7406 results for "canc*"

in 45.20 milliseconds.

• Comprehensive peripheral blood immunoprofiling reveals five immunotypes with immunotherapy response characteristics in cancer patients

  The lack of comprehensive diagnostics and consensus analytical models for evaluating the status of a patient’s immune system has hindered a wider adoption of immunoprofiling for treatment monitoring and response prediction in cancer patients. To address this unmet need, we developed an immunoprofiling platform that uses multiparameter flow cytometry and RNA-seq to characterize immune cell heterogeneity in the peripheral blood of healthy donors and patients with advanced cancers. Using unsupervised clustering, we identified five immunotypes with unique distributions of different cell types, and gene expression profiles.

  Study EGAS50000000286

• Molecular underpinnings of dedifferentiation and aggressiveness in chromophobe renal cell carcinoma

  This study expands our understanding of aggressive chromophobe renal cell carcinoma (ChRCC), provides insight into molecular mechanisms of tumor progression, and informs pathologic classification and diagnostics. Tumor and adjacent normal samples were collected from 11 patients treated in affiliated hospitals of the University of Texas Southwestern Medical Center (UTSW), including Parkland Hospital. Seven of the eleven patients consented to depositing their genomic data to public repository.

  Study EGAS50000000287

• Whole Genome Sequencing of HER2-Positive Metastatic Extramammary Paget’s Disease: A Case Report

  Extramammary Paget’s disease (EMPD) is a rare cancer that occurs within the epithelium of the skin. Whole genome sequencing of the tumor and matched blood was performed. Whole genome sequencing revealed the underlying copy number variation landscape in HER2-positive metastatic EMPD. The presence of alternative signalling pathways and genetic variants suggests potential interactions with HER2 signalling, which possibly contributed to the HER2 overexpression and observed response to HER2-directed therapy combined with other agents in a comprehensive treatment regimen.

  Study EGAS50000000243

• Heterogeneity and evolution of DNA mutation rates in microsatellite-stable colorectal cancer

  A mutation accumulation experiment in colorectal cancer (CRC) derived tumoroids, aimed at measuring the spontaneous rates of accumulation of new single-nucleotide sequence variations in seven microsatellite stable CRCs and one microsatellite unstable CRC. Mutations accumulated over six+six months were identified via whole genome sequencing of clonal tumoroids.

  Study EGAS50000000284

• The neo-open reading frame peptides that comprise the tumor framome are a rich source of neoantigens for cancer immunotherapy

  Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate whole genome and long-read transcript sequencing of cancers to identify the collection of neo-open reading frame peptides (NOPs) expressed in tumors. We termed this collection of NOPs the tumor framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe a class of hidden NOPs that derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of non-coding regions of the genome downstream of a rearrangement breakpoint, i.e. where no gene annotation or evidence for transcription exists. The entire collection of NOPs represents a vast number of possible neoantigens particularly in tumors with many structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T cells specific for hidden NOPs in peripheral blood from a patient with lung cancer. This work highlights NOPs as a major source of possible neoantigens for personalized cancer immunotherapy and provides a rationale for analyzing the complete cancer genome and transcriptome as a basis for detection of NOPs.

  Study EGAS00001006021

• Transcriptomic profiling of prostate cancer metastasis xenograft models reveals conservation of bone microenvironment signatures

  Study EGAS00001004770

• Lipomatous tumors with 12q amplification

  The project concerns whole genome sequencing (short-read and long-read) and RNA-sequencing of lipomatous tumors with 12q-amplification. A subset of lipomatous tumors is driven by amplification of genes mapping to chromosome arm 12q, including the MDM2 gene. The goals of the study were to compare expression levels of genes mapping to 12q in tumors with amplification in rod-shaped or circularized chromosomes as well as to assess and compare the structural variants in those tumors. In total, 20 samples were analyzed, and the data were correlated with genomic data on bulk and single cell DNA from the same tumors. The fastq files from the tumors were uploaded to EGA.

  Study EGAS50000000062

• resistance to FGFR inhibitor in FGR2 cancers from DNA sequencing

  WES from FGR2 resistant patient tumors

  Study EGAS50000000305

• Platinum-based chemotherapy induces opposing effects on immunotherapy response-related spatial and stromal biomarkers in the bladder cancer microenvironment

  The goal of the current project was to investigate the modulation of the tumor-immune microenvironment (TME) by neo-adjuvant platinum-based chemotherapy in muscle-invasive bladder cancer. Furthermore, we aimed to focus on how this modulation affects biomarkers of response to immune checkpoint inhibitors. Additionally, we aimed to explore the differences between MVAC and gemcitabine-containing platinum-based regimens regarding their effects on the bladder TME.

  Study EGAS50000000309

• Impact of genetic variants in clinical outcome of a cohort of patients with oropharyngeal squamous cell carcinoma

  Study EGAS00001004430

• HiDEF-seq single-molecule sequencing of single-strand mismatches and damage

  Our study sought to resolve, with single-molecule fidelity, the mismatches and damage events that precede DNA mutations. Using a novel single-molecule, long-read sequencing method (HiDEF-seq) we detect base substitutions when present in either one or both DNA strands. We also detect cytosine deamination, a common type of DNA damage, with single-molecule fidelity. This study profiled 134 samples from diverse tissues, including from individuals with cancer predisposition syndromes. These samples revealed single-strand mismatch and damage signatures. Since double-strand DNA mutations are only the endpoint of the mutation process, our approach enables new studies of how mutations arise in a variety of contexts, especially in cancer and aging.

  Study EGAS50000000318

• single cell data from HPV-positive head and neck cancer patients receiving induction CTLA-4 and PD-1 immune checkpoint blockade

  Baseline and on-treatment tumor samples from human papillomavirus-positive oropharynx cancer patients receiving anti-CTLA-4 and anti-PD-1 immune checkpoint blockade were analyzed by single-cell RNA and TCR sequencing.

  Study EGAS50000000335

• Non-invasive prediction of immunotherapy response (NIPIT) project

  This project aims to find transcriptomic biomarkers for immunotherapy response prediction in several cancer types. So far, we have performed poly-A RNA-seq using whloe blood and peripheral blood mononuclear cells from 33 non-small cell lung cancer patients, collected before and after the start of immunotherapy.

  Study EGAS50000000266

• Paired Biopsy Project: West Coast Dream Team

  This project aims to analyze the paired metastatic biopsy samples from patients with metastatic castration-resistant prostate cancer (mCRPC), collected before the initiation of the first-line androgen receptor signaling inhibitor (ARSI) for mCRPC and after radiographic disease progression on that ARSI, to understand the resistance mechanisms. We generated both whole genome sequencing (WGS) and RNA-seq data on these samples. A majority of these samples have been deposited in the public domain along with prior publications, and this project contains the 16 WGS samples that have not yet been deposited.

