated with those units equilibrate the thermal erosion of the craton root and allow for its stability between 100 and 200 km depth. Above 80 km depth, the crustal part is strongly affected by intruding bodies (melt and gas) which produces large negative anomalies in both velocity and density beneath the main magmatic centres. In addition to the global impact of a superplume, the velocity and density anomaly pattern suggests a 3-D distribution of the crust and mantle lithospheric stretching, which is likely to be controlled by inherited fabrics and enhanced by lateral compositional and hydration variations at the Tanzanian craton-orogenic belt boundary.
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| 12. |
- Look, MP, et al.
(författare)
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Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 8377 breast cancer patients
- 2002
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 94:2, s. 116-128
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Tidskriftsartikel (refereegranskat)abstract
- Background: Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAT-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, we reanalyzed individual patient data provided by members of the European Organization for Research and Treatment of Cancer-Receptor and Biomarker Group (EORTC-RBG). Methods: The study included 18 datasets involving 8377 breast cancer patients. During follow-up (median 79 months), 35% of the patients relapsed and 27% died. Levels of uPA and PAI-1 in tumor tissue extracts were determined by different immunoassays; values were ranked within each dataset and divided by the number of patients in that dataset to produce fractional ranks that could be compared directly across datasets. Associations of ranks of uPA and PAI-1 levels with relapse-free survival (RFS) and overall survival (OS) were analyzed by Cox multivariable regression analysis stratified by dataset, including the following traditional prognostic variables: age, menopausal status, lymph node status, tumor size, histologic grade, and steroid hormone-receptor status. All P values were two-sided. Results: Apart from lymph node status, high levels of uPA and PAI-1 were the strongest predictors of both poor RFS and poor OS in the analyses of all patients. Moreover, in both lymph node-positive and lymph nodenegative patients, higher uPA and PAI-1 values were independently associated with poor RFS and poor OS. For (untreated) lymph node-negative patients in particular, uPA and PAI-1 included together showed strong prognostic ability (all P<.001). Conclusions: This pooled analysis of the EORTC-RBG datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. For patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategies.
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