14430 results for ""Pennsylvania+German"+ACS+study+'Socius'+open+access"

in 25.20 milliseconds.

• Ongoing Replication Stress Tolerance and Clonal T Cell Responses Distinguish Liver and Lung Recurrence and Patient Outcomes in Pancreatic Ductal Adenocarcinoma

  Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) survive longer when disease spreads to the lung but not to the liver. We generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease progression results in lung metastasis without liver metastases (lung cohort). Lung cohort patients generally survived longer than liver cohort patients, independent of tumor subtype. We developed a pORG gene signature that distinguishes primary tumors in the liver and lung cohorts. We identified ongoing replication stress (RS) response pathways in high pORG/liver cohort tumors, while low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid PDAC is associated with tolerance to ongoing RS, limited tumor immunity, and less favorable outcomes; whereas low RS, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes. As expected, we found high frequencies of KRAS, TP53, CDKN2A, and SMAD4 gene alterations in our tumor samples. High pORG activity (GSVA scores) in our primary tumors appear to be positively correlated with alteration frequencies in both TP53 and CDKN2A. We did not see a correlation with alterations in KRAS as almost all the tumor samples have KRAS alterations. From a de-identified dataset of 1,873 patients diagnosed with and/or treated for PDAC at our institution between 2004 and 2020, we identified 422 patients for which we had specimens with sequencing data (N=374) and/or specific evidence of disease metastasis site(s) from the OHSU cancer registry or disease-relevant computed tomography (CT) scans to allow cohort classification. Note that our study includes RNA-Seq, DNA-Seq panel, and TCR-Seq (T-cell Receptor Sequencing) data, but that this dbGaP submission just includes the patients/samples with RNA-Seq and/or DNA-Seq panel data. Therefore, this submission includes 290 samples from 278 patients. TCR sequence data is available on the Adaptive Biotechnologies platform. Clinical course timepoints, patient demographics, stage, grade, nodal involvement, resection margins, and angiolymphatic invasion were provided as deidentified data by the OHSU cancer registry with quality control data verification in a subset by pathologists (BB and TM). We reviewed all available computed tomography (CT) scans for all patients with primary tumor resection dates recorded by the cancer registrar, with tumor samples analyzed by RNA-seq, DNA-seq, or TCR-seq, and/or with additional information indicating metastatic spread (e.g., metastatic samples received for related studies). We abstracted the site of all lesions proven to be metastatic by biopsy and/or that clearly increased in size during progression or decreased in size during treatment as long as a radiologist described the lesion as “likely”, “suspicious for”, “concerning for”, or “favor” metastasis. Clinical imaging was reviewed by a radiologist (AG) to validate patient assignments to the liver, lung, and neither liver nor lung (other recurrence site) cohorts. Time to recurrence was calculated from the earliest of either the recurrence date provided by the OHSU cancer registry, or the date of earliest lesion abstracted from CT reports. The subject attributes reported in this submission were up to date at the time of our data freeze, which occurred July 2021.

  Study phs003597

• Prediction of Resistance and Sensitivity to HER2 Targeted Therapy in the Neoadjuvant Setting