  Study EGAS50000000327

• Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia

  Purpose Genomic alterations of IKZF1 are common and associated with adverse clinical features in B-ALL, but the relationship between the type of IKZF1 alteration, disease subtype and outcome are incompletely understood. Patients and Methods We used transcriptome and genomic sequencing, and SNP microarray data to determine leukemia subtype and genomic alterations for 688 pediatric patients with B-ALL enrolled into St. Jude Total Therapy 15 and 16 studies. Results IKZF1 alterations were identified in 115 (16.7%) patients, commonly in BCR::ABL1 (78%) and CRLF2-rearranged, BCR::ABL1-like B-ALL (70%), and were associated with five-year cumulative incidence of relapse (CIR) of 14.8 ± 3.3% compared to 5.0 ± 0.9% for patients without any IKZF1 alteration (P < 0.0001). IKZF1 deletions of exon 4-7 (P = 0.0002), genomic IKZF1plus with any IKZF1 deletion (P = 0.006) or with focal IKZF1 deletion (P = 0.0007), and unfavorable genomic subtypes (P < 0.005) were independently adversely prognostic. Patients with both IKZF1 exon 4-7 deletion and unfavorable genomic subtype had a significantly increased risk of relapse (HR = 58.3; 95% CI, 11.9 – 285.4, P < 0.0001) whereas IKZF1 sequence mutations were not independently predictive of outcome. Conclusions Genomic IKZF1plus with any IKZF1 deletion, IKZF1 deletion of exon 4-7, and unfavorable subtype confer increased risk of relapse. The combination of unfavorable genomic subtype and IKZF1 deletion of exon 4-7 identified patients at greatest risk of relapse despite MRD-directed therapy. The type of IKZF1 alteration together with subtype are informative for risk stratification and predict response in patients with B-ALL.

  Study EGAS50000000106

• Systematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types

  The complexity of the tumor microenvironment poses significant challenges in cancer therapy. Here, to comprehensively investigate the tumor-normal ecosystems, we perform an integrative analysis of 4.9 million single-cell transcriptomes from 1,070 tumor and 493 normal samples in combination with pan-cancer 137 spatial transcriptomics, 8,887 TCGA, and 1,261 checkpoint inhibitor-treated bulk tumors. We define a myriad of cell states constituting the tumor-normal ecosystems and also identify hallmark gene signatures across different cell types and organs. Our atlas characterizes distinctions between inflammatory fibroblasts marked by AKR1C1 or WNT5A in terms of cellular interactions and spatial co-localization patterns. Co-occurrence analysis reveals interferon-enriched community states including tertiary lymphoid structure (TLS) components, which exhibit differential rewiring between tumor, adjacent normal, and healthy normal tissues. The favorable response of interferon-enriched community states to immunotherapy is validated using immunotherapy-treated cancers (n=1,261) including our lung cancer cohort (n=497). Deconvolution of spatial transcriptomes discriminates TLS-enriched from non-enriched cell types among immunotherapy-favorable components. Our systematic dissection of tumor-normal ecosystems provides a deeper understanding of inter- and intra-tumoral heterogeneity.

  Study EGAS50000000324

• ROBUST (NCT02285062)

  The ROBUST clinical trial is a Phase III, randomized, double-blind, placebo-controlled study designed to compare the efficacy and safety of lenalidomide plus R-CHOP chemotherapy (R2-CHOP) versus placebo plus R-CHOP in newly diagnosed Diffuse Large B-cell Lymphoma (DLBCL). Molecular data was collected for all patients at screening, but the only patients of the Activated B-cell (ABC) cell-of-origin subtype were eligible for study inclusion and clinical follow-up. We have performed unsupervised clustering on this cohort and identified 7 novel transcriptional subtypes of DLBCL, one of which represents a high-risk subset of patients with high MYC expression, ABC-associated biology, and low immune infiltration.

  Study EGAS50000000333

• Single cell transcriptomic profiles of advanced melanoma patients treated with checkpoint inhibitor immunotherapy

  Little is known about the resistant clones within the tumour ecosystem treated with immunotherapy. This work provides a comprehensive and integrative analysis of each individual non-responding melanoma patients, including clinical features integrated with single cell analysis, which is critical to understand features of resistance in order to improve cancer patients’ outcomes.

  Study EGAS50000000339

• Decoding Human Endogenous Retrovirus Expression in Liver Metastatic Colorectal Cancers: Implications for Diagnosis and Prognosis

  The association between Human Endogenous RetroVirus (HERV) expression and cancer can be considered to both reflect the epigenetic deregulation of cancer and facilitate oncogenesis through its promoter/enhancer action on genes. More than 50% of colorectal cancers develop liver metastases and HERV has never been studied in this setting. We collected 400 RNAseq samples from more than 200 patients with primary and liver metastases from published and unpublished databases. We corroborated our findings with tandem mass spectrometry from primary colorectal cancer and single-cell RNAseq from liver metastatic colorectal cancer (lmCRC). We identified global stability in HERV expression between liver metastases and primary colorectal cancers, suggesting an early oncogenic footprint. Therefore, we proposed a list of seventeen HERV loci for lmCRC characterization with ERV-derived peptides but no expression in normal tissues. Among them, we discovered six prognostic markers after surgical resection of lmCRC. Four of them, HERVH_Xp22.32a, HERVH_20p11.23b, HERVH_13q33.3, HERVH_13q31.3, showed poor prognostic value when expressed (log-rank p-value 0.028, 0.0083, 9e-4, 0.05, respectively). HERVH_Xp22.2c (log-rank p-value 0.032) and HERVH_8q21.3b (only in multivariate models) were associated with better prognosis when expressed. These markers showed a cumulative effect on survival when expressed. Some HERVs were associated with decreased cytotoxic immune cells and most of them correlated with cell cycle pathways. Our findings provide new insights into lmCRC classification and suggest novel prognostic biomarkers and potential therapeutic targets.

  Study EGAS50000000307

• A single-cell multi-omic atlas of nodal B-cell non-Hodgkin lymphomas

  Nodal B-cell non-Hodgkin lymphomas (B-NHL) are a clinically diverse set of cancers thought to originate from distinct stages of B-cell maturation. To characterize intratumor heterogeneity across B-NHL entities, we performed CITE-Seq (cellular indexing of transcriptomes and epitopes) on 51 lymph node samples including mantle cell lymphoma (MCL, n = 8), follicular lymphoma (FL, n = 12), germinal center (GCB, n = 5) or activated B-cell (non-GCB/ABC, n = 7) diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma (MZL, n = 11) tumors, in addition to non-malignant reactive lymph nodes (rLN, n = 8). We also performed 5 prime scRNA-seq with immune receptor profiling for 11 of these samples (2 rLN, 2 MCL, 3 FL, 2 DLBCL, and 2 MZL).

  Study EGAS50000000342

• WES analysis of tumor samples

  Whole exome sequencing was performed on paired tumor (N=8) from ER+ advanced breast cancer, obtained prior to combined CDK4/6i and endocrine therapy and at disease progression.

  Study EGAS50000000430

• Spatially Resolved Tumor Ecosystems and Cell States in Gastric Adenocarcinoma Progression and Evolution

  Gastric cancer (GC) is a major cause of global cancer mortality with high levels of heterogeneity, and intratumoral heterogeneity (ITH) represents a significant barrier to GC patient outcomes. In this study, we applied GeoMx DSP technology to identify ITH in GC. We found spatially colocalized RNA-based intratumor subgroups within samples, each correlated with distinct spatially oriented TME and immune profiles. The findings broadening our understanding of the spatial and molecular complexity of GC ITH and offering a valuable data resource for future exploration and discovery.

  Study EGAS50000000345

• Targeted capture, whole genome sequencing, and RNAseq to identify rearrangements in B-cell lymphomas

  This study contains whole genome and custom targeted capture sequencing of mature B-cell lymphomas (DLBCL, FL, BL, HGBCL-DH-BCL2, HGBCL-DH-BCL6) to identify translocation breakpoints of common oncogene rearrangements (MYC, BCL2, BCL6). It is complemented by RNAseq data where available. Complete details are available in the publication Hilton et al, 2024, Blood. Capture sequencing: 357 samples; 364 unique libraries; cram file format aligned to hg38 Whole genome sequencing: 12 samples; 12 unique libraries; cram file format aligned to grch37 RNAseq: 257 samples; 257 unique libraries; fastq file format

  Study EGAS50000000328

• Single cell RNAseq of PBMC from bladder cancer patients

  Study EGAS00001004458

• Tumor microenvironment-induced FOXM1 regulates ovarian cancer stemness

  RNAseq from patient-derived primary tumor cells, cultured or not on organotypic cultures mimicking the tumor microenvironment

  Study EGAS50000000355

• Clinical and molecular features of early onset pancreatic cancer

  A retrospective cohort study on the clinical and molecular features of early onset pancreatic cancers (i. e. diagnosed at <50 years old) in comparison with later onset tumors.

