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• Perceptions, Prevalence, and Patterns of Cannabis Use among Cancer Patients in NCI-Designated Cancer Centers

  This study aimed to better understand the evolving landscape of cannabis use among patients undergoing cancer treatment across diverse geographic regions. It sought to characterize patterns of use, patient perceptions, and contextual influences such as legal status and provider engagement that affect cannabis use. Given the shifting legal environment, this study addresses a critical gap in the literature by providing data on how cancer patients integrate cannabis into their care. The available delivery methods of cannabis have also undergone dramatic changes and now include edibles, oils, tinctures, topicals, and inhaled forms. State-based policy changes are rapidly changing. Yet research on cannabis use by cancer patients across a variety of geographic settings remains limited. The extent of cannabis use, the perceived and real benefits and risks of use, potential interactions with cancer treatment and other medications, and impact on comorbid conditions are uncertain. Clinicians should be aware of the extent of use in order to assess potential drug-drug interactions, side effects, and contraindications; hence, an understanding of how cancer patients and clinicians engage in discussions about cannabis use is essential. Twelve NCI-designated cancer centers were awarded supplemental funding to conduct surveys assessing cannabis use among recently diagnosed cancer patients. Selected sites were in 8 states with varied legal status for medical and recreational cannabis use at the time of the survey. The 12 cancer centers independently received approval from their institutional review boards (IRB) and collected data from September 2021 to August 2023. Eligible participants were cancer patients or survivors who resided in their respective cancer center's catchment area. Cancer centers were responsible for sampling patients within their catchment area with the goal of 1,000 completed surveys. Ten out of 12 cancer centers drew probability samples of patients from patient lists defining their catchment area with some stratifying the sample in various ways including by cancer type, by sex, by race/ethnicity or by a combination of demographic variables.

  Study phs004046

• McGill Epigenomics Mapping Centre

  The McGill Epigenomics Mapping Centre (EMC) and Data Coordination Centre (EDCC) were established in 2012 at the McGill University and Genome Quebec Innovation Centre (Montreal, Canada) to support large-scale human epigenome mapping for a broad spectrum of cell types and diseases. Previous epigenetic studies have provided profiles of specific chromatin marks in relation to basic biological processes, and future studies of molecular mechanisms must build upon these proofs-of-concept by integrating sequence-based variation with multiple levels of epigenetic and transcriptional regulation across the genome of human tissues and animal disease models. This project leverages the high-throughput sequencing infrastructure and expertise in genomics and transcriptomics at the McGill Innovation Centre to carry out this research. Controlled access to the data by collaborators and the greater scientific community is gained via a portal, which takes advantage of Compute Canada high-performance computing cluster resources to manage the large volume of data associated from the generation of reference epigenome maps. McGill University is one of two Canadian mapping and data coordination centres, the other based at the Michael Smith Genome Sciences Centre in Vancouver, British Columbia. The generation of comprehensive epigenome maps at McGill University is part of a larger international effort that is coordinated by the International Human Epigenome Consortium (IHEC), whose overall long-term objective is to determine the extent to which the epigenome shapes human populations over generations and in response to the environment. This project is funded under the Canadian Epigenetics, Environment, and Health Research Consortium (CEEHRC) by the Canadian Institutes of Health Research and by Genome Quebec, with additional support from Genome Canada. The computing and networking infrastructure, and part of the software development, are provided by Compute Canada and CANARIE.

  Study EGAS00001000995

• Population Structure and Genetic Diversity in Argentinean populations

  Argentina was one of the last places peopled when humans entered the Americas. Its earliest archeological sites are dated from 13,000 years BP, and throughout its history the region has exhibited broad cultural diversity, involving both hunter-gatherer and agro-pastoral societies, different linguistic families, the Southern expansion of the Inca Empire, the arrival of the Spanish conquistadors and slave trade from Africa. More recently, Argentina has had the highest proportion of influx of transoceanic migration between 1850 and 1940 of any Latin American country. Furthermore, the geographical distribution of immigrants was oriented towards the Pampa region of central-eastern Argentina and the Northeast, so different patterns of mixed ancestry throughout the country are expected. In this present work we aim to describe the history and structure of the Argentinean population. Thus far, we have collected DNA samples from 2904 participants from 15 dispersed regions in Argentina, from the Andean populations in the Northwest to the river lands of the Northeast. Our preliminary data includes genome-scale Illumina Exome Array 250K genotypes, plus next-generation sequencing data from uniformly spaced genomic regions targeted with a genotype-by- sequencing strategy (which covers 1.5% of the genome), for 375 participants from 9 of the 15 populations. We will identify proportions and patterns of European, African and Indigenous American ancestry in the Argentinean cohort via local ancestry inference. The first series of analyses will focus on genomic tracts of Indigenous American ancestry for fine-scale examination of sub-continental structure by comparing to a panel of 493 samples from 52 Indigenous American populations from throughout the Americas. Furthermore, this work will serve as a test of different low-cost strategies (exome genotype array vs. genotype-by-sequencing) for accurate inference of population structure in extant populations.

