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• Vanderbilt Genome-Electronic Records (VGER) Project: QRS Duration

  An important potential enabling resource for Personalized Medicine is the combination of a DNA repository with Electronic Medical Record (EMR) systems sufficiently robust to provide excellence in clinical care and to serve as resources for analysis of disease susceptibility and therapeutic outcomes across patient populations. The Vanderbilt EMR is a state of the art clinical and research tool (that includes >1.7 million records), and is associated with a DNA repository which has been in development for over 3 years; these are the key components of VGER, the Vanderbilt Genome-Electronic Records project, a part of NHGRI's eMERGE network. The VGER model acquires DNA from discarded blood samples collected from routine patient care, and can link these to de-identified data extracted and readily updated from the EMR. The phenotype we analyze here is the QRS duration on the electrocardiogram, since slow conduction (indicated by longer QRS duration) is a marker of arrhythmia susceptibility.

  Study phs000188

• ALLELE Consortium Glioblastoma Project

  Glioblastoma patient samples were sequenced for this project. The purposes of this project are: (1) to establish an umbrella protocol as a mechanism for identifying patients (in the USA and international sites) who agree to the collection, storage, and broad usage of their specimens and ongoing collection, and review of their medical information for the purposes of minimal-risk research and use of such data in clinical trials on which the patient may enroll; (2) to develop operations that facilitate investigator access to the data and/or tissue to conduct research, while minimizing risks to participants and promoting responsible conduct; and (3) to provide the infrastructure for the sharing of de-identified, coded samples, clinical data, and genomic data between participating investigators and institutions. Eligible patients include patients with known or suspected nervous system tumors or other neurologic diseases. Whole exome sequencing from the stated project will be released under this submission.

  Study phs003000

• Direct genetic transformation bypasses tumor-associated DNA methylation alterations

  Tumors represent dynamically evolving populations of mutant cells, and many advances have been made in understanding the biology of their progression. However, key unresolved questions remain about the conditions that support their initial transformation, which cannot be easily captured in patient populations but are instead modeled using transgenic cellular or animal systems. Here, we used extensive patient atlas data to define common features of the tumor DNA methylation landscape as they compare to healthy human cells and used this benchmark to screen 21 engineered human and mouse models for their ability to reproduce these patterns. Notably, we find that genetically induced cellular transformation can trigger global changes in DNA methylation levels that are consistent with extensive proliferation but rarely recapitulate the widespread de novo methylation of Polycomb targets as found in clinical samples. Our results raise pertinent questions about the relationship between genetic and epigenetic aspects of tumorigenesis and provide an important molecular reference for evaluating existing as well as newer tumor models.

  Study EGAS50000000902

• RNA-seq from human embryonic tissues (additional samples 2018)

  How the genome activates or silences transcriptional programmes governs organ formation. Little is known about this in human post-implantation embryos undermining our ability to benchmark the fidelity of in vitro stem cell differentiation or cell programming, or interpret noncoding variation as potential causes of disease. Here, by studying histone modification we identified genome-wide open chromatin states and active repression across thirteen tissues during human organogenesis. We integrated the data with transcription to build the first view of how promoter states from nearly 20,000 genes differentially regulate alternative organ fates, arguing against bivalency during human organogenesis. The data illustrate tissue-specific as well as complex patterns of enhancer activity functional in zebrafish and impute master transcription factors. Overlaying 739 noncoding de novo mutations in patients allowed phenotypic correlation of developmental disorders to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for understanding normal and abnormal human development.

  Study EGAS00001003738

• A microRNA-signature that correlates with cognition and is a target against cognitive decline

  While some individuals age without pathological memory impairments, others develop age-associated cognitive diseases. Since changes in cognitive function develop slowly over time in these patients, they are often diagnosed at an advanced stage of molecular pathology, a time point when causative treatments fail. Thus, there is great need for the identification of inexpensive and minimal invasive approaches that could be used for screening with the aim to to identify individuals at risk for cognitive decline that can then undergo further diagnostics and eventually stratified therapies. In this study we use an integrative approach combining the analysis of human data and mechanistic studies in model systems to identify a circulating 3-microRNA signature that reflect key processes linked to neural homeostasis and informs about cognitive status. We furthermore provide evidence that expression changes of this signature represent multiple mechanisms de-regulated in the aging and diseased brain and are a suitable target for RNA therapeutics.