  Women with breast cancers that overexpress HER2 are at greater risk for disease progression and death than women whose tumors do not overexpress HER2. Trastuzumab, a recombinant humanized monoclonal antibody against the extracellular domain of the HER2 protein blocks downstream signaling of HER2 and substantially improves the efficacy of chemotherapy in women with metastatic and early-stage HER2-positive breast cancers. Because resistance to trastuzumab eventually results in progressive disease in the metastatic setting and contributes to recurrence following adjuvant trastuzumab-based therapy, it is important to develop agents other than trastuzumab that target HER2 signaling through different mechanisms of action. Lapatinib is an oral, small molecule, dual tyrosine kinase inhibitor of HER2 and EGFR. Lapatinib has shown a lack of cross-resistance with trastuzumab in preclinical studies and activity in women with HER2-positive, metastatic breast cancer that has progressed during trastuzumab treatment. Trastuzumab blocks the downstream signaling of HER2 by binding to the extracellular domain of the receptor. Lapatinib binds to the intracellular domains of HER2 and EGFR and prevents activation of downstream signaling pathways. Because of this different mechanism of action, lapatinib may be effective in trastuzumab-resistant disease. The study will also provide important safety information on trastuzumab and lapatinib combinations immediately following anthracycline exposure, and also provide an initial direct comparison of cardiac effects of trastuzumab and lapatinib when incorporated into a standard sequential adriamycin and cyclophosphamide (AC) followed by weekly paclitaxel neoadjuvant regimen. Availability of a second agent that can interrupt HER2-signaling pathways through completely different mechanisms than those of trastuzumab offers the potential for further improvement in the management of patients with HER2-overexpressing breast cancer in both the adjuvant and metastatic setting. Co-administration of both trastuzumab and lapatinib with chemotherapy may be important in improving outcomes in subsets of HER2-positive breast cancers. However, use of two inhibitors of the HER2 pathway will increase costs and may increase toxicity, so it will be important to identify the subsets of patients who would benefit from the dual therapy. Inhibition of HER2 with a single agent clearly is sufficient for many patients as evidenced by the results of the trastuzumab trials. Therefore, co-administration to unselected populations of women with HER2-positive breast cancers would not represent an optimal approach. Given the activity of lapatinib, it is likely that it will also be sufficiently active in inhibiting HER2-pathway activation in some patients to allow for its use as the sole inhibitor of the HER2 pathway. Different populations may also derive greater benefit from one of the HER2-blocking agents relative to the other. Identification of potential predictive factors for pathologic complete response to the combination or to either agent administered alone in neoadjuvant trials would provide important information for adjuvant trials designed to definitively address these important issues. This study will compare 3 combined chemotherapy regimens: AC followed by paclitaxel plus trastuzumab and lapatinib, AC followed by paclitaxel plus lapatinib, and AC followed by paclitaxel plus trastuzumab given before surgery to patients with HER2-positive breast cancer.Tumor samples were collected prior to and post-treatment, and RNA sequencing was performed with this version.

  Study phs003275

• Recurrent DNMT3B gene rearrangements are associated with unfavorable outcome in dicentric (9;20)-positive pediatric BCP-ALL