  Study EGAS00001001663

• The G2 gene expression signature and MYC overexpression are independent poor prognostic factors in childhood high-grade osteosarcoma

  Purpose In high-grade osteosarcoma, prognostic factors at diagnosis are insufficient for stratifying patients into relevant subgroups. Recently, a transcriptomic study developed the G1/G2 gene expression signature, in which the G2 signature was associated with unfavorable survival. An orthogonal study identified MYC amplification as an unfavorable prognostic factor using targeted next-generation sequencing. The purpose of this study was to validate the independent prognostic value and to investigate the combined prognostic value of the G1/G2 signature with, MYC amplification and/or MYC expression for survival prediction. Material and methods This study included pediatric and adolescent patients with high-grade osteosarcoma. RNA sequencing was performed in 48 patients. Whole-exome sequencing was performed in 40 patients. Gene expression signature scores, MYC amplification (defined as > 7 copies) and MYC expression levels were calculated. Multivariable Cox proportional hazards analysis was performed for event-free survival (EFS) (primary endpoint) and overall survival (OS) (secondary endpoint). Results In the full cohort, the 3-year event-free survival rate was 37%. In multivariable Cox regression analysis with metastatic disease stage (n=21, 44%) as covariate, the G2 signature and MYC expression were independently associated with worse outcomes in terms of EFS (Hazard ratio (HR) 3.32, 95% confidence interval (CI) 1.34-8.21 and HR 3.38, 95%-CI 1.71-6.66, respectively) and OS (HR 4.07, 95%-CI 1.19-13.9 and HR 2.88, 95%-CI 1.22-6.76, respectively). MYC amplification was not associated with EFS or OS in univariable analysis (HR 1.88, 95% -CI 0.74-4.77 and HR 0.79, 95%-CI 0.21-3.05, respectively). Conclusion The G2 gene expression signature and MYC expression were independently associated with unfavorable outcomes in a pediatric cohort of patients with high-grade osteosarcoma. The combined prognostic value warrants further prospective validation and could potentially serve as a stratification marker for future osteosarcoma treatment protocols.

  Study EGAS00001008073

• Same-day genomic and epigenomic diagnosis of brain tumors using realtime nanopore sequencing

  Molecular classification of cancer has entered clinical routine to inform diagnosis, prognosis and treatment decisions. At the same time, new tumor entities have been identified that cannot be defined histologically. For central nervous systems tumors, the current World Health Organization classification explicitly demands molecular testing, e.g. for 1p/19q- codeletion or IDH mutations, to make an integrated histomolecular diagnosis. However, a plethora of sophisticated technologies is currently needed to assess different genomic and epigenomic alterations and turnaround times are in the range of weeks, which makes standardized and widespread implementation difficult and hinders timely decision making. Here, we explored the potential of a pocket-size nanopore sequencing device for multimodal and rapid molecular diagnostics of cancer. Low-pass whole genome sequencing was used to simultaneously generate copy number (CN) and methylation profiles from native tumor DNA in the same sequencing run. Single nucleotide variants in IDH1, IDH2, TP53, H3F3A and the TERT promoter region were identified using deep amplicon sequencing. Nanopore sequencing yielded ~0.1X genome coverage within six hours and resulting CN and epigenetic profiles correlated well with matched microarray data. Diagnostically relevant alterations, such as 1p/19q codeletion, and focal amplifications could be recapitulated. Using ad hoc random forests, we could perform supervised pan-cancer classification to distinguish gliomas, medulloblastomas and brain metastases of different primary sites. Single nucleotide variants in IDH1, IDH2 and H3F3A were identified using deep amplicon sequencing within minutes of sequencing. Detection of TP53 and TERT promoter mutations shows that sequencing of entire genes and GC-rich regions is feasible. Nanopore sequencing allows same-day detection of structural variants, point mutations and methylation profiling using a single device with negligible capital cost. It outperforms hybridization-based and current sequencing technologies with respect to time-to diagnosis and required laboratory equipment and expertise, aiming to make precision medicine possible for every cancer patient, even in resource restricted settings.

  Study EGAS00001002213

• Immune induction strategies to enhance the sensitivity to PD-1 blockade in metastatic triple negative breast cancer: the TONIC-trial

  The response rate in metastatic triple negative breast cancer (TNBC) to PD-1 blockade is low, highlighting an urgent clinical need for strategies that render the TNBC tumor microenvironment (TME) more sensitive to PD-1 blockade. Immunomodulatory mechanisms have been proposed for both chemotherapy and irradiation, but it has not been established whether these therapies may improve efficacy of PD-1 blockade by favorably changing the TME. In the first stage of this adaptive, non-comparative phase II trial (TONIC-trial; NCT02499367), 67 patients with metastatic TNBC were randomized to nivolumab without induction or to one of four induction treatments, consisting of irradiation of one metastatic lesion (3x8 Gy) or a two- week low-dose regimen of cyclophosphamide, cisplatin or doxorubicin, all followed by nivolumab. In the overall cohort of 66 evaluable patients, the objective response rate (ORR; iRECIST16) was 20% (95% CI: 11%-31%), with two complete responses and 11 partial responses. The majority of clinical responses were observed on nivolumab in the cisplatin (ORR 23%; 3/13) and doxorubicin (ORR 35%; 6/17) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes, involved in PD-1/PD-L1, and T-cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNFα-signaling after doxorubicin. In addition, we observed a trend towards increased T-cell infiltration, measured using T-cell receptor (TCR) sequencing, after doxorubicin. Together, the clinical and translational data of this study testing different immune induction strategies prior to nivolumab suggest that short-term doxorubicin and cisplatin may induce a more favorable TME and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant further confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.

