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• Altered chromosomal topology drives oncogenic programs in gastrointestinal stromal tumors

  Metabolic lesions with pleiotropic effects on epigenetic regulation and other cellular processes are widely implicated in cancer, yet their oncogenic mechanisms remain poorly understood. Succinate dehydrogenase (SDH) deficiency causes a subset of gastrointestinal stromal tumors (GISTs) with DNA hyper-methylation. Here we associate this hyper-methylation with changes in chromosome topology that activate oncogenic programs. To investigate epigenetic alterations in this disease, we systematically mapped DNA methylation, CTCF insulators, enhancers and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs. Although these respective subtypes share similar enhancer landscapes, we identified hundreds of putative insulators where DNA methylation replaced CTCF binding in SDH-deficient GISTs. We focused on disrupted insulators that partitions super-enhancers from FGF3, FGF4 and the KIT oncogene. Recurrent loss of this insulator alters locus topology in SDH-deficient GISTs, allowing aberrant physical interaction between enhancers and oncogenes. CRISPR-mediated excision of the corresponding CTCF motif in an SDH-intact model disrupted the boundary and up-regulated FGFs and KIT expression. Our findings reveal how a metabolic lesion destabilizes chromatin structure to facilitate the initiation and selection of epigenetic alterations that drive oncogenic programs in the absence of canonical mutations.

  Study phs001906

• Clinical Resistance to Crenolanib in Acute Myeloid Leukemia Due to Diverse Molecular Mechanisms

  FLT3 mutations are commonly detected in Acute Myeloid Leukemia (AML) patients and are associated with poor prognosis. Crenolanib, a potent type I pan-FLT3 (GeneID:2322) inhibitor, is effective against both internal tandem duplications (ITD) and resistance-conferring tyrosine kinase domain (TKD) mutations. While crenolanib monotherapy has demonstrated significant clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. To investigate the mechanisms of crenolanib resistance, we performed whole exome sequencing of AML patient samples before and after crenolanib treatment (122 samples from 59 patients). Unlike other FLT3 inhibitors, crenolanib did not induce FLT3 activation loop mutations, and mutations of the FLT3 "gatekeeper" residue were infrequent. Instead, mutations of NRAS (GeneID:4893) and IDH2 (GeneID:3418) arose, mostly as FLT3-independent subclones, while TET2 (GeneID:54790) and IDH1 (GeneID:3417) predominantly co-occurred with the FLT3-mutant clone and were enriched in crenolanib poor-responders. The remaining patients exhibited post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse non-FLT3 genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restored crenolanib sensitivity.

  Study phs001628

• Genetic Analysis of Desmoplastic Melanoma

  Desmoplastic melanoma is an infrequent variant of melanoma with sarcomatous histology, distinct clinical behavior, and unknown pathogenesis. We performed low-coverage genome and high-coverage exome sequencing of 20 desmoplastic melanomas, followed by targeted sequencing of 293 genes to validate candidate genes. A high mutation burden (median 62 mutations/Mb) ranked desmoplastic melanoma among the most highly mutated cancers. Mutation patterns strongly implicate UV-radiation as the dominant mutagen, indicating a superficially located cell of origin. Novel alterations included recurrent promoter mutations of NF-kappa B inhibitor epsilon, NFKBIE (IkBε) in 14.5% of samples. Commonly mutated oncogenes in melanomas, in particular BRAF(V600E) and NRAS(Q61K/R), were absent. Instead, other genetic alterations known to activate the MAPK and PI3K signaling cascades were identified in 73% of samples, affecting NF1, CBL, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, PTPN11, MET, RAC1, SOS2, NRAS, and PIK3CA, some of which being candidates for targeted therapies. Reprinted from: Shain, A. H. et al. Exome sequencing of desmoplastic melanoma identifies recurrent NFKBIE promoter mutations and diverse activating mutations in the MAPK pathway. Nat. Genet. With permission from Nature Genetics

