Mutational dynamics and immune evasion in diffuse large B-cell lymphoma explored in a relapse-enriched patient series

Peer reviewe

Attenuation correction in PET/MR: A performance assessment of UTE-based and Dixon-based methods for PET attenuation correction

Hybrid positron emission tomography/magnetic resonance imaging (PET/MR) scanners are one of the latest tools available in the field of medical imaging, and are expected to outperform the well-established PET/X-ray computed tomography (CT) scanners in a large range of fields. The perhaps largest challenge that has to be overcome before this can be achieved, is that of attenuation correction (AC) of the acquired PET images, as there is no direct relation between the MR image intensity of a tissue and its attenuating properties, as is the case in CT.This study investigated the performance of two PET AC methods provided with the biograph mMR PET/MR scanner installed at St. Olavs Hospital (Trondheim, Norway); one for head imaging based on an ultra-short echo-time (UTE) sequence, and one for whole-body imaging based on a Dixon sequence. These AC methods were compared to the `gold standard' of CT-based AC, based on activity concentrations in PET images from mMR examinations of lymphoma and lung cancer patients, corrected with the different AC methods (UTE, Dixon and CT).The results of the study show that the UTE-based AC method leads to an underestimation of PET activity in the brain of up to 9 \% in the investigated regions of interest. This is caused by underestimation of bone in the cranial region. The exclusion of bone in the Dixon-based AC method leads to underestimation of PET activity in the thorax/abdomen, indicated by an underestimation of 4 \% in the liver. The two MR-based AC methods are thus not sufficiently accurate to be utilised for quantification in PET imaging

Image Quality and Detectability in Siemens Biograph PET/MRI and PET/CT Systems - A Phantom study

Background The technology of modern positron emission tomography (PET) systems continuously improving, and with it the possibility to detect smaller lesions. Since first introduced in 2010, the number of hybrid PET/magnetic resonance imaging (MRI) systems worldwide is constantly increasing. It is therefore important to assess and compare the image quality, in terms of detectability, between the PET/MRI and the well-established PET/computed tomography (CT) systems. For this purpose, a PET image quality phantom (Esser) with hot spheres, ranging from 4 to 20 mm in diameter, was prepared with fluorodeoxyglucose and sphere-to-background activity concentrations of 8:1 and 4:1, to mimic clinical conditions. The phantom was scanned on a PET/MRI and a PET/CT system for both concentrations to obtain contrast recovery coefficients (CRCs) and contrast-to-noise ratios (CNRs), for a range of reconstruction settings. The detectability of the spheres was scored by three human observers for both systems and concentrations and all reconstructions. Furthermore, the impact of acquisition time on CNR and observer detectability was investigated. Results Reconstructions applying point-spread-function modeling (and time-of-flight for the PET/CT) yielded the highest CRC and CNR in general, and PET/CT demonstrated slightly higher values than PET/MRI for most sphere sizes. CNR was dependent on reconstruction settings and was maximized for 2 iterations, a pixel size of less than 2 mm and a 4 mm Gaussian filter. Acquisition times of 97 s (PET/MRI) and 150 s (PET/CT) resulted in similar total net true counts. For these acquisition times, the smallest detected spheres by the human observers in the 8:1 activity concentration was the 6-mm sphere with PET/MRI (CNR = 5.6) and the 5-mm sphere with PET/CT (CNR = 5.5). With an acquisition time of 180 s, the 5-mm sphere was also detected with PET/MRI (CNR = 5.8). The 8-mm sphere was the smallest detected sphere in the 4:1 activity concentration for both systems. Conclusion In this experimental study, similar detectability was found for the PET/MRI and the PET/CT, although for an increased acquisition time for the PET/MRI

Personal Cancer Genome Reporter: Variant interpretation report for precision oncology

Summary Individual tumor genomes pose a major challenge for clinical interpretation due to their unique sets of acquired mutations. There is a general scarcity of tools that can (i) systematically interrogate cancer genomes in the context of diagnostic, prognostic, and therapeutic biomarkers, (ii) prioritize and highlight the most important findings and (iii) present the results in a format accessible to clinical experts. We have developed a stand-alone, open-source software package for somatic variant annotation that integrates a comprehensive set of knowledge resources related to tumor biology and therapeutic biomarkers, both at the gene and variant level. Our application generates a tiered report that will aid the interpretation of individual cancer genomes in a clinical setting. Availability and implementation The software is implemented in Python/R, and is freely available through Docker technology. Documentation, example reports, and installation instructions are accessible via the project GitHub page: https://github.com/sigven/pcgr. Supplementary information Supplementary data are available at Bioinformatics online

Personal Cancer Genome Reporter: Variant interpretation report for precision oncology