  The dicentric chromosome dic(9;20)(p11∼13;q11), occurs in 2% of pediatric acute lymphoblastic leukemia (ALL) cases. However, the prognostic significance of the dic(9;20) alterations and the mechanism in which these alterations drive leukemogenesis remains elusive. Our study describes the demographic, clinical, prognostic, and molecular characteristics of the dic(9;20)-positive ALL in a cohort of 57 pediatric BCP-ALL patients. Targeted RNA-seq and Array CGH analysis unraveled heterogeneous breakpoints on chromosomes 9 and 20 and frequent deletions of the IKZF1 gene. Together with the intrinsic susceptibility for deletions in CDKN2A, CDKN2B, and PAX5 genes in the dic(9;20)-positive ALL, these patients are eligible for treatment escalation in the AIEOP-BFM ALL 2017 clinical study. Survival analysis revealed poor 5-year event-free survival (pEFS) of 69% in dic(9;20)-positive ALL cases, compared to BCP-ALL patients enrolled in modern treatment studies. Strikingly, we identified six dic(9;20)-positive cases with rearrangements involving the DNMT3B gene, and poor 5-year pEFS of 25% (SE = 20%), compared to 79% (SE = 9%) for the remaining cohort (P = 0.011). Despite the loss of the methyltransferase domain of the DNMT3B gene in most cases with DNMT3B rearrangements, we did not observe major changes in the global methylation patterns. Differential gene expression analysis of DNMT3B-rearranged ALL unraveled a dysregulation of genes involved in hematopoiesis, lymphocyte maturation, and the PI3K/AKT signaling pathway. After confirmation in an independent cohort, DNMT3B-rearranged ALL cases should be considered high-risk for relapse and treated accordingly. We provide clinical data sets of Array CGH, targeted RNA-seq, total RNA-seq, whole genome bisulfite (WGBS) and whole genome DNA sequencing (WGS) obtained from bone marrow (BM) or peripheral blood (PB) mononuclear cells of 57 pediatric patients with dicentric chromosome dic(9;20) positive Acute lymphocytic leukemia (ALL), from which in 6 cases DNMT3B gene rearrangement was identified. This data is complemented by total RNA-seq and WGBS of samples from 4 additional ALL patients with a t(12;21) translocation and ETV6-RUNX1 gene fusion. DNA was isolated from BM or PB lymphocytes using Qiagen QIAamp DNA Blood Midi Kit to perform i) Array CGH of 58 dic(9;20) positive samples by hybridizing 500ng DNA using a Agilent 400K SurePrint G3 Custom CGH Human Genome Microarray (e-Array design 84704) ii) WGBS of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples using Tecan TrueMethyl oxBS-Seq module for library preparation and Illumina NovaSeq 6000 platform to run 2x151 cycles iii) WGS of DNMT3B rearrangement positive samples using Illumina Lotus DNA Library Prep Kit followed by sequencing running 2x160 cycles on an Illumina NovaSeq 6000 platform. RNA was isolated from PB lymphocytes using the PerkinElmer Chemagic 360 instrument, followed by i) targeted RNA-seq of 56 dic(9;20) positive samples prepared using Illumina TruSight RNA Pan-Cancer Panel and sequenced on an Illumina MiSeq platform running 2x75 cycles ii) total RNA-seq of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples utilizing TruSeq Stranded Total RNA Library Prep Gold kit and running 2x100 cycles on an Illumina NovaSeq 6000 platform.

  Study EGAS00001007383

• Disorders/Differences of Sex Development (DSD) Study Performed at UCLA in Collaboration with the DSD-Translational Research Network (DSD-TRN), with the Support of the Gabriella Miller Kids First Pediatric Research Program

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. Whole Genome Sequence (WGS) and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Disorders/Differences of Sex Development (DSD) are congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical. DSD are chronic medical conditions collectively affecting ~1% of the population, frequently requiring life-long care by multiple specialists, and carrying a significant public health burden. Some are associated with life-threatening events, such as adrenal crises in Congenital Adrenal Hyperplasia (CAH). DSD are also associated with increased infertility, cancer, gender dysphoria risks, psychosocial distress and pervasive challenges to health-related quality of life (HRQoL) for patients and families. DSD are broadly classified into three categories: sex chromosome DSD, 46,XY DSD and 46,XX DSD, and further classified according to the type of gonad found in the patient (ovary, testis, ovotestis). We were able to increase significantly the diagnostic success for DSD using Whole Exome Sequencing (WES), with the identification of disease-causing and likely pathogenic variants in a third of a cohort of 46,XY patients. We have therefore proposed a shift in the diagnostic approach to DSD to use next-gen sequencing as a first-line clinical test, which could lead to faster and more accurate diagnosis, and orient further clinical management, limiting unnecessary, costly, and often invasive endocrine testing and imaging. However many remain unexplained (over half of the XY cases, a significant minority of XX cases, including most ovotesticular DSD, and most syndromic cases). In addition, the very large phenotypic variability in cases with known variants in the same gene is unexplained. We here propose to use Whole-Genome Sequencing (WGS), which dramatically improves upon exome sequencing, covering both coding and non-coding parts of the genome more uniformly, as an approach to not only improve diagnostic yield, but also to identify novel genes and regulatory elements involved in DSD.