  Study EGAS00001005627

• Blood DNA Methylation in Post-Acute Sequelae of COVID-19 (PASC): a Prospective Cohort Study

  Background: DNA methylation integrates environmental signals with transcriptional programs. COVID-19 infection induces changes in the host methylome. While post-acute sequelae of COVID-19 (PASC) is a long-term complication of acute illness, its association with DNA methylation is unknown. No universal blood marker of PASC, superseding single organ dysfunctions, has yet been identified. Methods: In this single center prospective cohort study, PASC, post-COVID without PASC, and healthy participants were enrolled to investigate their symptoms association with peripheral blood DNA methylation data generated with state-of-the-art whole genome sequencing (WGS). PASC-induced quality-of-life deterioration was scored with a validated instrument, SF-36. Analyses were conducted to identify potential functional roles of differentially methylated loci, and machine learning algorithms were used to resolve PASC severity. Findings: 103 patients with PASC (22.3% male, 77.7% female), 15 patients with previous COVID-19 infection but no PASC (40.0% male, 60.0% female), and 27 healthy volunteers (48.1% male, 51.9% female) were enrolled. Whole genome methylation sequencing revealed 39 differentially methylated regions (DMRs) specific to PASC, each harboring an average of 15 consecutive positions, that differentiate patients with PASC from the two control groups. Motif analyses of PASC-regulated DMRs identify binding domains for transcription factors regulating circadian rhythm and others. Some DMRs annotated to protein coding genes were associated with changes of RNA expression. Machine learning support vector algorithm and random forest hierarchical clustering reveal 28 unique differentially methylated positions (DMPs) in the genome discriminating patients with better and worse quality of life.

  Study phs003658

• Circulating tumor DNA dynamics reveal KRAS G12C mutation heterogeneity and response to treatment with the KRAS G12C inhibitor divarasib in solid tumors

  Purpose: To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study. Experimental design: Plasma samples were collected for serial ctDNA profiling at baseline (Cycle 1 Day 1 prior to treatment) and multiple on-treatment time points (Cycle 1 Day 15 and Cycle 3 Day 1). Results: KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non-small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as Cycle 1 Day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction. Conclusion: Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.

  Study EGAS50000000315

• Comprehensive genomic analysis of colorectal cancer with microsatellite instability

  Microsatellite instability-high (MSI-H) colorectal cancers (CRCs) account for 10?15% of all CRCs. MSI-H CRC is characterized by a large number of somatic insertions/deletions (indels) resulting from either mutations within or the silencing of genes involved in the DNA mismatch repair (MMR) system. A subset of MSI-H CRCs is associated with Lynch syndrome (LS), which is caused by germline MMR gene mutations, leading to hereditary cancer predisposition. Other than frequent somatic mutations in BRAF, the transformation mechanisms underlying MSI-H CRC are largely unknown. Here, genomic DNA from 149 MSI-H CRC specimens was analyzed using whole-exome sequencing, and 93 of these samples were subjected to genome-wide DNA methylation analysis. Furthermore, transcriptome sequencing was conducted on 111 samples. Genomic/epigenomic analyses identified three subgroups within our cohort: (1) MSI-H CRCs with silenced MLH1 that share frequent indels, a specific mutation/copy number alteration profile and promoter DNA methylation; (2) LS-associated MSI-H CRCs with MMR genes containing germline mutations; and (3) the remaining MSI-H CRCs with frequent somatic disruptive mutations of MLH1 or MSH2. Unexpectedly, only the first group was found to frequently carry fusion-type protein kinases (15% of this group and 9.9% of all MSI-H CRCs) that are promising therapeutic targets. Thus, MSI-H CRCs can be classified into three subgroups with distinctive genomic as well as epigenomic statuses, probably reflecting the oncogenic processes of these cancers. Fusion-type kinases are enriched in MSI-H CRCs, shedding new light on potential treatment strategies.

  Study JGAS000113

• Neoadjuvant immunotherapy leads to pathological responses in MMR proficient and MMR deficient early stage colon cancers

  PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.

  Study EGAS00001004160

• Single-cell transcriptomic profiling of hepatoblastoma tumor organoids

  10X Genomics single-cell transcriptomic profiling of hepatoblastoma tumor organoids using Chromium Next GEM Single-Cell 3’ Reagent Kits v3.1 or 3’ CellPlex Multiplexing Kit. Single-cell transcriptomics data (bam files) of hepatoblastoma tumor organoids: 3E, 8F1, 10F2, 13F2, 13F2 late, 13E, 17E, 17F1, 22E, 27F1, 28F1, 31E, 96F1, 121E and 135. Single-cell solutions were obtained from fresh organoid samples using enzymatic digestion.

  Dataset EGAD50000000796