  Study phs000977

• Mapping Genes for Mammographic Density

  We recruited 1,521 women from the Old Order Amish (OOA) population of Lancaster County, Pennsylvania, with the primary goal of identifying genetic factors that influence mammographic density. All women were between the ages of 40 and 88 years, with a mean of 54 years. Additional study design details, including eligibility criteria, are described elsewhere (Douglas et al., 2008). The present-day OOA of Lancaster County are the descendants of approximately 550 individuals from central Western Europe who immigrated to the U.S. in the early eighteenth century. All living individuals derive from a single, 14-generation pedigree (Lee et al., 2010). Although the OOA are a genetically closed founder population, allele frequencies and LD profiles are remarkably similar between the OOA and U.S. participants in the International HapMap project (HapMap CEU) for common SNPs (MAF>/=5%) (Van Hout et al., 2010). We recently completed genome-wide linkage and association analyses of mammographic density, including dense and non-dense areas of the breast and the ratio of dense to total area of the breast. Summary-level data from our GWAS are available here and through the Marker of DEnsity (MODE) Consortium.

  Study phs000604

• Pediatric Investigation of Genetic Factors Linked with Renal Progression (PediGFR): Chronic Kidney Disease in Children Cohort (CKiD)

  The Pediatric Investigation for Genetic Factors Associated with Renal Progression (PediGFR) (RO1-DK082394) is an international collaborative study among three large prospective cohort studies of children with chronic kidney disease. The participating parent cohort studies are the "Chronic Kidney Disease in Children (CKiD)", the "Effect of Strict Blood Pressure Control and ACE Inhibition on CRF Progression in Pediatric Patients (ESCAPE)", and the "Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C)" study. In these cohorts, pediatric subjects with CKD have been prospectively followed with standardized measurements for renal progression. The current version of the upload includes the genotype and baseline phenotype for the CKiD cohort. In brief the CKiD study is a prospective study of children with chronic kidney disease (CKD) between the ages of 1 year to 16 years of age and an estimated glomerular filtration rate (eGFR) by Schwartz equation between 30 and 75 ml/min per 1.73m2. Included in this upload are the phenotypic data for anemia traits utilized for the sub-study, "Role of Genetic Variation in the Anemia of Chronic Kidney Disease" (K24DK078737), with the RBC trait and anemia data pertaining to CKiD as well.

  Study phs000650

• Whole-Exome Sequencing Study of Diabetic Nephropathy

  To identify rare variants of diabetic kidney disease (DKD), we conducted a whole-exome sequencing (WES) study. This study employed an extreme case–control design, which included a selection of the 593 most rapidly progressing DKD cases from the Chronic Renal Insufficiency Cohort (CRIC) Study (phs000524). In this two-stage WES study of DKD, participants with DKD from the CRIC were compared with control groups of participants without DKD from another cohort in the first stage. Suggestive signals identified in the first stage were confirmed in the second stage analysis among a diverse population with existing whole-genome sequencing (WGS) data. Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test implemented within our mixed model framework. As a result, we identified four novel gene loci, DIS3L2, KRT6B, ERAP2 and NPEPPS, that achieved exome-wide significance and may play an important role in the DKD disease course. This large WES study provides novel insights into DKD's molecular mechanisms.

  Study phs003429

• Nivolumab and Tumor Infiltrating Lymphocytes (TIL) in Advanced Non-Small Cell Lung Cancer

  We performed a trial of adoptive cell therapy using tumor infiltrating lymphocytes (TIL) in metastatic non-small cell lung cancer (NSCLC). We conducted a single-arm open- label phase 1 trial (NCT03215810) of TIL administered with nivolumab in 20 patients with advanced NSCLC. Patients had tumor metastases resected for TIL, and the sequencing data from these tumors is included herein. The primary endpoint was safety, and secondary endpoints included objective response rate, duration of response, and T-cell persistence. Autologous TIL was expanded ex vivo from minced tumors cultured with IL-2. Patients received initial nivolumab for 4 cycles. If they had subsequent evidence of progression, then they proceeded to receive cyclophosphamide and fludarabine lymphodepletion, TIL infusion, and interleukin-2, followed by maintenance nivolumab. The endpoint of safety was met according to pre-specified criteria. Of 13 evaluable patients, 3 had confirmed responses and 11 had reduction in tumor burden, with a median best change of 35%. Two patients achieved complete responses ongoing 1.5 years later. In exploratory analyses, we found T cells recognizing multiple types of cancer mutations were detected after TIL treatment, and were enriched in responding patients.

