From widespread faulting to localised rifting: Evidence from K-Ar fault gouge dates from the Norwegian North Sea rift shoulder

Although seismic and stratigraphic well information put tight constraints on rift basin evolution, eroded rift shoulders commonly expose polydeformed prerift basement whose deformation history may be difficult to constrain. In this work, we apply K-Ar dating of fault gouge samples from 18 faults to explore the brittle deformation of the well-exposed eastern rift margin to the northern North Sea rift. We find evidence of clay gouge formation since the Late Devonian, with distinct Permian and Jurassic fault activity peaks that closely match early stages of the two well-established North Sea rift phases. A marked decay in fault density away from the rift margin confirms a close relationship between rifting and onshore faulting. The results show that initial rift-related extension affected a much wider area than the resulting offshore rift. Hence our data support a rift model where strain is initially distributed over a several 100 km wide region, as a prelude to the development of the ~150–200 km wide Permo-Triassic northern North Sea rift as defined by large marginal faults. Towards the end of the second rift phase, strain localises even more strongly to the 25–50 km wide Viking Graben. Interestingly, a period of early widespread extension is seen for both phases of North Sea rifting and may be a general characteristic of continental rifting. The documented prerift faulting and fracturing of the basement since the Devonian weakened the basement and probably facilitated the widespread initial extension that subsequently localised to form the northern North Sea rift, with further localisation to its relatively narrow central part (Viking Graben).publishedVersio

Somatic mutations in acute promyelocytic leukemia (APL) identified by exome sequencing.

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Identification of recurring tumor-specific somatic mutations in acute myeloid leukemia by transcriptome sequencing.

Genetic lesions are crucial for cancer initiation. Recently, whole genome sequencing, using next generation technology, was used as a systematic approach to identify mutations in genomes of various types of tumors including melanoma, lung and breast cancer, as well as acute myeloid leukemia (AML). Here, we identify tumor-specific somatic mutations by sequencing transcriptionally active genes. Mutations were detected by comparing the transcriptome sequence of an AML sample with the corresponding remission sample. Using this approach, we found five non-synonymous mutations specific to the tumor sample. They include a nonsense mutation affecting the RUNX1 gene, which is a known mutational target in AML, and a missense mutation in the putative tumor suppressor gene TLE4, which encodes a RUNX1 interacting protein. Another missense mutation was identified in SHKBP1, which acts downstream of FLT3, a receptor tyrosine kinase mutated in about 30% of AML cases. The frequency of mutations in TLE4 and SHKBP1 in 95 cytogenetically normal AML patients was 2%. Our study demonstrates that whole transcriptome sequencing leads to the rapid detection of recurring point mutations in the coding regions of genes relevant to malignant transformation

Genomic 5-hydroxymethylcytosine levels correlate with <em>TET2 </em>mutations and a distinct global gene expression pattern in secondary acute myeloid leukemia.

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Monoallelic <em>CEBPA</em> mutations in normal karyotype acute myeloid leukemia: Independent favorable prognostic factor within <em>NPM1</em> mutated patients.

We and others have shown that cytogenetically normal (CN)-AML patients with biallelic CEBPA gene mutations (biCEBPA) represent a molecularly distinct group with a favorable prognosis. Patients carrying a monoallelic CEBPA mutation (moCEBPA), however, show no different outcome compared to patients with wildtype CEBPA, and these mutations are frequently associated with mutated NPM1 or FLT3-ITD. So far, no molecular or clinical hallmark has been identified to prognostically distinguish moCEBPA patients from patients with wildtype CEBPA. Therefore, we used the data of 663 CN-AML patients treated within the AMLCG 1999 trial to explore the prognostic value of moCEBPA in the context of concomitant clinical and molecular markers (mutated NPM1, FLT3-ITD). Multiple Cox regression in 515 patients adjusting for all available potential confounders revealed that the NPM1 mutation modified the prognostic value of moCEBPA with respect to overall survival (OS, p = 0.017) and event-free survival (EFS, p = 0.011). MoCEBPA was beneficial in NPM1 mutated patients: adjusted OS-hazard ratio (HR) 0.09, 95% confidence interval (CI) 0.01-0.63, p = 0.016; EFS-HR (95% CI) 0.16 (0.04-0.65), p = 0.010. In contrast, moCEBPA had no prognostic impact in patients with wildtype NPM1: OS-HR (95% CI) 1.08 (0.59-1.97), p = 0.804; EFS-HR (95% CI) 1.12 (0.64-1.96), p = 0.682. We found no prognostic effect modification for moCEBPA by FLT3-ITD. The presence of a moCEBPA mutation was shown to be associated with prolonged survival in NPM1 mutated CN-AML patients. Confirmation of these results in larger studies will clarify whether an additional moCEBPA mutation influences the risk stratification of patients with an NPM1 mutated/FLT3-ITD positive genotype