Individual tumor genomes pose a major challenge for clinical interpretation due to their unique sets of acquired mutations. There is a general scarcity of tools that can (i) systematically interrogate cancer genomes in the context of diagnostic, prognostic, and therapeutic biomarkers, (ii) prioritize and highlight the most important findings and (iii) present the results in a format accessible to clinical experts. We have developed a stand-alone, open-source software package for somatic variant annotation that integrates a comprehensive set of knowledge resources related to tumor biology and therapeutic biomarkers, both at the gene and variant level. Our application generates a tiered report that will aid the interpretation of individual cancer genomes in a clinical setting

Sample-Index Misassignment Impacts Tumour Exome Sequencing

Sample pooling enabled by dedicated indexes is a common strategy for cost-effective and robust high-throughput sequencing. Index misassignment leading to mutual contamination between pooled samples has however been described as a general problem of the latest Illumina sequencing instruments utilizing exclusion amplification. Using real-life data from multiple tumour sequencing projects, we demonstrate that index misassignment can induce artefactual variant calls closely resembling true, high-quality somatic variants. These artefactual calls potentially impact cancer applications utilizing low allelic frequencies, such as in clonal analysis of tumours. We discuss the available countermeasures with an emphasis on improved library indexing methods, and provide software that can assist in the identification of variants that may be consequences of index misassignment

Sample-Index Misassignment Impacts Tumour Exome Sequencing

Abstract Sample pooling enabled by dedicated indexes is a common strategy for cost-effective and robust high-throughput sequencing. Index misassignment leading to mutual contamination between pooled samples has however been described as a general problem of the latest Illumina sequencing instruments utilizing exclusion amplification. Using real-life data from multiple tumour sequencing projects, we demonstrate that index misassignment can induce artefactual variant calls closely resembling true, high-quality somatic variants. These artefactual calls potentially impact cancer applications utilizing low allelic frequencies, such as in clonal analysis of tumours. We discuss the available countermeasures with an emphasis on improved library indexing methods, and provide software that can assist in the identification of variants that may be consequences of index misassignment

Integrative genomic analysis of peritoneal malignant mesothelioma: Understanding a case with extraordinary chemotherapy response

Peritoneal malignant mesothelioma is a rare disease with a generally poor prognosis and poor response to chemotherapy. To improve survival there is a need for increased molecular understanding of the disease, including chemotherapy sensitivity and resistance. We here present an unusual case concerning a young woman with extensive peritoneal mesothelioma who had a remarkable response to palliative chemotherapy (platinum/pemetrexed). Tumor samples collected at surgery before and after treatment were analyzed on the genomic and transcriptional levels (exome sequencing, RNA-seq, and smallRNA-seq). Integrative analysis of single nucleotide and copy-number variants, mutational signatures, and gene expression was performed to provide a comprehensive picture of the disease. LATS1/2 were identified as the main mutational drivers together with homozygous loss of BAP1 and PBRM1, which also may have contributed to the extraordinary chemotherapy response. The presence of the S3 mutational signature is consistent with homologous recombination DNA repair defects due to BAP1 loss. Up-regulation of the PI3K/AKT/mTOR pathway after treatment, supported by deactivated PTEN through miRNA regulation, is associated with cancer progression and could explain chemotherapy resistance. The molecular profile suggests potential benefit from experimental targeting of PARP, EZH2, the PI3K/AKT/mTOR pathway and possibly also from immune checkpoint inhibition. In addition to providing the molecular background for this unusual case of peritoneal mesothelioma, the results show the potential value of integrative genomic analysis in precision medicine

ctDNA detected by ddPCR reveals changes in tumour load in metastatic malignant melanoma treated with bevacizumab

Bevacizumab is included in an increasing number of clinical trials. To find biomarkers to predict and monitor treatment response, cancer and angiogenesis relevant mutations in tumour and circulating tumour DNA (ctDNA) were investigated in 26 metastatic melanoma patients treated with bevacizumab. Patients with >1% BRAF/NRAS ctDNA at treatment start had significantly decreased progression free survival (PFS) and overall survival (OS) (PFS: p = 0.019, median 54 vs 774 days, OS: p = 0.026, median 209 vs 1064 days). Patients with >1% BRAF/NRAS ctDNA during treatment showed similar results (PFS: p = 0.002, OS: p = 0.003). ≤1% BRAF/NRAS ctDNA and normal lactate dehydrogenase (LDH) levels both significantly predicted increased response to treatment, but BRAF/NRAS ctDNA was better at predicting response compared to LDH at treatment start (OR 16.94, p = 0.032 vs OR 4.57, p = 0.190), and at predicting PFS (HR 6.76, p = 0.002) and OS (HR 6.78, p = 0.002) during therapy. ctDNA BRAF p.V600D/E/K and NRAS p.G12V/p.Q61K/L/R were better biomarkers for response prediction than TERT promoter mutations (OR 1.50, p = 0.657). Next generation sequencing showed that all patients with ≥2 mutations in angiogenesis-relevant genes had progressive disease, but did not reveal other biomarkers identifying responders. To conclude, ctDNA and LDH are useful biomarkers for both monitoring and predicting response to bevacizumab