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• Circulating kidney injury molecule-1 (KIM-1) and association with response to adjuvant immunotherapy in renal cell carcinoma

  Adjuvant immunotherapy is currently the standard of care for patients with resected renal cell carcinoma (RCC) at increased risk of recurrence, but there are no biomarkers available to guide treatment decisions. Kidney injury molecule-1 (KIM-1) has previously been described as a potential circulating biomarker in renal cell carcinoma. We evaluated biomarkers and outcomes among patients who participated in a randomized phase III trial of adjuvant atezolizumab versus placebo in resected RCC (IMmotion010). This trial did not meet its primary DFS endpoint in the intention-to-treat population. An affinity-based proximity extension proteomics assay was used to compare levels of circulating proteins among baseline (post-nephrectomy) serum samples and also with samples taken at time of recurrence. We demonstrate that serum KIM-1 was the most significantly enriched protein at recurrence versus baseline. Patients with serum KIM-1high at baseline had worse disease-free survival (DFS) (hazard ratio 1.68, 95% CI 1.35-2.09), but also had improved DFS when treated with adjuvant atezolizumab versus placebo (hazard ratio 0.72, 95% CI 0.52-0.99). An increase in KIM-1 during follow-up was associated with worse DFS compared to patients with no increase in KIM-1. Comparison of transcriptomic expression profiles in paired primary and recurrent tumor samples revealed that metastatic recurrence is associated with upregulation of transcriptional programs associated with tumor proliferation and myeloid immune suppression. Downregulation of an MHC class I signature was seen among patients with recurrence after treatment with atezolizumab but not placebo, suggesting this is a mechanism of resistance to PD-L1 immunotherapy. These analyses suggest that elevated post-nephrectomy serum KIM-1 enriches for benefit from adjuvant immunotherapy in RCC, and that biomarker driven adjuvant therapy should be evaluated as a potential new paradigm in RCC trials.

  Study EGAS50000001285

• IL2 data set including 59 samples

  The dataset is referenced by EGA Study ID EGAS00001003605, which includes the short-reads data for 59 samples. All short-reads data files are in fastq format.

  Dataset EGAD00001004967

• Single-cell Analysis of Neoplastic Plasma Cells Identifies Myeloma Pathobiology Mediators and Potential Targets

  Multiple myeloma is a clonal plasma cell (PC) dyscrasia that arises from precursors and has been studied utilizing approaches focused on CD138+ cells. By combining single-cell (sc)RNA- with scB-cell receptor (BCR)-sequencing, we differentiate monoclonal/neoplastic from polyclonal/normal PCs, and find more dysregulated genes, especially in precursor patients, than by analyzing bulk PCs. To determine if this approach can identify oncogenes that contribute to disease pathobiology, MAD2L1 and MAT2A are validated as targets with drug-like molecules that suppress myeloma growth in pre-clinical models. Moreover, functional studies show a role of LAMP5, which is uniquely expressed in neoplastic PCs, in tumor progression and aggressiveness via interactions with c-MYC. Finally, a monoclonal antibody recognizing cell-surface LAMP5 shows efficacy as an antibody-drug conjugate and in a chimeric antigen receptor-guided T-cell format. These studies provide additional insights into myeloma biology and identify potential targeted therapeutic approaches that can be applied to reverse myeloma progression.

  Study EGAS50000000802

• Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.

  Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.

  Study EGAS00001000750

• Type 1 Diabetes Genetics Consortium (T1DGC): Multi-Ethnic ImmunoChip Study

  Type 1 diabetes (T1D) is characterized by an autoimmune attack that destroys the insulin-producing pancreatic beta cells and is driven by diverse genetic and environmental factors. Between 8-100 chromosome regions are known to contain variants that alter T1D risk, substantially fewer than many other common diseases. Less is known about the contribution of T1D risk alleles in non-European populations, despite recent increases in T1D diagnoses in multiple non-European ancestry groups. To address these gaps in T1D genetics, we doubled the sample size from the previous largest T1D association study, genotyped ancestrally diverse T1D cases, controls, and affected families with the Illumina ImmunoChip array, and imputed additional variants using a large haplotype reference panel. After quality filtering, a total of 61,427 participants and 140,333 genotyped ImmunoChip variants were included in analysis, providing dense coverage in 188 autosomal regions ("ImmunoChip regions") and sparse genotyping in other regions of the genome. Each participant was assigned to one of five ancestry groups using k-means clustering of ImmunoChip genotype principal components: European (EUR, N = 47,319), African Admixed (AFR, N = 4,290), Finnish (FIN, N = 6,991), East Asian (EAS, N = 588) and Other Admixed (AMR, N = 2,239). In total, 16,159 T1D cases, 25,386 controls (unrelated) and 6,143 trio families (i.e., an affected child and both parents) were genotyped and included in association analyses. Imputation with the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) multi-ethnic reference panel was used to improve discovery power and fine-mapping resolution. After imputation, the number of variants in ImmunoChip regions with imputation R-squared > 0.8 and MAF > 0.005 in each ancestry group was 322,084 (AFR), 166,274 (EUR), 163,612 (FIN), 137,730 (EAS) and 188,550 (AMR). Imputed genotypes were compared in the same participants who have whole genome sequencing data, resulting in high concordance. Unrelated cases and controls (N = 41,545) were analyzed initially, assuming an additive inheritance model. T1D trio families (N = 6,143 trios, some trio families were multiplex and analyzed as multiple trios) were analyzed separately, with meta-analysis of case-control and trio results used for discovery of regions associated with T1D (p < 5×10-8). Summary-level data at each SNP (genotype and imputed) for type 1 diabetes (outcome) are provided in dbGaP.

