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- Steinthorsdottir, V, et al.
(author)
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Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women
- 2020
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 5976-
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Journal article (peer-reviewed)abstract
- Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
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| 2. |
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| 3. |
- Degasperi, Andrea, et al.
(author)
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A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies
- 2020
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In: Nature Cancer. - : Springer Science and Business Media LLC. - 2662-1347. ; 1:2, s. 249-263
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Journal article (peer-reviewed)abstract
- Mutational signatures are patterns of mutations that arise during tumorigenesis. We present an enhanced, practical framework for mutational signature analyses. Applying these methods to 3,107 whole-genome-sequenced (WGS) primary cancers of 21 organs reveals known signatures and nine previously undescribed rearrangement signatures. We highlight interorgan variability of signatures and present a way of visualizing that diversity, reinforcing our findings in an independent analysis of 3,096 WGS metastatic cancers. Signatures with a high level of genomic instability are dependent on TP53 dysregulation. We illustrate how uncertainty in mutational signature identification and assignment to samples affects tumor classification, reinforcing that using multiple orthogonal mutational signature data is not only beneficial, but is also essential for accurate tumor stratification. Finally, we present a reference web-based tool for cancer and experimentally generated mutational signatures, called Signal (https://signal.mutationalsignatures.com), that also supports performing mutational signature analyses.
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| 4. |
- Kashyap, Abhishek S., et al.
(author)
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Antagonists of IGF : Vitronectin Interactions Inhibit IGF-I-Induced Breast Cancer Cell Functions
- 2016
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In: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 15:7, s. 1602-1613
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Journal article (peer-reviewed)abstract
- We provide proof-of-concept evidence for a new class of therapeutics that target growth factor: extracellular matrix (GF: ECM) interactions for the management of breast cancer. Insulinlike growth factor-I (IGF-I) forms multiprotein complexes with IGF-binding proteins (IGFBP) and the ECM protein vitronectin (VN), and stimulates the survival, migration and invasion of breast cancer cells. For the first time we provide physical evidence for IGFBP-3: VN interactions in breast cancer patient tissues; these interactions were predominantly localized to tumor cell clusters and in stroma surrounding tumor cells. We show that disruption of IGF-I: IGFBP: VN complexes with L27-IGF-II inhibits IGF-I: IGFBP: VN-stimulated breast cancer cell migration and proliferation in two-and three-dimensional assay systems. Peptide arrays screened to identify regions critical for the IGFBP-3/-5: VN and IGF-II: VN interactions demonstrated IGFBP-3/-5 and IGF-II binds VN through the hemopexin-2 domain, and VN binds IGFBP-3 at residues not involved in the binding of IGF-I to IGFBP-3. IGFBP-interacting VN peptides identified from these peptide arrays disrupted the IGF-I: IGFBP: VN complex, impeded the growth of primary tumor-like spheroids and, more importantly, inhibited the invasion of metastatic breast cancer cells in 3D assay systems. These studies provide first-in-field evidence for the utility of small peptides in antagonizing GF: ECM-mediated biologic functions and present data demonstrating the potential of these peptide antagonists as novel therapeutics.
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