  Study phs001178

• Relationship between low LDL cholesterol concentrations not due to statin therapy and risk of type 2 diabetes: a US-based cross-sectional observational study using electronic medical records

  Lipid lowering therapy using HMG-CoA reductase inhibitors (statins) is associated with an approximately 9-12% increase in the risk of new-onset type 2 diabetes (T2DM). The risk of diabetes could be increased by statins directly; however, genetic approaches have also implicated low LDL cholesterol (LDL-C) concentrations as a risk factor for T2DM. Mendelian randomization studies using functional variants in both HMGCR (GeneID:3156) and PCSK9 (GeneID:255738) genes found a higher risk of T2DM in individuals with variants associated with lower LDL-C concentrations. Since PCSK9 and HMGCR are involved in lipid metabolism through distinct molecular pathways, the altered glycemic effect associated with variants in both genes is likely to be the result of their common effect on LDL-C concentrations. Despite the findings from statin clinical trials and genetic studies, there is little direct evidence implicating low LDL-C concentrations with increased risk of T2DM. Individuals who have very low LDL-C concentrations not due to lipid lowering therapy can provide insights into the relationship between low LDL-C concentrations and T2DM. Here, we used de-identified electronic health records (EHRs) to test the hypothesis that low LDL-C concentrations are associated with T2DM.

  Study phs001588

• Sporadic Amyotrophic Lateral Sclerosis (ALS): Parent-Offspring and Twin Sequencing Study

  Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that affects the nerves in the brain and spinal cord, leading to muscle weakening and eventual paralysis and death. Ten percent of ALS cases are thought to be familial while the majority of cases are sporadic and the causative factors unknown. Dr. Roger Pamphlett of the University of Sydney has collected a unique cohort of consented trios where the child has ALS but the parents are unaffected. Since the age of onset is so late, it is very difficult to obtain this kind of trio. We have performed whole exome sequencing on these trios to identify de novo and recessive germline variants associated with sporadic ALS. In addition, Dr. Pamphlett has assembled a collection of consented discordant monozygotic twins, where one twin has ALS and the other is unaffected. We performed whole genome sequencing on these twin pairs to identify postzygotic variants that may contribute to sporadic ALS susceptibility. Finally, we have the opportunity to compare the sequence and gene expression in affected and unaffected tissues from blood, brain and/or spinal cord samples from consented ALS patients to look for somatic mutations or gene expression changes that may further our understanding of the disease.

  Study phs000831

• The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma

  Patients with metastatic uveal melanoma (UM) have an abysmal prognosis. Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. Here we test if epigenetic therapy would enhance PD-1 immunotherapy in patients with metastatic UM. We report the results of the PEMDAC phase 2 clinical trial (n=29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic UM. The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Extensive genomics studies were performed using DNA/RNA and single cell sequencing and flow cytometry. Objective responses and prolonged survival were seen in three patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM. Further exploration of combined immunotherapy and epigenetic therapy in metastatic UM is warranted.

  Study EGAS00001005478

• Summary statistics from genome-wide association study in glioma of 12,488 cases and 18,169 controls.

  Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,488 cases and 18,169 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

  Study EGAS00001003372

• RNA-seq study of human long-term and short-term hematopoietic stem cells from umblical cord blood with lentiviral overexpression of S1PR3

  To investigate the molecular and biological pathways altered by S1PR3OE in human hematopoietic stem cells (HSC), we performed RNA-sequencing (RNA-seq) of LT- and ST-HSC 3 days after transduction with control or S1PR3 overexpression (OE) lentiviral vectors. LT-HSC and ST-HSC from 3 pool of CB lin- were FACS-purified, cells were prestimulated for 4 hours and transduced with lentiviral vectors. At day 3, 2000-5300 BFP+ cells were FACS-purified for RNA isolation with a PicoPure kit. We were able to isolate only 1600-1800 BFP+ cells from LT-HSC control samples as opposed to 4000-5400 BFP+ cells from S1PR3OE samples. Thus, we pooled all control BFP+ LT-HSC cells into one sample for RNA-seq analysis. BFP- LT-HSC from control vector transduction were purified from CB1 as an additional LT-HSC control. Nextera libraries generated from 10 ng RNA from 5 LT-HSC samples (2 controls, 3 S1PR3OE) and 6 ST-HSC samples (3 controls, 3 S1PR3OE) were subjected to 125 bp, paired-end RNA-sequencing on the Illumina HiSeq 2500 with an average of 50 million reads/sample at the Center for Applied Genomics, Sick Kids Hospital.