  Study EGAS50000000362

• The evolution of ovarian high grade serous carcinoma from STIC lesions

  We performed Ampliseq on 11 samples on a targeted panel of 17 genes.

  Study EGAS50000000361

• 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

• Single-cell RNA sequencing of human skin tumors (BCC, SCC and Melanoma)

  Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. Here, we elucidate the yet unresolved intra-tumoral CAF variety in three skin cancer types at molecular and spatial single-cell resolution in a large cohort. We show that two out of three CAF subtypes contribute to tumor immune surveillance with distinct mechanisms. Matrix CAFs (mCAFs) ensheath tumor nests and synthesize extracellular-matrix to prevent T cell invasion. Immunomodulatory CAFs (iCAFs), which express proinflammatory and immunomodulatory factors, are only detected in high abundance in aggressive tumors. Strikingly, iCAFs but not tumor cells are (apart from immune cells) the exclusive cell type producing chemokines and, thus, play a key role in immune cell recruitment and activation. Mechanistically, we show that cancer cells transform adjacent healthy fibroblasts into cytokine-expressing iCAFs, which subsequently recruit immune cells and modulate the immune response. In conclusion, targeting CAF variants holds promise for improved efficacy of immunotherapy.

  Study EGAS50000000365

• Diagnosis of pediatric central nervous system tumors using methylation profiling of cfDNA from cerebrospinal fluid

  In this study, we explore the potential of classifying pediatric brain tumors based on methylation profiling of the cell-free DNA in cerebrospinal fluid (CSF). For this proof-of-concept study, we collected 20 cerebrospinal fluid samples of pediatric brain cancer patients via a ventricular drain placed for reasons of increased intracranial pressure. For 11 patients in this study we collected matched tumor DNA. This cohort contains fastQ files of cfRRBS data of these samples.

  Study EGAS50000000377

• Patient-derived models of primary breast cancer for preclinical development of novel neoadjuvant therapies

  Generation of the first large-scale cohort of mouse intraductal patient-derived xenograft (MIND-PDX) models of primary invasive breast cancer (IBC) and a collection of matched PDX-derived organoids (PDXO) representing all molecular subtypes of IBC, including estrogen receptor (ER-) positive breast cancer. Furthermore, we show that our IBC-MIND cohort can serve as a platform to test experimental neoadjuvant treatment options in different molecular subtypes of breast cancer.

  Study EGAS50000000398

• TOTHER3

  Patritumab deruxtecan in HER2-negative breast cancer: part B results of the window-of-opportunity SOLTI TOT-HER3 trial and biological determinants of early response

  Study EGAS50000000385

• Colorectal cancer functional annotation - MPRA

  We performed a Massively Parallel Reporter Assay (MPRA) in colorectal cancer (CRC) cell lines HT29 and SW403 and normal colon cell line HCEC-1CT. We specifically targeted the regions around the CRC GWAS loci to identify which variants alter transcription.

  Study EGAS50000000406

• Heterogeneity and evolution of DNA mutation rates in microsatellite-stable colorectal cancer

  A mutation accumulation experiment in colorectal cancer (CRC) derived tumoroids, aimed at measuring the spontaneous rates of accumulation of new single-nucleotide sequence variations in seven microsatellite stable CRCs and one microsatellite unstable CRC. Mutations accumulated over six+six months were identified via whole genome sequencing of clonal tumoroids. 150x WGS for 7 samples.

  Study EGAS50000000425

• AYA glioma NGS

  Gliomas are a major cause of cancer-related death in adolescents and young adults (AYA, ages 15-39 years). Different molecular alterations drive gliomas in children and adults leading to distinct biology and clinical consequences. At the convergence of these age groups - the AYA population – little is known about the implications of pediatric vs adult-type alterations. To address this, we analyzed a population-based cohort of 1456 clinically and molecularly characterized gliomas aged 0-39 years. Potentially targetable pediatric-type alterations were found in 31% of AYA gliomas and conferred superior outcomes compared to adult-type alterations. This submission includes the generated NGS data for children, adolescent, and young adults with gliomas. Data includes targeted panel of glioma genes and low-pass WGS (1x coverage).

  Study EGAS50000000383

• Genomic characterization of retinoblastoma

  Study EGAS00001005248

• Surgery in combination with immune checkpoint therapy as an effective treatment for patients with metastatic cancer.

  Abstract Surgical removal of primary tumors was shown to reverse tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT)-containing treatments is not understood. Here, we report the first prospective, non-comparative clinical trial (N=104) using three different ICT-containing strategies plus cytoreductive or “debulking” surgery to remove the primary tumor-bearing kidney or a metastatic lesion as a treatment for patients (N=43) with metastatic clear cell renal cell carcinoma (mccRCC). For those patients (N=61) who were not candidates for cytoreductive surgery, a biopsy was obtained instead for correlative biological studies. Our data demonstrated that the combination of ICT with cytoreductive surgery was safe and feasible in patients with mccRCC. The 2-year overall survival was 84% with a median OS of 54.7 months for patients who received ICT containing regimens plus surgery. Immune-monitoring studies with co-detection by indexing (CODEX) identified distinct tumor spatial conformation of cellular subsets as a novel and improved predictor of response to ICT. Importantly, single-cell RNA-sequencing data demonstrated that surgical removal of the tumor increased antigen-presenting dendritic cell population with a concurrent reduction in KDM6B expressing immune-suppressive myeloid cells in the peripheral blood. Together, this study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated potential enhancement of immune responses following ICT plus cytoreductive surgery in patients with metastatic disease.

  Study EGAS00001005667

• Gene Expression Signature in Normal Mammary Gland from 83 Breast Cancer Patients Indicates Pre-tumorous Changes and Adverse Outcomes

  This study assessed the transcriptomic profiles of 242 samples from 83 breast cancer patients with unfavorable outcomes, including paired uninvolved mammary gland samples collected at varying distances from primary lesions. As a reference, control samples from 53 mammoplasty individuals without cancer history were studied. A custom panel of 634 genes linked to breast cancer progression and metastasis was employed for expression profiling (targeted RNA sequencing), followed by whole-transcriptome (RNA sequencing) verification experiments and statistical analyses to discern molecular signatures and their clinical relevance.

  Study EGAS50000000011

• Fragmentomics profiling and quantification of plasma Epstein-Barr virus DNA enhance prediction of future nasopharyngeal carcinoma.

  This study evaluated the clinical utility of fragmentomics analysis of plasma Epstein-Barr virus (EBV) DNA in nasopharyngeal carcinoma (NPC) screening. The first-round EBV-positive blood samples from a two-round large-scale prospective NPC screening cohort were analyzed. The EBV DNA of subjects who developed NPC in the second round displayed a distinctive mononucleosomal size pattern, an NPC-associated end motif profile, and aberrations in methylation deduced by fragmentomics-based methylation analysis (FRAGMA). Subjects with these aberrant fragmentomics features and higher EBV DNA quantity showed a dramatically increased risk of NPC development, demonstrating the potential of plasma DNA fragmentomics in predicting future cancer risk.

