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• Comprehensive Genomic Characterization of Refractory Multiple Myeloma Reveals a Complex Mutational and Structural Landscape Associated with Drug Resistance (H067)

  Outcome of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) is still very poor. To elucidate the genetic landscape of relapsed/refractory MM (RRMM) we performed whole genome and transcriptome sequencing of 39 heavily pretreated RRMM patients with at least double refractoriness revealing complex structural changes and a high mutational load (H067/K08K). We found a median of 67 structural variants and 116 nonsynonymous exonic mutations per patient. Assessment of oncogenic drivers showed NRAS, BRAF, TP53, KRAS, SLC4A7, FAM46C, DIS3, RB1, KMT2C, MLLT4, EWSR1, HCFC2, and COPS3 as significantly mutated. We found multiple genomic regions with bi-allelic events affecting known tumor suppressor genes, most frequently TP53, RB1, and TRAF3. Supervised analysis of mutational signatures showed a major contribution of Cosmic signature 6 associated with deficiency in DNA mismatch repair and the ‘BRCAness’ signature which coincided with mutations in genes known to confer PARP inhibitor sensitivity. Recurrently mutated gene networks included genes with relevance for PI and IMiD activity, the latter including in particular members of the Cereblon and the COP9 signalosome complex. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies.

  Study EGAS00001004363

• Chromoanasynthesis as a Cause of Jacobsen Syndrome

  Jacobsen syndrome (OMIM #147791) is a rare multisystem genomic disorder involving craniofacial abnormalities, intellectual disability, other neurodevelopmental defects and terminal truncation of chromosome 11q, typically deleting ~170 to >340 genes. We describe the first case of Jacobsen syndrome caused by congenital chromoanasynthesis, an extreme form of complex chromosomal rearrangement. Six duplications and five deletions occurred on one copy of chromosome 11q with microhomology signatures in the breakpoint junctions, indicating an all-at-once replication-based rearrangement mechanism in a gametocyte or early post-zygotic cell. Eighteen genes were deleted from the Jacobsen region, including KIRREL3, which is associated with intellectual disability. Patients of any age with abnormal immune function who have recurrent or unusual infections, whose blood tests show evidence of immune dysfunction, or who have GVHD, XSCID, CGD or LAD may be eligible for this study. Patients' parents, siblings, grandparents, children, aunts, uncles and first cousins of any age also may be included. Healthy normal volunteers between 18 and 85 years of age are recruited as controls.

  Study phs002036

• Induction of HIV-1 Env-Specific Peripheral Blood Plasmablasts and Clonal Persistence as Bone Marrow Plasma Cells Following Vaccination in Humans

  Induction of persistent HIV-1 Envelope (Env) specific antibody (Ab) is a primary goal of HIV vaccine strategies, however, it is unclear if HIV Env immunization in humans induces bone marrow plasma cells, the presumed source of long-lived systemic Ab. To define the features of Env-specific plasma cells after vaccination, samples were obtained from HVTN 105, a phase I trial testing the same gp120 protein immunogen, AIDSVAX B/E, as used in RV144, along with a DNA immunogen in various prime/boost strategies. Boosting regimens that included AIDSVAX B/E induced robust peripheral blood plasmablast responses. The Env-specific immunoglobulin repertoire of the plasmablasts was dominated by VH1 gene usage and targeting of the V3 region. Numerous plasmablast-derived immunoglobulin lineages persisted in the bone marrow greater than eight months after immunization, including in the CD138+ long-lived plasma cell compartment. These findings identify a cellular linkage for the development of sustained Env-specific Ab following vaccination in humans.

  Study phs002027

• Genomic Analysis of Fibrolamellar Hepatocellular Carcinoma

  Fibrolamellar hepatocellular carcinoma (FL-HCC) is a very rare and distinct subtype of hepatocellular carcinoma that occurs in the previously healthy livers of adolescents and young adults. The low incidence rate has kept FL-HCC an understudied cancer, thus the list of FL-HCC markers is limited and the genetic alterations driving its growth have remained unknown. In order to gain a better understanding of the molecular mechanisms underlying FL-HCC initiation and progression, we performed an in-depth genomic analyses of one tumor followed by immunohistochemistry validation on seven other tumors. We showed the expression of neuroendocrine markers in FL-HCC. In addition, DNA/RNA sequencing revealed that common cancer pathways are not visibly altered in FL-HCC but identified two novel structural variants, both resulting in fusion transcripts. Through in vitro studies, we demonstrated the oncogenic properties of these fusion transcripts. These experiments further highlight the tumorigenic role of gene fusions in the etiology of pediatric solid tumors and identify both candidate biomarkers and possible therapeutic targets for this lethal pediatric disease.