  Study EGAS00001004798

• FASTQ files of total RNA-Seq data from the POPS PET (pre-eclamptic) samples

  All the samples were obtained from the Pregnancy Outcome Prediction–a prospective cohort study of nulliparous women attending the Rosie Hospital, Cambridge (UK) for their dating ultrasound scan between January 14, 2008, and July 31, 2012. Ethical approval for the study was given by the Cambridgeshire 2 Research Ethics Committee (reference number 07/H0308/163) and all participants provided written informed consent. Cases of preeclampsia (PET) were defined on the basis of the 2013 ACOG criteria and cases of small for gestational age (SGA)infants were confined to severe SGA, i.e. a customized birth weight <5th percentile. Chorionic villi from the corresponding placentas (free from decidua, visible infarction, calcification, hematoma, or damage) were collected and processed within 30 minutes of separation from the uterus. After repeated washes in chilled phosphate buffered saline, the samples were placed in RNA later (Applied Biosystems) and stored at -80°C. Total placental RNA was extracted using mirVana Isolation Kit (Ambion). For each placenta, approximately 5 mg of tissue were homogenized in the Lysis/Binding solution for 20 sec at 6 m/s using a bead beater (FastPrep24) and Lysing Matrix D Tubes (MP Biomedicals). The samples were then spun at 13,000 rpm for 5 min at 4°C and the supernatants recovered. Afterwards, the manufacturer's instructions were followed. Immediately after the RNA extraction, placental RNA samples were DNase-treated using DNA-free DNA Removal Kit (Ambion), aliquoted, and stored in -80°C. Quantity and quality of the RNA samples were assessed using the Agilent 2100 Bioanalyzer, the Agilent RNA 6000 Nano Kit (Agilent Technologies), and Qubit fluorometer. Libraries were prepared starting with 300-500 ng of good quality total RNA (RIN ≥7.5) using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Human/Mouse/Rat (Illumina), according to the manufacturer's instructions. The kit contains 96 uniquely indexed adapter combinations in order to allow pooling of multiple samples prior to sequencing. After determining their size (with the Agilent 2100 Bioanalyzer and the Agilent High Sensitivity DNA Kit by Agilent Technologies) and concentration (by qPCR with the KAPA Illumina ABI Prism Library Quantification Kit, Kapa Biosystems), libraries have been pooled and sequenced (single-end, 125 bp) using a Single End V4 Cluster Kit and an Illumina HiSeq2500 or HiSeq4000 instrument.

  Dataset EGAD00001003508

• FASTQ files of total RNA-Seq data from the POPS SGA (Small for Gestational Age) samples