  Study EGAS50000000395

• Uncovering the potential of circulating tumor DNA for pediatric precision oncology

  Pediatric solid high-risk malignancies mostly lack molecular biomarkers for early tumor detection, assessment of minimal residual disease or therapy monitoring. Small patient numbers, limited sample volumes, low tumor mutational burden, and few recurrent alterations in pediatric tumors pose further challenges to liquid biopsy analyses for this patient population. Within the prospective, multinational molecular profiling program INFORM, we collected liquid biopsies from 130 children patients followed by optimized isolation of cell-free DNA (cfDNA). CfDNA was subjected to whole-genome, whole-exome, and targeted panel sequencing applying liquid biopsy-adapted protocols. Integration with tissue-derived molecular information and orthogonal comparison revealed low-coverage whole genome sequencing (lcWGS) as a reliable method for tumor detection. In silico integration of fragment length with differentially weighted genome segment alterations into a ctDNA estimation score (CES) significantly increased sensitivity and specificity to 95% and allowed for plasma-based tumor detection in 93% of patients. Performance of whole exome sequencing (WES) and panel sequencing for detection of molecular targets being predictive for matched treatment responses varied between groups of high-risk entities and cumulative evidence for presence of cancer by all three methods was found in 92% of patients. In-depth analyses for selected patients also demonstrated great the potential of liquid biopsies to decipher temporal and spatial tumor evolution. This study establishes improved methods for liquid biopsy analyses in pediatric oncology and provides the rationale for well-informed implementation of these approaches in future clinical trials to improve the clinical management of high-risk pediatric cancer patients.

  Study EGAS50000000393

• Colorectal cancer cells possess an equipotent capacity to enter a developmental pausing-like state to survive chemotherapy

  Study EGAS00001004773

• Non-KMT2Ar infant Acute Lymphoblastic Leukemia Sequencing

  Integrated genomic analysis of non-KMT2A rearranged infant ALL reveals clinically relevant alterations and common disease origins with childhood ALL. Whole genome and whole transcriptome sequencing from 21 infant ALL patients with no matched normal DNA sequencing.

  Study EGAS50000000405

• Targeted DNA sequencing and mRNA sequencing data from patients with peritoneal metastasis from colorectal cancer

  Patients with peritoneal metastasis from colorectal cancer (PM-CRC) have inferior prognosis and respond particularly poorly to chemotherapy. This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC. Tumor samples (230) from a Norwegian national cohort undergoing surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) for PM-CRC were subjected to targeted DNA sequencing, and associations with clinical data were analyzed. mRNA sequencing was conducted on a subset of 30 samples to compare gene expression in tumors harboring BRAF or KRAS mutations and wild-type tumors.

  Study EGAS50000000404

• Array-based methylation analysis of SDHB-deficient pheochromocytoma and paraganglioma

  Study EGAS00001007844

• plasma DNA LINE-1 targeted bisulfite sequencing: a new non-invasive multi-cancer detection marker

  The detection of circulating tumor DNA, which allows non-invasive tumor molecular profiling and disease follow-up, promises optimal and individualized management of patients with cancer. However, detecting small fractions of tumor DNA released when the tumor burden is reduced remains a challenge. We developed a PCR-based targeted bisulfite method coupled to deep sequencing to detect methylation patterns of L1PA elements,which we named DIAMOND (for Detection of Long Interspersed Nuclear Element Altered Methylation ON plasma DNA). We used sodium bisulfite chemical conversion to achieve base-pair resolution analysis and designed a multiplexed PCR based on 8 amplicons covering L1PAs .

  Study EGAS50000000446

• Tumor inflammation and mutational burden are differentially associated with response to nivolumab or nivolumab plus ipilimumab in metastatic colorectal cancer

  Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Exploratory biomarker analyses of tumor and microbiome samples from CheckMate 142 were performed to evaluate associations between various biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures was associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden and degrees of microsatellite instability were associated with improved response per investigator assessment and survival benefit with nivolumab plus ipilimumab. While interpretation is limited by the exploratory nature of these analyses, they suggest that tumor antigenicity rather than baseline tumor inflammation might be important for the combinatorial efficacy. Validation of these findings in larger, randomized studies is necessary.

  Study EGAS50000000416

• DNA methylation database for gynecological cancer detection, classification and assay development

  DNA methylation changes are associated with cancer the best predictor of the presence of cancer. In order to detect and classify gynecological cancer, we performed MeD-seq to generate DNA methylation profiles of vulvar, cervical, endometrial, fallopian tube and ovarian cancers and their associated healthy tissues. DNA methylation profiles were used to find general cancer, regional cancer and specific cancer biomarkers that can be used for cancer detection, classification and treatment monitoring.

  Study EGAS50000000417

• Systematic Growth Factor Profiling Platform for 3D Tumor Models Reveals EstradiolResponsive Cellular Mechanisms of Immunotherapy Resistance

  Epithelial ovarian cancer (EOC) exhibits significant molecular heterogeneity, which is thought to be influenced by the tumor microenvironment (TME). However, the specific factors driving this heterogeneity remain poorly understood. In this study, we integrated growth factoromics and genomic data to identify TME factors contributing to EOC heterogeneity and immunosuppression. Our analysis revealed distinct subgroups of EOC samples with differential responsiveness to specific growth factors, particularly estradiol and R-spondin. Notably, samples with high responsiveness to estradiol and Wnt (C1 cluster) were enriched in the Mesenchymal (MES) molecular subtype, while samples with high responsiveness to R-spondin (C2 cluster) were associated with the Differentiated (DIF) and Immunoreactive (IMR) subtypes. We discovered that the G protein-coupled estrogen receptor (GPER), rather than the classical estrogen receptor alpha (ERα), was the key mediator of estrogen responsiveness and a determinant of molecular subtype classification. Single-cell sequencing analysis identified subsets of estrogen-responsive malignant cell (MAL.PDCD5) and cancer-associated fibroblast (FB.TNFSF10), which were associated with immunosuppressive patterns in the TCGA cohort. Importantly, the interaction between these cell populations significantly increased upon estrogen treatment, suggesting a potential mechanism by which estrogen signaling may contribute to the development of an immunosuppressive TME. Our findings highlight the critical role of estrogen signaling in shaping the molecular heterogeneity and immunosuppressive TME of EOC and provide novel insights into potential therapeutic targets for overcoming immunosuppression in this malignancy.

  Study EGAS50000000422

• Molecular analysis of CRC in patients with Primary Sclerosing Cholangitis (PSC) and Inflammatory Bowel Disease (IBD)

  Study EGAS00001004497

• Cergentis FFPE-TLC

  In this study, formalin-fixed paraffin-embedded targeted locus capture (FFPE-TLC) sequencing is used as a novel technology for targeted detection of tumor-specific genomic structural variants (SVs) in the primary tumor of 29 colorectal cancer patients with metastatic disease. The tumor region was macrodissected and sequenced for 29 patients, and the "normal" region of the same slide was macrodissected and sequenced for 8 of these patients. SVs were found in the common fragile site (CFS)-associated genes MACROD2, PRKN, FHIT and WWOX as well as SVs caused by three LINE transposable elements. Tumor-specificity of selected SVs was independently verified by droplet digital PCR of tumor tissue DNA and their applicability as plasma circulating tumor DNA biomarkers was demonstrated.

