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• Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

  Follicular lymphoma (FL) is an incurable B-cell malignancy characterized by the t(14;18) and mutations in one or more components of the epigenome. Whilst frequent gene mutations in signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlap with the closely-related diffuse large B cell lymphoma (DLBCL). A combination of discovery exome and extended targeted sequencing revealed recurrent somatic mutations in RRAGC uniquely enriched in FL patients (17%). More than half of the mutations preferentially co-occurred with ATP6V1B2 and ATP6AP1 mutations, components of the vacuolar H+-adenosine triphosphate ATPase (v-ATPase) known to be necessary for amino acid-dependent mTORC1 activation. RagC mutants increased raptor binding whilst rendering mTORC1 signaling resistant to amino acid deprivation through nucleotide-independent mechanisms. Collectively, the activating nature of the RRAGC mutations, their existence within the dominant clone and stability during disease progression supports their potential as an excellent candidate to be therapeutically exploited.

  Study EGAS00001001190

• whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases

  Esophageal cancer is one of the most aggressive cancers and the sixth leading cause of cancer death worldwide1. Approximately 70% of the global esophageal cancers occur in China and over 90% histopathological forms of this disease are esophageal squamous cell carcinoma (ESCC)2-3. Currently, there are limited clinical approaches for early diagnosis and treatment for ESCC, resulting in a 10% 5-year survival rate for the patients. Meanwhile, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we show a comprehensive genomic analysis in 158 ESCC cases, as part of the International Cancer Genome Consortium (ICGC) Research Projects (http://icgc.org/icgc/cgp/72/371/1001734). We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases and additional 70 ESCC cases were subjected to array comparative genomic hybridization (a-CGH) analysis.

  Study EGAS00001000709

• Real-time response profiling through serial plasma analyses during FOLFOX treatment in patients with colorectal cancer

  Response evaluation of cancer therapeutics relies on the assessment of the change in tumor burden, which is performed in accordance with defined criteria every 8-12 weeks. However, predictive factors for response are not available for the majority of patients with advanced stage colorectal cancer. Here we show that measurement of circulating tumor DNA (ctDNA) levels during one of the most commonly administered drug regimens, i.e. FOLFOX, allows an early, real-time assessment of treatment response. During the 48-hour FOLFOX application, we serially assessed plasma DNA and observed that ctDNA levels initially decreased during the first 23 hours. In patients with stable disease or partial response, ctDNA levels remained low, whereas in patients with progressive disease, ctDNA levels increased at the end of the treatment cycle predicting clinical and radiologic response correctly. Hence, ctDNA monitoring during treatment may contribute to an early outcome prediction with significant implications for the management of patients.

  Study EGAS00001004213

• Early evolutionary branching across spatial domains predisposes to clonal replacement under chemotherapy in neuroblastoma

  Neuroblastoma (NB) is one of the most lethal childhood cancers due its propensity to treatment resistance. By spatial mapping of subclone geographies before and after chemotherapy across 89 tumor regions from 12 NBs, we find that densely packed territories of closely related subclones present at diagnosis are replaced under effective treatment by islands of distantly related survivor subclones, originating from a different most recent ancestor compared to lineages dominating before treatment. Conversely, in tumors that progressed under treatment, ancestors of subclones dominating later in disease are present already at diagnosis. Chemotherapy treated xenografts and cell culture models replicates these two contrasting scenarios and shows branching evolution to be a constant feature of proliferating NB cells. Phylogenies based on whole genome sequencing of 505 individual NB cells indicate that a rich repertoire of parallel subclones, emerges already with the first oncogenic mutations and lays the foundation for clonal replacement under treatment.

  Study EGAS00001007650

• Cross-species Comparison Reveals Therapeutic Vulnerabilities Halting Glioblastoma Progression

  The growth of a tumor is tightly linked to the distribution of its cells along a continuum of activation states. Here, we systematically decode the activation state architecture (ASA) in a glioblastoma (GBM) patient cohort through comparison to adult murine neural stem cells. Modelling of these data forecast how tumor cells organize to sustain growth and identifies rate of activation as the main predictor of growth. Accordingly, patients with a higher quiescence fraction exhibit improved outcomes. Further, DNA methylation arrays enable ASA- related patient stratification. Comparison of healthy and malignant gene expression dynamics reveals dysregulation of the Wnt- antagonist SFRP1 at the quiescence to activation transition. SFRP1 overexpression renders GBM quiescent and increases overall survival of tumor-bearing mice. Surprisingly, it does so through reprogramming the tumor’s stem-like methylome into an astrocyte- like one. Our findings offer a framework for patient stratification with prognostic value, biomarker identification, and therapeutic avenues to halt GBM progression.