  Study EGAS00001003535

• Separation of chronic myeloid leukemia stem cells from normal hematopoietic stem cells at single-cell resolution

  Chronic myeloid leukemia (CML) is a clonal disease, initiated and sustained by a subpopulation of CML stem cells (CML-SC) containing the BCR::ABL1 oncogene. Genetic markers that enrich for CML-SC have been identified, including CD26 being most specific. Genome sequencing analysis remain yet to be performed at single cell level in order to determine differences and heterogeneity in the genetic profile of CML-SC versus normal hematopoietic stem cells (HSC). Here we show that CD26 and CD33 separate CML-SC from normal HSC in freshly isolated bone marrow samples from newly diagnosed CML patients. DNA sequencing confirms that single CML-SC derived colonies are positive for BCR::ABL1 and harbor a recurrent set of patient-specific clonal somatic mutations across different CML-SC derived colonies. In contrast, marker-negative (CD26-CD33-) HSC from the same patients are negative for the BCR::ABL1 oncogene and do not carry recurrent, clonal mutation across different colonies. These results support the concept that CD26/CD33 expression separates genetically defined, clonal mutant CML-SC from normal HSC that carry individual sets of random mutations in CML patients. We provide whole exome DNA sequencing data for 23 clinical samples of CML-SC plus two buccal swipes derived normal samples. CML samples are comprised of 4 to 8 replicates from two patients, at diagnosis and after treatment. Single CML stem cells before treatment and single non-transformed HSC at remission were selected from bone marrow samples by FACS, according to genetic markers CD33+CD26+ at diagnosis and CD33+CD26-/CD33-CD26- at remission. WES libraries of colony forming assays derived CML-SC and HSC populations were prepared using Agilent SureSelect Human All Exon V6 kit and sequenced running 150 cycles (2x 75bp paired-end) on an Illumina NextSeq 500 platform. Following GATK best practices for somatic mutation calling, novel CML variants and random mutation events during remission phase were obtained.

  Study EGAS00001006904

• Genome-wide DNA methylation sequencing identifies epigenetic perturbations in the upper airways under long-term exposure to moderate levels of ambient air pollution

  While the link between exposure to high levels of ambient particulate matter (PM) and increased incidences of respiratory and cardiovascular diseases is widely recognized, recent epidemiological studies have shown that low PM concentrations are equally associated with adverse health effects. As DNA methylation is one of the main mechanisms by which cells regulate and stabilize gene expression, changes in the methylome could constitute early indicators of dysregulated signaling pathways. So far, little is known about PM-associated DNA methylation changes in the upper airways, the first point of contact between airborne pollutants and the human body. Here, we focused on cells of the upper respiratory tract and assessed their genome-wide DNA methylation pattern to explore exposure-associated early regulatory changes. Using a mobile epidemiological laboratory, nasal lavage samples were collected from a cohort of 60 adults that lived in districts with records of low (Simmerath) or moderate (Stuttgart) PM10 levels in Germany. PM10 concentrations were verified by particle measurements on the days of the sample collection and genome-wide DNA methylation was determined by enzymatic methyl sequencing at single-base resolution. We identified 231 differentially methylated regions (DMRs) between moderately and lowly PM10 exposed individuals. A high proportion of DMRs overlapped with regulatory elements, and DMR target genes were involved in pathways regulating cellular redox homeostasis and immune response. In addition, we found distinct changes in DNA methylation of the HOXA gene cluster whose methylation levels have previously been linked to air pollution exposure but also to carcinogenesis in several instances. The findings of this study suggest that regulatory changes in upper airway cells occur at PM10 levels below current European thresholds, some of which may be involved in the development of air pollution-related diseases.

  Study EGAS00001007374

• Long read transcriptome of DM1 patients whole blood

  DM1 is characterized by dysregulation of alternative mRNA splicing, to an quantitative as well as qualitative extend that is heterogenous between clinically similar patients. Hundreds of transcripts have been identified that can be misspliced in DM1, and for many of these it is still unclear whether they generate stable proteins in DM1 patients. We generated long-read transcriptome data of DM1 patients whole blood after hemoglobin depletion. Each sample is a mix of 5 patients of varying age.

  Study EGAS50000000196

• Spatiotemporal immune atlas of the first clinical-grade gene-edited pig-to-human kidney xenotransplant

  Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. We transplanted a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and studied the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells were uncommon in the porcine kidney cortex early after xenotransplantation and consisted of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages expressed genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft was detected. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression is sufficient to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.

  Dataset EGAD50000000359