  Study phs002468

• CIRdb: Array genotype data

  The current inhabitants of the Canary Islands have a unique genetic makeup in the European diversity landscape due to the existence of African footprints from recent admixture events, especially of North African components (>20%). The underrepresentation of non-Europeans in genetic studies and the sizable North African ancestry, which is nearly absent from all existing catalogs of worldwide genetic diversity, justify the need to develop CIRdb, a population-specific reference catalog of natural genetic variation in the Canary Islanders. Based on array genotyping of the selected unrelated donors and comparisons against available datasets from European, sub-Saharan, and North African populations, we illustrate the intermediate genetic differentiation of Canary Islanders between Europeans and North Africans and the existence of within-population differences that are likely driven by genetic isolation. In addition, here we describe the overall design and the methods that are being implemented to develop CIRdb.

  Study EGAS00001006050

• Whole exome sequencing reveals the mutational spectrum of testicular germ cell tumours

  Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole exome sequencing of 42 TGCTs to comprehensively study the mutational profile of TGCT. The mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per megabase [Mb]) as compared to the common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT.

  Study EGAS00001001084

• Discovery and validation of an ancillary genomic test of malignancy for primary melanocytic tumors

  Background:Pathological diagnosis of melanocytic tumors can be difficult and prone to error. More accurate and reliable ancillary investigations than those currently available are required to improve diagnostic accuracy. Goals: (1) to generate a genomic model for distinguishing benign (nevi) from malignant (melanoma) melanocytic skin tumors, developed from a customized gene panel evaluated on a cohort of 250 nevi and melanomas. (2) To evaluate the performance of the genomic model in melanocytic tumors of uncertain diagnosis/behavior. Details: The cohort of 250 melanomas and naevi was split into a discovery set and a validation set. Our genomic model obtained an area under the curve of 95% in the discovery cohort and 96% for the validation cohort. Based on a Youden index threshold, the resulting classifier shows high specificity (>95% in the discovery and validation cohorts), with sensitivities >80% in the discovery and validation cohorts. Evaluation of the genomic model on a cohort of 110 melanocytic tumors identifies key driver mutations in agreement with the likely pathway of origin of the tumors. The probability of melanoma (p=0.02) from the genomic model was significantly associated with pathology-based estimates of malignancy for melanocytic tumors lacking pathway-defining genomic aberrations (conventional tumors). The genomic model identified 8/36 (22%) conventional tumors with unresolved malignancy to have a high probability of melanoma, with 7/8 of these cases showing negative/non-aberrant results with either fluorescent in-situ hybridization, PRAME and/or p16 immunostains. Furthermore, no evidence of malignant behavior based on the genomic model was seen in 4 conventional borderline tumors with more than 1 year follow-up. Conclusion: This genomic model can become a clinically useful ancillary tool that is highly specific for differentiating melanomas from nevi.

  Study EGAS50000000887

• EstMB cohort participants sequenced with MGISEQ-2000 platform

  Participants collected a fresh stool sample immediately after defecation using a sterile Pasteur pipette and placed it in a 15 mL conical polypropylene tube. They were instructed to collect the sample as close as possible to their study center visit. Samples were transported and stored at −80 °C until DNA extraction. Microbial DNA was extracted from 200 mg of stool using a QIAamp DNA Stool Mini Kit (Qiagen), following manufacturer's instructions, after all samples were collected. DNA was quantified using a Qubit 2.0 Fluorometer with a dsDNA Assay Kit (Thermo Fisher Scientific). Library preparation and circularization of equimolarly pooled libraries were done with MGIEasy FS DNA Library Prep Set (MGI Tech Co, Ltd, Shenzhen, China) according to the standard protocol. The sequencing was performed with MGISEQ-2000 High-throughput Sequencing Set (FCL PE150) according to the manufacturer’s instructions (MGI Tech, Shenzhen, China)

  Dataset EGAD50000002213

• Exploring the Genomic Dark Matter of Neurodevelopmental Disorders

  Neurodevelopmental Disorders (NDDs) are a group of disorders that typically manifest early in development and may give rise to impaired cognition, communication, adaptive behavior, and psychomotor skills. This study aims to take a more comprehensive view into the genomic landscape of structural variants implicated in NDDs with intellectual disability (ID). We have evaluated the genome of families with a genetically unsolved severe NDD via optical genome mapping. This study identified likely pathogenic or pathogenic structural variants in known NDD genes, including BCL11A, OPHN1, PHF8, SON, and NFIA. Data is available in VCF format, following the standard filtering settings in Bionano Access and available as "variants_combine_filters_inMoleRefine1.vcf" files.

  Study phs002937