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- Dork, T, et al.
(author)
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Two truncating variants in FANCC and breast cancer risk
- 2019
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 12524-
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Journal article (peer-reviewed)abstract
- Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
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- Johansson, Henrik J., et al.
(author)
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Breast cancer quantitative proteome and proteogenomic landscape
- 2019
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
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Journal article (peer-reviewed)abstract
- In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.
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- Blumel, Edda, et al.
(author)
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Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4+ T cells in cutaneous T-cell lymphoma
- 2019
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In: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 8:11
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Journal article (peer-reviewed)abstract
- Staphylococcus aureus is implicated in disease progression in cutaneous T-cell lymphoma (CTCL). Here, we demonstrate that malignant T cell lines derived from CTCL patients as well as primary malignant CD4+ T cells from Sézary syndrome patients are considerably more resistant to alpha-toxin-induced cell death than their non-malignant counterparts. Thus, in a subset of Sézary syndrome patients the ratio between malignant and non-malignant CD4+ T cells increases significantly following exposure to alpha-toxin. Whereas toxin-induced cell death is ADAM10 dependent in healthy CD4+ T cells, resistance to alpha-toxin in malignant T cells involves both downregulation of ADAM10 as well as other resistance mechanisms. In conclusion, we provide first evidence that Staphylococcus aureus derived alpha-toxin can tilt the balance between malignant and non-malignant CD4+ T cells in CTCL patients. Consequently, alpha-toxin may promote disease progression through positive selection of malignant CD4+ T cells, identifying alpha-toxin as a putative drug target in CTCL.
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- Masseron, T., et al.
(author)
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Homogeneous analysis of globular clusters from the APOGEE survey with the BACCHUS code
- 2019
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In: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 622
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Journal article (peer-reviewed)abstract
- Aims: We seek to provide abundances of a large set of light and neutron-capture elements homogeneously analyzed that cover a wide range of metallicity to constrain globular cluster (GC) formation and evolution models.Methods: We analyzed a large sample of 885 GCs giants from the SDSS IV-Apache Point Observatory Galactic Evolution Experiment (APOGEE) survey. We used the Cannon results to separate the red giant branch and asymptotic giant branch stars, not only allowing for a refinement of surface gravity from isochrones, but also providing an independent H-band spectroscopic method to distinguish stellar evolutionary status in clusters. We then used the Brussels Automatic Code for Characterizing High accUracy Spectra (BACCHUS) to derive metallicity, microturbulence, macroturbulence, many light-element abundances, and the neutron-capture elements Nd and Ce for the first time from the APOGEE GCs data.Results: Our independent analysis helped us to diagnose issues regarding the standard analysis of the APOGEE DR14 for low-metallicity GC stars. Furthermore, while we confirm most of the known correlations and anticorrelation trends (Na-O, Mg-Al, C-N), we discover that some stars within our most metal-poor clusters show an extreme Mg depletion and some Si enhancement. At the same time, these stars show some relative Al depletion, displaying a turnover in the Mg-Al diagram. These stars suggest that Al has been partially depleted in their progenitors by very hot proton-capture nucleosynthetic processes. Furthermore, we attempted to quantitatively correlate the spread of Al abundances with the global properties of GCs. We find an anticorrelation of the Al spread against clusters metallicity and luminosity, but the data do not allow us to find clear evidence of a dependence of N against metallicity in the more metal-poor clusters.Conclusions: Large and homogeneously analyzed samples from ongoing spectroscopic surveys unveil unseen chemical details for many clusters, including a turnover in the Mg-Al anticorrelation, thus yielding new constrains for GCs formation/evolution models.
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