  Study EGAS50000000427

• Atezolizumab Plus Chemotherapy With or Without Bevacizumab in Advanced Biliary Tract Cancer: Clinical and Biomarker Data From the Randomized Phase II IMbrave151 Trial

  PURPOSE Biliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment (TME) and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti-VEGF) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition. PATIENTS AND METHODS This randomized, double-blind, proof-of-concept Phase II study enrolled patients (n=162) with previously untreated advanced BTC (IMbrave151; NCT04677504). Patients were randomized 1:1 to receive 3-weekly cycles of atezolizumab (1200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2; CisGem) on Days 1 and 8 every 3 weeks for up to 8 cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary endpoint was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n=95) and mutation profiling (n=102) on baseline tumor samples. RESULTS Between February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo

  Study EGAS50000000387

• Genomic and clinical characterization of a familial GIST kindred intolerant to imatinib

  Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome sequencing of the germline and tumor. Affected individuals with GIST harbored a germline variant found within exon 13 of the KIT gene, (c.1965T>G; p.Asn655Lys, p.N655K) and a variant in the MSR1 gene (c.877C>T; p.Arg293*, pR293X). Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, and resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.

  Study EGAS50000000372

• Copy number variations and fragmentation features in cell-free DNA predict response in advanced non-small cell lung cancer patients under anti-PD-(L)1 therapy

  Anti-PD-(L)1 therapy is routinely used in metastatic NSCLC. However, response rates vary and biomarkers predicting treatment efficacy are lacking. Liquid biopsies allow monitoring of residual disease during therapy. Residual circulating tumor DNA (ctDNA) after therapy represents a predictive marker for adverse outcome. Here, we assessed copy number variations (CNVs) in serial plasma samples of NSCLC patients receiving PD-(L)1 blockade. We profiled CNV and fragmentation features in 118 plasma samples of advanced NSCLC patients by low-coverage whole genome sequencing taken at baseline, after four therapy cycles and at disease progression. CNVs and fragment features (i.e., fragment length, end motifs, position) were significantly altered in patients compared to healthy donors. Furthermore, fragment length changes at baseline and residual CNVs after four therapy cycles correlated with short progression-free survival. Our results highlight the suitability of plasma-based CNV and fragment analysis for disease monitoring and as a predictive marker for response duration in NSCLC patients under anti-PD-(L)1 therapy.

  Study EGAS50000000441

• A 3D genome atlas of breast cancer progression (BRCA3D)

  In this study, we aimed to understand how the 3D genome changes during breast cancer development and progression, in situ. Towards this goal, we collected cells from patient biopsies and performed Hi-C on four types of biopsies representing different stages of disease progression: healthy mammary tissue, primary breast tumours, liver metastasis and malignant pleural effusions. We survey the changes in the 3D genomes at the level of structural variation, compartments and TADs, as well as ERα associated distal interactions.

  Study EGAS50000000444

• Multiple Myeloma GWAS Meta-analysis

  Meta-analysis of Multiple Myeloma genome-wide association study datasets. Included are meta-analyses with and without the UK Biobank dataset.

  Study EGAS50000000292

• Multi-omic analysis of SDHB-related PCPG

  Hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) are rare tumours with a high propensity to metastasize although their clinical behaviour is unpredictable. To characterize the genomic landscape of these tumours and identify metastasis biomarkers, we performed multi-omic analysis on 94 tumours from 79 patients using six molecular methods including: whole-genome sequencing (WGS) of tumour and matched blood (n=94), whole transcriptome sequencing (RNA-seq) (n=91), small-RNA seq (n=90), DNA methylation profiling (n=93). Droplet-based (10x) single nuclei (sn)RNA-seq and snATAC-seq was applied to 9 and 7 cases, respectively. Additionally snATAC-seq was applied to one sample of normal adrenal medulla.

  Study EGAS50000000346

• Genome and transcriptome sequencing of cancer of unknown primary tumours

  Genome and transcriptome sequencing of cancer of unknown primary tumours was used to determine yield of clinical biomarkers for a molecular guided trial or for resolving cancer type of origin. This study includes profiling of germline DNA and tumour DNA by whole genome sequencing of tissue and cfDNA biopsies, as well as targeted genome sequencing using two panels, including Comprehensive cancer panel (CCP) and TruSight Oncology 500 (TSO500). This study also includes profiling of tumour RNA by whole transcriptome sequencing.

  Study EGAS50000000452

• Circulating immune cell landscape in colorectal cancer patients

  To understand the circulating immune cells in colorectal cancer patients, we performed single-cell RNA sequencing for 14 PBMC samples from 14 colorectal cancer patients.

  Study EGAS50000000590

• Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer (NABUCCO Cohorts 1 and 2)

  Study EGAS00001004521

• Prediction of homologous recombination deficiency identifies colorectal tumors sensitive to PARP inhibition

  BRCAness is a well-established feature in breast, ovarian, prostate and pancreatic carcinomas, our recent findings indicate that up to 15% of colorectal cancers (CRC) also harbor defects in the HR pathway, presenting promising opportunities for innovative therapeutic strategies in CRC patients. We developed a new tool called HRDirect, which builds upon the HRDetect algorithm and is able to predict HRD from reference-free tumor samples. We validated HRDirect using matched breast cancer and CRC patient samples. Subsequently, we assessed its efficacy in predicting response to the PARP inhibitor olaparib by comparing it with two other commercial assays: AmoyDx HRD by Amoy Diagnostics and the TruSight Oncology (TSO) _500 HRD panel by Illumina NGS technology. While all three approaches successfully identified the most PARPi-sensitive CRC models, HRDirect demonstrated superior precision in distinguishing resistant models compared to AmoyDX and TSO500-HRD, which exhibited overlapping scores between sensitive and resistant cells. Furthermore, we propose integrating HRDirect scoring with ATM immunohistochemical analysis as part of our "composite biomarker approach" to enhance the identification of HRD tumors, with an immediate translational and clinical impact for CRC personalized treatment.

  Study EGAS50000000426

• Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine

  Study EGAS00001004525

• Drug Development against Tumor Microtube Networks in Glioblastoma

  Glioblastomas are aggressive brain tumors that resist current therapies by hijacking neurodevelopmental programs to invade the brain and form resilient multicellular networks. Tumor Microtubes (TMs), neurite-like processes extended by cancer cells, drive this pathobiology, but TM-inhibiting drugs are lacking. Here we developed a comprehensive, combined in vitro and in vivo drug screening approach, including novel AI-based analysis tools of TM parameters. Two Protein Kinase C (PKC) activators, TPPB and PMA, exhibited robust inhibition of TM formation in cell-based assays. Since unconnected glioblastoma cells exhibit increased sensitivity to cytotoxic therapy in vivo, brain tumor-bearing mice received TPPB, the most consistent TM-inhibiting compound, in combination with radiotherapy. Long-term intravital 2-photon microscopy confirmed anti-TM and anti-tumor effects of the co-treatment. Mechanistically, TPPB treatment inhibited several key molecular and functional components of TM-related glioblastoma cell network communication and decreased the expression of TTYH1, a key driver of invasive TMs. By establishing a novel screening pipeline for anti-TM drug development, our study identifies a druggable TM master regulator pathway and a small molecule with robust anti-TM effects. It provides a proof-of-principle that disrupting TMs and disconnecting tumor networks is a pharmacologically feasible strategy to make therapies against glioblastoma more effective.

  Study EGAS50000000477

• Personalized peptide vaccination among 173 patients with IDH wildtype glioblastoma: a retrospective analysis

  Tumors from 173 GBM patients were analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. Exome libraries for 173 glioblastoma tumors and matched normal DNA were sequenced on Illumina platform, alongside whole transcriptomes from the tumor samples. Paper Abstract: Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. GBM tumors from 173 patients were analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. Among all patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis was 31.9 months (95% CI: 25.0-36.5). Side effects were infrequent and were predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides was detected in blood samples of 87 of 99 (88%) monitored patients. T-cell responses to vaccinated neoepitope peptides were durable in most patients. Significantly prolonged survival was observed for patients with multiple vaccine-induced immune responses (53 months) compared to those with no/low induced responses (27 months; P=0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.