  All the samples were obtained from the Pregnancy Outcome Prediction–a prospective cohort study of nulliparous women attending the Rosie Hospital, Cambridge (UK) for their dating ultrasound scan between January 14, 2008, and July 31, 2012. Ethical approval for the study was given by the Cambridgeshire 2 Research Ethics Committee (reference number 07/H0308/163) and all participants provided written informed consent. Cases of preeclampsia (PET) were defined on the basis of the 2013 ACOG criteria and cases of small for gestational age (SGA)infants were confined to severe SGA, i.e. a customized birth weight <5th percentile. Chorionic villi from the corresponding placentas (free from decidua, visible infarction, calcification, hematoma, or damage) were collected and processed within 30 minutes of separation from the uterus. After repeated washes in chilled phosphate buffered saline, the samples were placed in RNA later (Applied Biosystems) and stored at -80°C. Total placental RNA was extracted using mirVana Isolation Kit (Ambion). For each placenta, approximately 5 mg of tissue were homogenized in the Lysis/Binding solution for 20 sec at 6 m/s using a bead beater (FastPrep24) and Lysing Matrix D Tubes (MP Biomedicals). The samples were then spun at 13,000 rpm for 5 min at 4°C and the supernatants recovered. Afterwards, the manufacturer's instructions were followed. Immediately after the RNA extraction, placental RNA samples were DNase-treated using DNA-free DNA Removal Kit (Ambion), aliquoted, and stored in -80°C. Quantity and quality of the RNA samples were assessed using the Agilent 2100 Bioanalyzer, the Agilent RNA 6000 Nano Kit (Agilent Technologies), and Qubit fluorometer. Libraries were prepared starting with 300-500 ng of good quality total RNA (RIN ≥7.5) using the TruSeq Stranded Total RNA Library Prep Kit with Ribo-Zero Human/Mouse/Rat (Illumina), according to the manufacturer's instructions. The kit contains 96 uniquely indexed adapter combinations in order to allow pooling of multiple samples prior to sequencing. After determining their size (with the Agilent 2100 Bioanalyzer and the Agilent High Sensitivity DNA Kit by Agilent Technologies) and concentration (by qPCR with the KAPA Illumina ABI Prism Library Quantification Kit, Kapa Biosystems), libraries have been pooled and sequenced (single-end, 125 bp) using a Single End V4 Cluster Kit and an Illumina HiSeq2500 or HiSeq4000 instrument.

  Dataset EGAD00001003507

• Clinical outcomes and immune correlates of response to nivolumab plus chemoradiotherapy in women with locally-advanced cervical cancer – NiCOL study

  Concurrent chemoradiotherapy (CRT) with blockade of the PD-1 pathway may enhance immune-mediated tumor control through increased phagocytosis, cell death, and antigen presentation. The NiCOL phase 1 trial was designed to determine safety, tolerance, and immune correlates of response to the PD-1 blocking antibody, nivolumab, with and following concurrent CRT in 16 women with locally advanced cervical cancer (LACC). Three patients experienced grade 3 dose-limiting toxicities. The overall response rate was 93.8% [95%CI: 69.8%-99.8%] with a 2-year PFS of 75% [95% CI: 56.5%-99.5%]. Compared to patients with progressive disease (PD), progression-free (PF) subjects showed a brisker stromal immune infiltrate, higher proximity of tumor-infiltrating CD3+ T cells to PD-L1+ tumor cells and of Foxp3+ T cells to proliferating CD11c+ myeloid cells. PF had higher baseline levels of PD-1 on EMRA CD4+ T cells and ICOS-L on tumor-associated macrophages (TAMs) vs PD, which instead displayed enhanced PD-L1 expression on TAMs and higher, circulating frequencies of proliferating Tregs at baseline. Concomitant nivolumab plus definitive CRT is safe and associated with encouraging PFS rates. Further validation in the subset of LACC displaying pre-existing, adaptive immune activation is warranted.

  Study EGAS00001007297

• NIPT samples for systematic evaluation of NIPT aneuploidy detection software tools

  This dataset contains two sets of samples. The reference sample set consists of a total of 669 samples that had been reported previously to be euploid by the NIPTIFY screening test. The validation sample set is based on a previously published validation study by Zilina et al. (1), consisting of 423 samples, of which 259 were high-risk pregnancies that had undergone diagnostic invasive prenatal analysis (1). All samples were sequenced with Illumina NextSeq 500 platform, producing 85 bp single-end reads with an average per-sample coverage of 0.32× at the University of Tartu, Institute of Genomics Core Facility, according to the manufacturer’s standard protocols, as described previously (1). This study was performed with the approval of the Research Ethics Committee of the University of Tartu (#315/T-13). 1. Zilina O, Rekker K, Kaplinski L, Sauk M, Paluoja P, Teder H, et al. Creating basis for introducing non‐invasive prenatal testing in the Estonian public health setting. Prenat Diagn [Internet]. 2019 Dec 6;39(13):1262-8. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/pd.5578

