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Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland are rare tumours that can be difficult to distinguish from each other and other salivary gland tumour subtypes. Using next-generation sequencing, we identify a recurrent FBXW11 missense mutation (p.F517S) in BCA that is mutually exclusive with the previously reported CTNNB1 p.I35T gain-of-function (GoF) mutation with these mutations collectively accounting for 94% of BCAs. In vitro, mutant FBXW11 is characterised by defective binding to β-catenin and higher protein levels within the nucleus. This is consistent with the increased nuclear expression of β-catenin and activation of the Wnt/β-catenin pathway. The genomic profiles of BCAC are distinct from BCA, with hotspot DICER1 and HRAS mutations and putative driver mutations affecting PI3K/AKT and NF-κB signalling pathway genes. These findings have important implications for the diagnosis and treatment of BCA and BCAC, which, despite histopathologic overlap, may be unrelated entities. Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland are rare tumours. Here the authors report that BCA and BCAC patients possess distinct genomic profiles despite histopathological similarities, and identify a recurrent FBXW11 missense mutation (p.F517S) which leads to accumulation of β-catenin in BCA and higher expression of Wnt/β-catenin targets.

Analysis of mutational signatures is a powerful approach for understanding the mutagenic processes that have shaped the evolution of a cancer genome. Here we present SigProfilerAssignment, a desktop and an online computational framework for assigning all types of mutational signatures to individual samples. SigProfilerAssignment is the first tool that allows both analysis of copy-number signatures and probabilistic assignment of signatures to individual somatic mutations. As its computational engine, the tool uses a custom implementation of the forward stagewise algorithm for sparse regression and nonnegative least squares for numerical optimization. Analysis of 2,700 synthetic cancer genomes with and without noise demonstrates that SigProfilerAssignment outperforms four commonly used approaches for assigning mutational signatures. SigProfilerAssignment is freely available at https://github.com/AlexandrovLab/SigProfilerAssignment with a web implementation at https://cancer.sanger.ac.uk/signatures/assignment/.

The somatic mutations found in a cancer genome are imprinted by different mutational processes. Each process exhibits a characteristic mutational signature, which can be affected by the genome architecture. However, the interplay between mutational signatures and topographical genomic features has not been extensively explored. Here, we integrate mutations from 5,120 whole-genome sequenced tumours from 40 cancer types with 516 topographical features from ENCODE to evaluate the effect of nucleosome occupancy, histone modifications, CTCF binding, replication timing, and transcription/replication strand asymmetries on the cancer-specific accumulation of mutations from distinct mutagenic processes. Most mutational signatures are affected by topographical features with signatures of related aetiologies being similarly affected. Certain signatures exhibit periodic behaviours or cancer-type specific enrichments/depletions near topographical features, revealing further information about the processes that imprinted them. Our findings, disseminated via COSMIC, provide a comprehensive online resource for exploring the interactions between mutational signatures and topographical features across human cancer. biorxiv;2022.05.29.493921v2/FIGU1F1figu1 Comprehensive topography analysis of mutational signatures encompassing 82,890,857 somatic mutations in 5,120 whole-genome sequenced tumours integrated with 516 tissue-matched topographical features from the ENCODE project.The accumulation of somatic mutations from most mutational signatures is affected by nucleosome occupancy, histone modifications, CTCF binding sites, transcribed regions, or replication strand/timing.Mutational signatures with related aetiologies are consistently characterized by similar genome topographies across tissue types.Topography analysis allows both separating signatures from different aetiologies and understanding the genomic specificity of clustered somatic mutations.A comprehensive online resource, disseminate through the COSMIC signatures database, that allows researchers to explore the interactions between somatic mutational processes and genome architecture within and across cancer types. Comprehensive topography analysis of mutational signatures encompassing 82,890,857 somatic mutations in 5,120 whole-genome sequenced tumours integrated with 516 tissue-matched topographical features from the ENCODE project. The accumulation of somatic mutations from most mutational signatures is affected by nucleosome occupancy, histone modifications, CTCF binding sites, transcribed regions, or replication strand/timing. Mutational signatures with related aetiologies are consistently characterized by similar genome topographies across tissue types. Topography analysis allows both separating signatures from different aetiologies and understanding the genomic specificity of clustered somatic mutations. A comprehensive online resource, disseminate through the COSMIC signatures database, that allows researchers to explore the interactions between somatic mutational processes and genome architecture within and across cancer types.