  Study EGAS50000000449

• Prognostic whole-genome and transcriptome signatures in colorectal cancers

  Colorectal cancer (CRC) is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. To understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary CRCs in a population-based cohort with long-term follow-up. This study constitutes the largest integrated genome and transcriptome analysis of CRC to date, and links mutations, gene expressions and patient outcomes.

  Study EGAS50000000124

• Identifying New Genetic Subtypes in Follicular Lymphoma

  Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and was associated with a lower proliferative history compared to the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Collectively, our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

  Study EGAS50000000435

• Spatially resolved niche and tumor microenvironmental alterations in gastric cancer peritoneal metastases

  Peritoneal metastases (PM) in gastric cancer (GC) portend a poor prognosis, yet our understanding of tumor microenvironmental (TME) characteristics associated with GCPM remain limited. Here, we analyzed intrinsic genomic alterations and transcriptomic programs predictive of GCPM in a prospective cohort of 248 patients, identifying CDH1, PIGR, and ELF3 mutations as predictors. By inspecting the spatial dynamics of the TME, we find that tumor compartment infiltration of pro-tumorigenic cell types such as inflammatory cancer-associated fibroblasts (CAFs) predict peritoneal recurrence. Next, in a cross-sectional study of 205 samples from 55 patients, distinct pathways and immune compositions in GCPM relative to liver metastases highlight the TME's significance in transcoelomic metastases. Notably, several putative therapeutic targets exhibited distinct expression patterns between PTs and PMs. Our findings highlight transcriptomic variations and niche reprogramming in the GCPM peritoneal environment, revealing roles of myeloid dendritic cells, effector memory CD8+ T cells, and CAFs in metastatic progression.

  Study EGAS50000000501

• Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard and high risk myeloma

  Study EGAS00001004558

• SCLC MeDIP

  Mimicry of neuronal features are emerging as malignant regulators of cancer growth and metastasis. Neuroendocrine (NE) cancers and small cell lung cancers (SCLC) in particular have been shown to share expression profiles marking various stages of neuronal differentiation. Here, methylation profile from SCLC patients' tumour and normal tissue has been investigated genome wise.

  Study EGAS50000000506

• Chemotherapy induces myeloid-driven spatial T-cell exhaustion in ovarian cancer

  Gene expression profiles of single cells from 26 chemo-naïve and IDS tumor tissue and ascites samples from 17 HGSC patients

  Study EGAS50000000607

• Rare germline variants in patients with personal and family history of colorectal cancer

  A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to find novel high/moderate penetrance CRC susceptibility genes, we performed whole-exome sequencing on germline blood samples of seven familial cases from Poland with a double primary CRC.

  Study EGAS50000000606

• BulkRNAseq - Notch Signaling Maintains a Progenitor-Like Subclass of Hepatocellular Carcinoma

  To identify the Notch signaling components expressed in both the human cancer cells and mouse stromal cells that typically comprise PDX tumors, we performed bulk RNA sequencing. Our results demonstrate that a JAG1-NOTCH2 signaling axis within the human cancer cell population drives the Notch dependency in the super-responder models, with NOTCH2 serving as the functionally relevant receptor.

  Study EGAS50000000515

• Plasma mutation profile of precursor lesions and colorectal cancer using the Oncomine Colon cfDNA Assay

  Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Early detection of precursor lesions or early-stage cancer could hamper cancer development or improve survival rates. Liquid biopsy, which detects tumor biomarkers, such as mutations, in blood, is a promising avenue for cancer screening. To assess the presence of genetic variants in plasma cell-free tumor DNA from patients with precursor lesions and colorectal cancer using the commercial Oncomine Colon cfDNA Assay. Cell-free DNA (cfDNA) samples from the blood plasma of 52 Brazilian patients were analyzed. Eight patients did not have any significant lesions (five normal colonoscopies and three hyperplastic polyps), 24 exhibited precursor lesions (13 nonadvanced adenomas, ten advanced adenomas, and one sessile serrated lesion), and 20 patients with cancer (CRC). The mutation profile of 14 CRC-associated genes were determined by next-generation sequencing (NGS) using the Oncomine Colon cfDNA Assay in the Ion Torrent PGM/S5 sequencer.

  Study EGAS50000000471

• Large B cell lymphomas with CCND1 rearrangement have different immunoglobulin gene breakpoints and genomic profile than mantle cell lymphoma

  Next-generation sequencig data including whole-genome sequencing, whole-exome sequencing, and capture-based gene panels of large B cell lymphomas with CCND1 rearrangementas described in Özoğul,Montaner, Pol et al 2024.

  Study EGAS50000000564

• Synergy study: "Tissue resident CD8+ T cell clonal expansion in advanced triple negative breast cancer is associated with response to chemoimmunotherapy"

  Dataset of 10x Genomics 5'prime single-cell RNA sequencing of 40 tumor biopsy samples or triple negative breast cancer. Samples are taken before and after immuno checkpoint blockade treatment. Processed according the 10X genomics protocol, sequenced on Immumina NovaSeq6000. Raw sequencing reads are further processed with Cellranger 3.0 to get gene-expression matrices.

  Study EGAS50000000527

• Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial

  Purpose: The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). Here, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake, and to dissect the mechanisms involved in T-DM1 resistance. Experimental design: RNA was extracted from metastasis biopsies obtained at study inclusion in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with RNA sequencing data. Lesions were compared based on the level of [89Zr]trastuzumab uptake (dichotomized into high/low classes) as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT. Results: We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases (one lesion/patient). Pathways involved in extracellular matrix (ECM) organization, glycosylphosphatidylinositol synthesis, and collagen formation were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions that showed no metabolic response to T-DM1. Interestingly, immune-related processes (e.g., Fc gamma receptor activation, complement cascade) were associated with high [89Zr]trastuzumab uptake and metabolic response. Conclusions: To our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings point toward a role of ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, and highlight the potential of molecular imaging to depict tumor microenvironment features.

  Study EGAS50000000470

• Ballett

  TSO500 study: The project, called "BALLETT" (Belgian Approach of Local Laboratory Extensive Tumor Testing), has a double goal: (1) show the relevance of broad molecular profiling to improve oncological patients care, (2) demonstrate that broad molecular testing can be performed in a decentralized setting by local diagnostics laboratories in a fully standardized and uniform way while complying with the highest quality standards. NCT05058937 The publication number is: Your manuscript ID is bcr-2023-256124. Title: CUP and BRAF V600E meeting the BEACON combination.

  Study EGAS50000000478

• Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer

  Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on Magnetic Resonance Imaging (MRI). All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.

  Study EGAS50000000483

• Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers

  Ovarian cancer is the leading cause of death from gynecological cancers worldwide. No effective screening methods exist, and tumors are commonly detected at advanced stages where treatment is much less effective. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women from the European Union or the United States with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model that incorporated multi-analyte fragmentome data and protein measurements, we detected ovarian cancer with high specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I–IV, respectively (AUC=0.96, 95% CI: 0.94-0.99), including 90% of high grade serous ovarian cancers. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I–IV (p=0.001, two-sided test of equal proportions). Additionally, our approach distinguished benign masses from ovarian cancers with high accuracy (AUC of 0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.