  Dataset EGAD00001007712

• ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas

  We have sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas

  Study EGAS00000000075

• DO NOT USE - Whole genome sequencing of SI-NETs from six patients

  Small intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, often displays a curious multifocal phenotype with several intestinal tumors centered around a regional lymph node metastasis, yet the typical path of evolution of these lesions remains unclear. Here, we determined the complete genome sequences of 24 tumor and 3 adjacent normal tissue samples with their paired normal blood samples (totally 33 whole genomes) from 6 patients with multifocal SI-NETs, allowing elucidation of phylogenetic relationships between multiple intestinal tumors and metastases in individual patients.

  Study EGAS00001005009

• ICGC Prostate Cancer Whole Genome Sequencing

  To characterize the subclonal genomic architecture of androgen-deprived metastatic prostate cancer, we performed whole-genome sequencing (WGS) of 51 tumours from 10 patients to an average sequencing depth of 55x, including multiple metastases from different anatomic sites in each patient and, in five cases, the prostate tumour. Noncancerous DNA from blood or other tissue is used as reference comparison for each patient. The patients are part of PELICAN (Project to ELIminate Lethal Cancer) rapid autopsy study led by G. Steven Bova at Johns Hopkins University (USA) and Tampere University (Finland). As of September 2020, some of the studies using these data include: Gundem et al, Nature 2015 (PMID: 25830880). Additional EGAD00001000891 sample metadata is contained in Supplementary Information in this report.Tubio et al, Science 2014 (PMID: 25082706) Behjati et al, Nature Comm 2015 (PMID: 27615322) Wedge et al, Nature Genetics 2018 (PMID: 29662167)Pan-Cancer Analysis of Whole Genomes, Nature 2020 (PMID: 32025007)Rodriguez-Martin et al, Nature Genetics 2020 (PMID: 32024998)Woodcock et al, Nature Comm 2020 (In Press)

  Dataset EGAD00001000891

• Shallow Whole Genome Sequencing of Patient Derived Xenografts

  Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we leveraged a comprehensive collection of 27 molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. Genetic analyses revealed that treatment sensitivity was marked by genomic scars indicative of BRCAness, suggesting homologous recombination (HR) deficiency as a key determinant. Accordingly, we surveyed a manually curated panel of 44 genes with a documented role in HR for the potential presence of pathogenic mutations. We did not observe a specific enrichment of HR gene mutations based on response to FOLFIRI. This result, combined with the absence of widespread biallelic inactivation of the analyzed genes and the predominance of mutations categorized as variants of unknown significance, suggests that FOLFIRI sensitivity is not primarily governed by underlying mutations in HR genes responsible for mitigating the genotoxic effects of this therapeutic regimen.

  Dataset EGAD50000000277

• A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome

  Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.

  Study EGAS50000000021

• Whole exome sequencing of pediatric soft tissue sarcoma PDX models

  Childhood cancer remains one of the leading causes of death in pediatric patients in Europe. Pediatric sarcomas, comprising soft tissue sarcomas and malignant bone tumors, are a heterogenous group of malignancies, with more than 50 subtypes (WHO classification). Due to low case numbers, studying pediatric sarcomas requires accurate and reliable preclinical models. Here, we established 18 soft tissues sarcoma PDX models, including Ewing Sarcoma, Rhabdmyosarcoma and Osteosarcoma. We characterized these models by Whole Exome Sequencing and assessd the response to a wide range of drugs.