  Study phs002486

• Genomic Analysis of Prostate Tumor Heterogeneity in Metastasis

  To investigate the molecular changes, mutations, and signaling pathways that characterize the initial steps of prostate cancer metastasis to the lymph nodes, we analyzed 19 discrete lymph node (LN) metastases, 97 primary tumor foci, 39 benign lymph nodes, and 10 normal adjacent prostate tissue samples from 43 patients enrolled in a clinical trial (NCT01808222) of extended lymphadenectomy and metastasis excision guided by [18F]-fluciclovine PET imaging for high risk, newly diagnosed prostate cancer conducted at Emory University. These patients fell within high or very high-risk groups (T3a, Gleason score 8-10, or PSA greater than 20 ng/ml). Of these patients, 16 had LN metastases at least 4 mm in diameter, and 20 patients had no metastases. For metastatic patients, we performed RNA and Whole Exome Sequencing (WES) on three primary tumor foci, one benign LN, and all LN metastases greater than 4mm in diameter. For non-metastatic patients, we sequenced two primary tumor foci and one benign LN. In total, RNAseq was performed on 165 tissue samples from 43 patients, and WES was performed on 137 samples from 35 patients.

  Study phs003404

• Regulation of T Cell CXCL13 Production

  This study evaluated the signals that regulate production of the B cell chemoattractant CXCL13 by human CD4 T cells. Single-cell and bulk RNA-seq datasets evaluated the gene expression changes induced by TGF-beta and the aryl hydrocarbon receptor (AHR), two signals that regulate CXCL13 production. Bulk ATAC-seq data evaluated the epigenetic changes in T cell stimulated with an AHR agonist or antagonist. Ex vivo bulk RNA-seq data of sorted T cell subsets from blood of patients with lupus and control donors interrogated the gene expression differences in sorted T cell subsets. Ex vivo ATAC-seq data allowed comparison of epigenetic profiles of PD-1hi Tph cells from rheumatoid arthritis synovial fluid and PD-1hi T follicular helper (Tfh) cells from tonsil to PD-1low CD4 T cells from the same samples. Single-cell RNA-seq data of T cells from lupus patients before and after treatment with anifrolumab (anti-IFNAR) allowed interrogation of T cell populations that change with anifrolumab treatment. These datasets allowed for genomic interrogation of changes induced by AHR, TGF-beta, and interferon and their relationship to CXCL13 production.

  Study phs003582

• Transcription Factor Analysis of SLE

  Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with protean manifestations. This study identifies two histone marks of activation and the binding of p300 genome-wide in three cell types and three clinical subsets to better understand cell-specific effects and differences across clinical subsets. Results: We examined 20 patients with SLE and 8 controls and found the TNF, IL-2/STAT5, and KRAS pathways were identified across multiple cell types and ChIP data sets. Patients with cutaneous lupus and lupus nephritis generally had less dramatically altered chromatin than the general SLE group. Conclusions: NFkB and classical inflammatory pathways were strongly associated with increased peak heights across all cell types but were the highest-ranking pathway for all three antibodies in monocytes according to fgsea analysis. IL-6 Jak/STAT3 signaling was the most significant pathway association in T cells marked by H3K27ac change. Therefore, each cell type experiences the disease process distinctly although in all cases there was a strong theme of classical inflammatory pathways. These studies define important cell type differences and emphasize the breadth of the inflammatory effects in SLE.

  Study phs003713