  Study EGAS50000000484

• Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes

  Transition of cytosine to thymine in CpG dinucleotides is the most frequent type of mutation in cancer. This increased mutability is commonly attributed to spontaneous deamination of 5-methylcytosine (5mC), which is normally repaired by the base-excision repair (BER) pathway. However, the contribution of 5mC deamination in the increasing diversity of cancer mutational signatures remains poorly explored. Here, we integrate mutational signatures analysis in a large series of tumor whole genomes with lineage-specific epigenomic data to draw a detailed view on 5mC deamination in cancer. We uncover tumor type-specific patterns of 5mC deamination signatures in CpG and non-CpG contexts. We demonstrate that the BER glycosylase MBD4 preferentially binds to open chromatin domains, which correlates with lower mutational burden in these domains. We validate our findings by modelling BER deficiencies in isogenic cell models. Overall, we establish MBD4 as the main actor responsible for 5mC deamination repair in humans.

  Study EGAS50000000536

• Pipeline Olympics: Continuous benchmarking of computational workflows for DNA methylation sequencing data

  DNA methylation is a widely studied epigenetic mark and a powerful biomarker of cell type, age, environmental exposure, and disease. Genome-wide DNA methylation profiling is usually performed using whole-genome sequencing following selective conversion of unmethylated cytosines into thymines via bisulfite treatment or enzymatic methods. Numerous software tools facilitate processing of raw sequencing data for DNA methylation profiling, but a comprehensive benchmarking has been lacking. In this study, we systematically compared methods and tools for processing DNA methylation sequencing data. We established a dedicated benchmarking dataset comprising genome-wide DNA methylation profiling data for four reference samples using five experimental protocols each. The results of data processing were compared to highly quantitative locus-specific DNA methylation measurements available for 46 genomic loci. Based on this gold-standard reference dataset, we identified workflows that consistently demonstrated high performance. We present our results in an interactive application that provides a “living benchmark” ready for continuous updating as new workflows are proposed and require benchmarking against existing methods. In summary, our study provides guidance for any laboratory studying DNA methylation on a genome-wide scale.

  Study EGAS50000000541

• Single cell RNA and ATAC sequencing data from GBM patients

  Glioblastoma cells infiltrate and incorporate into the normal brain parenchyma. We conduct unbiased multimodal single-cell and spatial sequencing to capture GBM cells and the surrounding tumor microenvironment using a regional sampling strategy. For each patient, we profile the peritumoral region, tumor edge, and tumor core, providing a comprehensive characterization of the transcriptional and epigenetic landscape of GBM spatial heterogeneity, with a specific focus on infiltrative cells.

  Study EGAS50000000547

• Divergent WNT Signaling and Drug Sensitivity Profiles within Hepatoblastoma Tumors and Organoids

  Hepatoblastoma, the most prevalent pediatric liver cancer, almost always carries a WNT-activating CTNNB1 mutation, yet exhibits notable molecular heterogeneity. To characterize this heterogeneity and identify novel targeted therapies, we perform comprehensive analysis of hepatoblastomas and tumor-derived organoids using single-cell RNA-seq/ATAC-seq, spatial transcriptomics, and high-throughput drug profiling. We identify two distinct tumor epithelial signatures: hepatic ‘fetal’ and WNT-high ‘embryonal’, displaying divergent WNT signaling patterns. The fetal group is enriched for liver-specific WNT targets, while the embryonal group is enriched in canonical WNT target genes.

  Study EGAS50000000561

• Rapid brain tumor classification from sparse epigenomic data

  Although the intraoperative, molecular differential diagnosis of the approximately one hundred different brain tumor entities described to date has been a goal of neuropathology in the last decade, this has not yet been achieved in a clinically relevant time frame of less than one hour after biopsy collection. Recent advances in third-generation sequencing technologies have brought this once-elusive goal within reach. However, established machine learning techniques rely on concepts and methods, impractical for live diagnostic workflows in clinical applications. Here, we present MethyLYZR, a Naïve Bayesian framework enabling fully tractable live classification of cancer epigenomes. MethyLYZR can be run in parallel with an ongoing Nanopore experiment with negligible computational cost and provides clinically relevant and accurate cancer classification results within 15 minutes of sequencing. Therefore, only the time required for DNA extraction and the Nanopore sequencer's maximum parallel throughput remain limiting factors for even faster time-to-results. We demonstrate the potential utility of the MethyLYZR framework not only for the neurosurgical intraoperative use case but also for other oncologic indications and cell-free DNA from liquid biopsies.

  Study EGAS50000000559

• Identification and characterization of tertiary lymphoid structures in brain metastases

  Brain metastases (BrM) are the most common cancers in the brain. We performed transcriptome-wide gene expression profiling combined with spatial immune cell profiling to characterize the tumor immune microenvironment in BrM from different primary tumors. We found that BrM from lung carcinoma and malignant melanoma showed overall higher immune cell infiltration as compared to BrM from breast carcinoma. RNA sequencing-based immune cell deconvolution revealed gene expression signatures indicative of tertiary lymphoid structures (TLS) in subsets of BrM from lung cancer and melanoma. This finding was corroborated by multiplex immunofluorescence staining of immune cells in BrM tissue sections. Detection of TLS signatures was associated with prolonged survival after BrM diagnosis in lung cancer patients. Our findings highlight the cellular diversity of the tumor immune microenvironment in BrM of different cancer types and suggest a role of TLS formation for BrM patient outcome.

  Study EGAS50000000563

• Whole-genome sequencing of BRCA-mutant breast cancer patient samples from tumour, germline tissue and plasma

  The use of circulating tumor DNA (ctDNA) to profile mutational signatures presents a non-invasive opportunity for understanding cancer mutational processes. In this study we developed MisMatchFinder, a liquid biopsy approach for mutational signature detection using low- coverage whole-genome sequencing of ctDNA. Through analysis of plasma samples across multiple different cancers, we demonstrated that MisMatchFinder accurately infers single-base and doublet-base substitutions as well as indels to enhance detection of ctDNA and clinically relevant mutational signatures. This study contains fastq files from whole-genome sequencing of temporally matched tumour (fresh frozen biopsies), blood germline and plasma samples collected from a BRCA1-mutant breast cancer patient to directly compare mutation signature analysis using gold-standard tumour-germline paired variant calling with our novel ctDNA-based method (MisMatchFinder).

  Study EGAS50000000569

• Identification of HER2-positive breast cancer molecular subtypes with potential clinical implications in the ALTTO clinical trial

  In HER2-positive breast cancer, clinical outcome and sensitivity to HER2-targeted therapies are influenced by both tumor and microenvironment features. However, we are currently unable to depict the molecular heterogeneity of this disease with sufficient granularity. Here, by performing gene expression profiling in HER2-positive breast cancers from patients receiving adjuvant trastuzumab in the ALTTO clinical trial, we identified and characterized five molecular subtypes associated with the risk of distant recurrence: immune-enriched (IM), proliferative/metabolic-enriched (P/Met), mesenchymal/stroma-enriched (Mes/S), luminal (LUM), and ERBB2-enrichedERBB2-dependent (ERBB2-EERBB2-D). We next validated the biological profiles of the subtypes and explored their prognostic/predictive value in external cohorts, namely the NeoALTTO trial, SCAN-B, I-SPY2, METABRIC and TCGA. IM tumors presented better survival outcomes, in contrast to Mes/S and P/Met tumors, while LUM tumors and ERBB2-EERBB2-D were characterized by low and high rates of pathological complete response, respectively. Of note, these molecular subtypes provide the rationale for treatment approaches leveraging the heterogeneous biology of HER2-positive breast cancer.