Wnt signalling must be ‘just right’ to promote tumour growth. Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland are rare tumours that can be difficult to distinguish from each other and other salivary gland tumour subtypes. Due to their rarity, the genetic profiles of BCA and BCAC have not been extensively explored. Using whole-exome and transcriptome sequencing of BCA and BCAC cohorts, we identify a novel recurrent FBXW11 missense mutation (p.F517S) in BCA, that was mutually exclusive with the previously reported CTNNB1 p.I35T gain-of-function (GoF) mutation. These driver events collectively accounted for 94% of BCAs. In vitro, mutant FBXW11 had a dominant negative affect, characterised by defective binding to β-catenin and the accumulation of β-catenin in cells. This was consistent with the nuclear expression of β-catenin observed in BCA cases harbouring the FBXW11 p.F517S mutation and activation of the Wnt/β-catenin pathway. The genomic profiles of BCAC were distinct from BCA, with hotspot DICER1 and HRAS mutations and putative driver mutations affecting PI3K/AKT and NF-κB signalling pathway genes. A single BCAC, which may represent a malignant transformation of BCA, harboured the recurrent FBXW11 mutation. These findings have important implications for the diagnosis and treatment of BCA and BCAC, which, despite histopathologic overlap, may be unrelated entities.

Hand-wrist bone age assessment methods are not possible on typical EOS 2D/3D images without body position modifications that may affect spinal position. We aimed to identify and assess lesser known bone age assessment alternatives that may be applied retrospectively and without the need for extra imaging. After review of 2857 articles, nine bone age methods were selected and applied retrospectively in pilot study (thirteen individuals), followed by evaluation of EOS images of 934 4-24-year-olds. Difficulty of assessment and time taken were recorded, and reliability calculated. Five methods proved promising after pilot study. Risser 'plus' could be applied with no difficulty in 89.5% of scans (836/934) followed by the Oxford hip method (78.6%, 734/934), cervical (79.0%, 738/934), calcaneus (70.8%, 669/934) and the knee (68.2%, 667/934). Calcaneus and cervical methods proved to be fastest at 17.7s (95% confidence interval, 16.0s to 19.38s & 26.5s (95% CI, 22.16s to 30.75s), respectively, with Oxford hip the slowest at 82.0 s (95% CI, 76.12 to 87.88s). Difficulties included: regions lying outside of the image-assessment was difficult or impossible in upper cervical vertebrae (46/934 images 4.9%) and calcaneus methods (144/934 images, 15.4%); position: lower step length was associated with difficult lateral knee assessment & head/hand position with cervical evaluation; and resolution: in the higher stages of the hip, calcaneal and knee methods. Hip, iliac crest and cervical regions can be assessed on the majority of EOS scans and may be useful for retrospective application. Calcaneus evaluation is a simple and rapidly applicable method that may be appropriate if consideration is given to include full imaging of the foot.

Background Scoliosis is a complex three-dimensional deformity. While the frontal profile is well understood, increasing attention has turned to balance in the sagittal plane. The present study evaluated changes in sagittal spino-pelvic parameters in a large Hungarian population with adolescent idiopathic scoliosis. Methods EOS 2D/3D images of 458 scoliotic and 69 control cases were analyzed. After performing 3D reconstructions, the sagittal parameters were assessed as a whole and by curve type using independent sample t test and linear regression analysis. Results Patients with scoliosis had significantly decreased thoracic kyphosis ( p  < 0.001) with values T1–T12, 34.1 ± 17.1 o vs. 43.4 ± 12.7 o in control; T4–T12, 27.1 ± 18.8 o vs. 37.7 ± 15.1 o in control; and T5–T12, 24.9 ± 15.8 o vs. 32.9 ± 15.0 o in control. Changes in thoracic kyphosis correlated with magnitude of the Cobb angle ( p  < 0.001). No significant change was found in lumbar lordosis and the pelvic parameters. After substratification according to the Lenke classification and individually evaluating subgroups, results were similar with a significant decrease in only the thoracic kyphosis. A strong correlation was seen between sacral slope, pelvic incidence, and lumbar lordosis, and between pelvic version and thoracic kyphosis in control and scoliotic groups, whereas pelvic incidence was also seen to be correlated with thoracic kyphosis in scoliosis patients. Conclusion Adolescent idiopathic scoliosis patients showed a significant decrease in thoracic kyphosis, and the magnitude of the decrease was directly related to the Cobb angle. Changes in pelvic incidence were minimal but were also significantly correlated with thoracic changes. Changes were similar though not identical to those seen in other Caucasian studies and differed from those in other ethnicities. Scoliotic curves and their effect on pelvic balance must still be regarded as individual to each patient, necessitating individual assessment, although changes perhaps can be predicted by patient ethnicity.

Despite the widespread trends of secularization in the 20th century, religion has played an important role in several outbreaks of genocide since the First World War. And yet, not many scholars have looked either at the religious aspects of modern genocide, or at the manner in which religion has taken a position on mass killing. This collection of essays addresses this hiatus by examining the intersection between religion and state-organized murder in the cases of the Armenian, Jewish, Rwandan, and Bosnian genocides. Rather than a comprehensive overview, it offers a series of descrete, yet closely related case studies, that shed light on three fundamental aspects of this issue: the use of religion to legitimize and motivate genocide; the potential of religious faith to encourage physical and spiritual resistance to mass murder; and finally, the role of religion in coming to terms with the legacy of atrocity.