  Study EGAS50000000048

• Whole Genome Sequencing to Discover Familial Myeloma Risk Genes

  We identified germline KDM1A truncating mutations in patients with multiple myeloma (MM), and loss of heterozygosity (LOH) in tumors. KDM1A mutation burden is higher in sporadic MM patients than in controls, and mRNA levels are lower in MM compared with normal plasma cells. KDM1A pharmacological inhibition in vitro promotes myeloma cell proliferation, and in mice promotes plasma cell expansion, enhanced secondary immune response to T cell dependent antigens, and upregulation of MYC oncogene transcriptional targets. Our findings provide important new insights into the role of KDM1A to suppress B cell malignancies.

  Study phs001819

• Accurate Genome-Wide Germline DNA Profiling from Decade-Old Archival Tissue Specimens

  We evaluate the validity of repurposing archival tissue specimens for germline genetic studies. We performed lc-WGS and imputed genotypes on 10 pairs of matching blood and tumor tissue and benchmarked the accuracy of genome-wide genotypes, HLA haplotypes, and several polygenic risk scores (PRSs). The reported results indicate the high accuracy of germline genotypes and haplotypes obtained from archival tissue DNA. Using this methodology, we estimate breast cancer PRS in 36 Ductal carcinoma in situ (DCIS) patients and demonstrate its association with breast cancer subsequent event (BCSE).  

  Study phs002865

• Genomic Landscape of Cutaneous Diffuse Large B Cell Lymphoma

  Cutaneous diffuse large B cell lymphomas (DLBCL) are aggressive lymphomas with a poor prognosis. To elucidate their genetic bases, we performed whole exome capture and massively parallel sequencing on 19 tumor samples of diffuse large B cell lymphoma, leg type (DLBCL-LT) and 6 samples of secondary cutaneous diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS). Tumor specimens and their associated sequencing data were from multiple institutions, including Northwestern University (Chicago, IL), Massachusetts General Hospital (Boston, MA), and Medical University of Graz (Graz, Austria).

  Study phs001645

• Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer

  We generated a collection of patient-derived pancreatic normal and cancer organoids. We performed whole genome sequencing, targeted exome sequencing, and RNA sequencing on organoids as well as matched tumor and normal tissue if available. This dataset is a valuable resource for pancreas cancer researchers, and those looking to compare primary tissue to organoid culture. In our linked publication, we show that pancreatic cancer organoids recapitulate the mutational spectrum of pancreatic cancer. Furthermore, RNA sequencing of organoids demonstrates the presence of both transcriptional subtypes of pancreas cancer.

  Study phs001611

• Genomic Characterization of Meningiomas

  Meningiomas are the most common primary brain tumor in the US. Although the tumor suppressor gene NF2 is disrupted in approximately half of meningiomas, the complete spectrum of genetic changes in meningiomas remains poorly understood, particularly in the large subset of tumors without NF2 alterations. Therefore we performed whole-genome sequencing from 11 Grade I meningioma tumor-normal pairs and whole-exome sequencing from an additional 6 tumor-normal pairs to identify somatic mutations, insertions-deletions, copy-number alterations and rearrangements. We validated our results by performing focused sequencing across 48 additional meningiomas.

  Study phs000552

• Performance Characteristics of Selective Targeted Enrichment in Genetic Diagnostic Testing

  The Nex-StoCT and ACMG recommend that validation of an NGS-based diagnostic test include performance test characteristics for assay accuracy, analytical sensitivity and specificity, reproducibility and repeatability. To measure these parameters for the GEDi capture and sequencing test, 4 samples (three randomly selected patient samples and the NA12878 HapMap sample) were prepared and sequenced in triplicate on each of three separate days. We also performed WES and SNP array genotyping analyses of these 4 samples using Agilent V4+UTR whole exome enrichment kit and Illumina Omni 2.5 SNP arrays, respectively.

  Study phs000798