  Study EGAS50000000525

• Sensitive urothelial cancer detection via high volume urine DNA analysis

  Cystoscopy and imaging are the gold standard for urothelial cancer (UC) detection and surveillance, but cystoscopy is an uncomfortable procedure associated with adverse effects and a low diagnostic yield as only 10% of hematuria patients have UC. Urine tumor DNA (utDNA) is a non-invasive UC biomarker that has suffered from poor sensitivity for Ta stage tumors (<80%). We hypothesized that high urine volume analysis with a multi-gene panel could overcome these limitations, and developed a 100 mL utDNA laboratory platform (UroScout) that analyzes 25 commonly mutated UC genes and 8 copy number-altered loci for somatic alterations to detect UC.

  Study EGAS50000000630

• Tumor Profiler AML Study

  Multi-omics data generated from 22 samples from the Tumor Profiler AML cohort

  Study EGAS50000000577

• TransNEO neoadjuvant breast cancer study

  Study EGAS00001004582

• Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple negative breast cancer: phase 2 adaptive BELLINI trial. RNA-Seq

  The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary endpoint: two-fold increase in CD8+ T cells or IFNG), providing rationale for neoadjuvant ICI without chemotherapy. In window of opportunity cohorts A (4 weeks anti-PD1) and B (4 weeks anti-PD1 + anti-CTLA4), we observed immune activation in 53% (8/15) and 60% (9/15) of patients, respectively. High tumor-infiltrating lymphocytes (TILs) correlated with response. Based on these data, we opened cohort C for patients with high TILs (≥50%) who received 6 weeks neoadjuvant anti-PD1 + anti-CTLA4 followed by surgery (primary endpoint: pathological complete response, pCR). 53% (8/15) of patients had major pathological response (< 10% viable tumor) at resection, with 33% (5/15) having pCR. All cohorts met Simon’s two-stage threshold for expansion to stage II. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early TNBC.

  Study EGAS50000000567

• Single-cell targeted DNA-sequencing and protein sequencing

  We performed single-cell targeted DNA sequencing (MissionBio) on 13 high hyperdiploid B-ALL patients at diagnosis to study the genetic heterogeneity. For a number of patients single-cell surface protein antibody sequencing was added (DAB-seq) to better characterize the different cell types. Furthermore, additional samples during treatment were collected and analysed for some patients. In this way we want to study the clonal heterogeneity of these B-ALL samples, based both on mutations and CNVs, and identify resistant clones that could be targeted after relapse.

  Study EGAS50000000580

• Lactate metabolism in cancer stem cell fate regulation

  Tumors arise as a result of uncontrolled cell proliferation driven by mutations in the signaling pathways that regulate the balance between cell division and differentiation. Despite of that, in the tumor, cancer stem cells seem to retain their capability to differentiate, which can lead to differential chemotherapy response. We previously showed that intestinal stem cells and differentiated cells display specific metabolic features and that they interact through metabolites. Moreover, we found that altering mitochondrial metabolism is sufficient to lead and define stem cell differentiation. In cancer, cellular metabolism is highly derailed. However, how metabolic changes in the cancer cell contribute to cell fate decisions remains unknown. Recently, the crosstalk between metabolism and epigenetics has emerged as one of the players in tumor development. Here we aim to address the impact of the altered metabolism of cancer cells on their epigenome as a regulatory axis of cell identity and fate. We use human-derived tumor organoids where we introduce genetic encoded fluorescent-based reporters to visualize cell identity and metabolism at single cell level. We combine 4D live imaging with a recently developed machine learning method to re-construct cell-lineages, trace stem cell state and metabolic changes during tumor organoid development. We find that, mimicking the tumor metabolic microenvironment (Warburg effect-driven low-glucose high-lactate) leads to changes cellular metabolism and histone acetylation. Strikingly, these alterations provoke profound changes in tumor development by increasing the population of cancer stem cells and their proliferation and differentiation dynamics.

  Study EGAS50000000063

• Selective Elimination of Immunosuppressive T cells in Patients with Multiple Myeloma

  Study EGAS00001004915

• Characterization of copy number quiet oral cancer

  Copy number quiet head and neck squamous cell carcinoma are a distinct subset with relatively good prognosis. Previous work has indicated this subset is most commonly found in the oral cavity and is highly enriched for HRAS and CASP8 mutations. TP53 mutations are much less common than in CNA-quiet oral cancers. In this study we corroborate the validity of CNA-quiet tumors as a distinct subset in a large OSCC cohort and further chart clinical, genomic, and immunological characteristics of this subset.

  Study EGAS50000000558

• Cancer cell and tumor microenvironment biomarkers associated with disease-free survival with adjuvant nivolumab in the phase 3 CheckMate 274 trial

  In the CheckMate 274 trial, adjuvant nivolumab versus placebo demonstrated an improvement in the primary endpoint of disease-free survival (DFS) in patients with high-risk muscle-invasive urothelial carcinoma after radical resection. An extensive analysis of tumor biomarkers, including their associations with DFS, was performed. Analysis of genome-wide differential gene expression and known gene signatures found that immune-related genes and pathways, in particular an IFNγ signature, were predictive of DFS in nivolumab-treated patients. Predictive and prognostic associations, respectively, were found for tumor-infiltrating CD4 and CD8 T cells. Analysis of a composite predictive model suggested that CD4 gene expression and tumor cell PD-L1 expression had the greatest contributions to predicting outcomes in nivolumab-treated patients. These results reinforce recent studies establishing the importance of biomarkers of adaptive immunity, and in particular CD4 T cells, in influencing response to PD-1/PD-L1 blockade and establish the potential predictive rather than solely prognostic nature of such findings.

  Study EGAS50000000560

• Ex vivo modeling of precision immuno-oncology responses in lung cancer

  Single-cell RNA-sequencing (scRNA-seq) data from paired lung cancer organoids and immune cells. The experiment was performed using the Single Cell 5' solution of 10X Genomics. The dataset includes 15 samples from 4 multiplexed experiments. The multiplexing was performed using the Feature Barcoding technology of 10X Genomics.

  Study EGAS50000000593

• Targeted gene panel sequencing of leiomyosarcoma

  We conducted MSK-IMPACT sequencing of leiomyosarcoma.

  Study EGAS50000000595

• Whole-exome sequencing identifies new pathogenic germline variants in patients with colorectal polyposis

  Adenomatous polyposis confers an increased risk of colorectal cancer development. Here, we investigated probably underlying predisposition variants in patients with suspected colorectal polyposis without variants in APC and MUTYH genes by whole exome sequencing (WES). Twenty-seven patients were included and subjected to germline WES. After filtering out variants for sequencing quality, variant allele fraction frequency, and population frequency, variants were manually prioritized by the ACMG criteria. Among the variants identified, 17 were classified as pathogenic or likely pathogenic (in 12 patients). This study gives information of probably associated polyposis variants in Brazilian patients without germline pathogenic variants in APC and MUTYH genes, supporting the utilization of next-generation sequencing for screening in these patients beyond these genes.

  Study EGAS50000000591

• Somatic mutations in healthy and leukemic blood progenitors reveal evolutionary mechanisms underlying childhood leukemia and differential patient outcome

  Study EGAS00001004593

• Tumor Profiler Melanoma Study

  The Tumor Profiler Study is an observational trial combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making with an exploratory approach to improve the biological understanding of the disease. Technologies used are digital pathology, targeted NGS, single-cell RNA, single-cell DNA, bulk RNA, bulk proteotyping, single-cell CyTOF, imaging mass cytometry, pharmacoscopy, 4i Drug Response Profiling, and cell-free DNA. These technologies were applied to 240 tumor samples collected over 3 years across three cancer indications: metastatic melanoma, metastatic epithelial ovarian cancer, and acute myeloid leukemia (AML). Here, we publish the scRNA, scDNA, and bkRNA data of the melanoma cohort.

  Study EGAS50000000599