  Study EGAS00001008155

• The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

  Use single cell whole genome sequencing data from one iAMP21 patient SJBALL021901 to study the clonal evolution of iAMP21.

  Study EGAS00001006796

• Parkinson's Disease Cognitive Genetics Consortium (PDCGC) Stage I, NeuroX Dataset

  Cognitive impairment is a common and disabling problem in Parkinson's disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We are presently undertaking a large-scale, two-stage study designed to identify genetic risk factors for cognitive impairment in PD. The study population is divided into a discovery (Stage I) and a validation (Stage II) sample of patients enrolled in the PD Cognitive Genetics Consortium (PDCGC). Each patient has undergone a detailed neurological evaluation and cognitive testing. Clinical and genetic data for the project are stored and managed at the Coordinating Center at the University of Washington and VA Puget Sound Health Care System in Seattle. Stage I of the project is now complete; 1,219 PD patients were genotyped for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), working memory/executive function (Letter-Number Sequencing and Trail Making Test [TMT] A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation [JoLO]), and global cognitive function (Montreal Cognitive Assessment). We excluded individuals who were of non-European ancestry, failed genotyping, were missing data for one or more covariates, were related to another participant in the cohort, or failed to complete at least half of the cognitive tests. After these quality control measures were implemented, 1,105 participants remained and were included in all subsequent analyses. For common variants we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate corrected P-value (PFDR) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; PFDR = 2.7 x 10-4) for JoLO, PARP4 rs9318600 (PFDR = 0.006) and rs9581094 (PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 (PFDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts, and efforts to validate the findings in PDCGC Stage II are in progress.

  Study phs001664

• A Pilot Study of Neoadjuvant Nivolumab, Ipilimumab and Intralesional Oncolytic Virotherapy for HER2-Negative Breast Cancer

  This study was a single arm phase 1 trial that assessed the regimen safety and feasibility as well as tumor response in patients with localized HER2-negative breast cancer treated with talimogene laherparepvec (T-VEC) in combination with nivolumab and ipilimumab. The primary objective was to evaluate the safety and adverse event profile of this treatment combination. Six patients were enrolled, four having relapses after prior neoadjuvant chemotherapy, and two who were previously untreated. One patient had a pathological complete response, three patients had pathological partial responses, one showed no significant response, and one had disease progression. Biopsies demonstrated increased immune cell infiltration in samples from patients who responded to therapy. In this study, the checkpoint blockade immunotherapy combined with T-VEC provided responses in patients with advanced or relapsed HER2-negative breast cancer at the expense of long-term toxicities.

  Study phs003316

• Virtual Growing Child 5-Dimensional Functional Models for Treating Respiratory Anomalies (dMRI-VGC)