  Study phs000828

• Health Information National Trends Survey-SEER (HINTS-SEER)

  HINTS-SEER is a cross-sectional survey that sampled cancer survivors from three different SEER cancer registries. Sampling frames of survivors from each registry were stratified by time since diagnosis and race/ethnicity, with non-malignant tumors and non-melanoma skin cancers excluded. Respondents who consented completed a self-administered questionnaire sent through the mail and resulted in a total sample of 1,234 respondents. The goal of HINTS-SEER was to better understand the communication needs and practices, information preferences, risk behaviors and cancer knowledge of cancer survivors using a modified version of the Health Information National Trends Survey (HINTS) specifically designed for cancers survivors. Demographic information on the survivors showed that over 60% of the sample was 10 or more years since diagnosis with the most common cancers being male reproductive (24.6%), female breast (23%) and melanoma (9.6%) and gastrointestinal (8.6%). De-identified data is available in SAS, SPSS, and STATA formats, as part of a data package that also includes a history document, methodology report, data analysis recommendations, and a codebook.

  Study phs004065

• Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma

  Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG is frequently developed in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-seq, we identified ectopic expression of neuromuscular molecules in MG-associated thymoma (MG-thymoma). These molecules were originated from a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we named neuromuscular mTECs (nmTECs). MG-thymoma also exhibited microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell-cell interaction analysis also predicted the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma was further confirmed by immunohistochemically and by cellular composition estimation from MG-thymoma transcriptome. Altogether, this study suggests that nmTECs play a significant role in MG pathogenesis via ectopic expression of neuromuscular molecules.

  Study JGAS000482

• Genomic Analyses Identify Recurrent MEF2D Fusions in Acute Lymphoblastic Leukemia

  Chromosomal rearrangements are initiating events in acute lymphoblastic leukemia (ALL). Here, using RNA-sequencing (RNAseq) of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1164 B-ALL cases identified 30 cases with MEF2D rearrangements which include an additional fusion partner, FOXJ2, thus MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age, and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitors treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukemia, for which new therapeutic approaches should be considered.

  Study EGAS00001001952

• Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

  IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite D-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild-type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients, mutant IDH1 and 2HG are not required for later clonal expansions.

  Study EGAS00001001854

• Upper cortical layer-driven network impairment in schizophrenia

  Schizophrenia is one of the most wide-spread and complex mental disorders. To characterize the impact of schizophrenia, we performed single nucleus RNA sequencing (snRNA-seq) of >220,000 neurons from the dorsolateral prefrontal cortex of patients with schizophrenia and matched controls. Additionally, >115,000 neurons were analyzed topographically by immunohistochemistry. Compositional analysis of snRNA-seq data revealed a reduction in abundance of GABAergic neurons and a concomitant increase in principal neurons, most pronounced for upper cortical layer subtypes, which was substantiated by histological analysis. Many neuronal subtypes showed extensive transcriptomic changes, the most dramatic - in upper layer GABAergic neurons, including downregulation in energy metabolism and upregulation in neurotransmission. Transcription factor network analysis demonstrated a developmental origin of transcriptomic changes. Finally, Visium spatial transcriptomics further corroborated upper layer neuron vulnerability in schizophrenia. Overall, our results point towards general network impairment within upper cortical layers as a core substrate associated with schizophrenia symptomatology. Study is available on bioRxiv (https://doi.org/10.1101/2020.11.17.386458) and in upcoming publication.

  Study EGAS00001006495

• Intratumoral Heterogeneity and Clonal Evolution Induced by HPV Integration.

  The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines revealed a unique form of structural variation, termed heterocateny here, characterized by heterogeneous, interrelated, and repetative patterns of concatemerized virus and host DNA segments. Evidence of heterocateny was detected in extrachromosomal and/or intrachromosomal DNA in all cases. Unique breakpoint sequences shared across structurally heterogeneous virus-host concatemers within each cancer facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that unstable virus and virus-host concatemers in ecDNA or integrated form mediate insertion into and excision from chromosomes, capture, rearrangement, and rolling-circle amplification of host DNA, and chromosomal rearrangements. The data indicate that heterocatena is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intra-tumoral heterogeneity and clonal evolution.

  Study EGAS00001006652