  Objectives We are sharing a database of dynamic magnetic resonance imaging (dMRI) scans of normal children, which can serve as a reference standard to quantify regional respiratory abnormalities in young patients with various respiratory conditions and facilitate treatment planning and response assessment. The database can also be useful to advance future AI-based research on image-based object segmentation and analysis. Background In pediatric patients with respiratory abnormalities, it is important to understand the alterations in regional dynamics of the lungs and other thoracoabdominal components, which in turn requires a quantitative understanding of what is considered as normal in healthy children. Currently, such a normative database of regional respiratory structure and function in healthy children does not exist. Participants 200 normal children (ages 6-18 years) participated in our research study related to this dataset. DesignThe shared open-source normative database is from our ongoing virtual growing child (VGC) project, which includes 4D dMRI images representing one breathing cycle for each normal child and also segmentations of 10 objects at end expiration (EE) and end inspiration (EI) phases of the respiratory cycle in the 4D image. The lung volumes at EE and EI as well as the excursion volumes of chest wall and diaphragm from EE to EI, left and right sides separately, are also reported. The database has thus 4,000 3D segmentations from 200 normal children in total. The database is unique and provides dMRI images, object segmentations, and quantitative regional respiratory measurement parameters of volumes for normal children. All dMRI scans are acquired from normal children during free-breathing. The dMRI acquisition protocol was as follows: 3T MRI scanner (Verio, Siemens, Erlangen, Germany), true-FISP bright-blood sequence, TR=3.82 ms, TE=1.91 ms, voxel size ~1×1×6 mm3, 320×320 matrix, bandwidth 258 Hz, and flip angle 76o. With recent advances, for each sagittal location across the thorax and abdomen, we acquired 40 2D slices over several tidal breathing cycles at ~480 ms/slice. On average, 35 sagittal locations are imaged, yielding a total of ~1400 2D MRI slices, with a resulting total scan time of 11-13 minutes for any particular study participant.The collected dMRI scan data then went through the procedure of 4D image construction, image processing, object segmentation, and volumetric measurements from segmentations. 4D image construction: For the acquired dMRI scans, we utilized an automated 4D image construction approach to form one 4D image over one breathing cycle (consisting of typically 5-8 respiratory phases) from each acquired dMRI scan to represent the whole dynamic thoraco-abdominal body region. The algorithm selects 175-280 slices (35 sagittal locations × 5-8 respiratory phases) from the 1400 acquired slices in an optimal manner using an optical flux method. Image processing: Intensity standardization is performed on every time point/3D volume of the 4D image so that image values have the same tissue-specific meaning across all subjects. Object segmentation: For each subject, there are 10 objects segmented at both EE and EI time points in this database. They include the thoracoabdominal skin outer boundary, left and right lungs, liver, spleen, left and right kidneys, diaphragm, and left and right hemi-diaphragms. All dMRI scans utilize large field of view images, which include the full thorax and abdomen to the inferior aspect of the kidneys in the sagittal plane. We used a pretrained U-Net based deep learning network to first segment all objects, and then all auto-segmentation results were visually checked and manually refined as needed, under the supervision of a radiologist with over 25 years of expertise in MRI and thoracoabdominal radiology. Manual segmentations have been performed for all objects in all datasets. Volumetric measurements based on object segmentations for lung volumes (left and right separately) at EE and EI, as well as for chest wall and diaphragm excursion volumes (left and right separately) are reported. ConclusionsThe provided database is unique and provides dMRI images, object segmentations, and quantitative regional respiratory measurement parameters of volumes for normal children. The database has 4,000 3D segmentations from 200 normal children, which to our knowledge is the largest and only such dMRI dataset to date. All images and object segmentations are saved in DICOM. All DICOM files (176,574 in total) have been anonymized, and PHI has been removed. The database can be used as a reference standard to quantify regional respiratory abnormalities in young patients with various respiratory conditions and facilitate treatment planning and response assessment. The large amount of object segmentations can potentially benefit AI-based research on image-based object segmentation and analysis.

  Study phs004002

• Mucociliary Clearance Consortium (MCC) Longitudinal Study of Primary Ciliary Dyskinesia: Participants 5-18 Years of Age

  The purpose of this longitudinal study protocol is to define age-related prevalence of phenotypic characteristics and the progression of key features of lung disease in participants with one of these disorders, Primary Ciliary Dyskinesia (PCD). In PCD, the abnormal structure and function of cilia results in impaired clearance of secretions and consequent obstruction and chronic recurrent infection in the airways, sinuses and middle ears. Although it seems likely that the onset of PCD airway disease occurs early in childhood, as has been reported for cystic fibrosis (CF), the clinical course of PCD lung disease is not well defined, nor, is the time course of emergence of specific microbial pathogens, or the age of onset and rate of progression of airway disease and bronchiectasis. This longitudinal study is designed to define the rate of progression of PCD lung function in participants between 5-18 years of age using spirometry which tracks well with lung impairment and prognosis in other disorders of the airways such as cystic fibrosis. This longitudinal protocol will also systematically track other specific outcomes, including pathogens infecting the airways (assessed by respiratory cultures), and age at onset and progression of airway damage and bronchiectasis (assessed by high-resolution computerized tomography, HRCT, of the chest). Blood will be collected for DNA to test for genetic mutations. The blood samples will be processed to establish a cell line (lymphocyte transformation) for a source of DNA for future genetic studies, in participants with disease. For participants unable to provide a blood sample, a buccal sample will be obtained for DNA.

  Study phs000596