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• Genomic analysis of primary plasma cell leukemia reveals complex structural alterations and high risk mutational patterns

  Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by poor overall survival despite advances in anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype we performed whole exome sequencing in 23 patients with newly diagnosed pPCL. The results reveal an enrichment of complex structural changes and high risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular pPCL patients with traditional low risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group.

  Study phs002022

• Xeroderma Pigmentosum, Complementation Group C, (XPC) and Non-XPC Cutaneous Squamous Cell Carcinoma (cSCC) Mutation Rate Study

  Base mutations occur at higher frequencies within heterochromatin and late-replicating DNA. In this study, we show that regional differences in mutation frequency are absent in portions of the genome that are not transcribed within cutaneous squamous cell carcinomas (cSCCs) with an XPC-\- genetic background. The XPC-\- genetic background predicates a loss of global genome nucleotide excision repair (GG-NER), thus our data shows that regional differences in mutation frequency are a result of differential access of DNA repair protein. Unexpectedly, we also note that greater transcription reduces mutations on both strands of genes in heterochromatin, and only to those levels observed in euchromatin, in a XPC-dependent fashion. Therefore, transcription likely reduces mutation prevalence by increasing access to DNA repair proteins. This tripartite relationship between DNA repair, transcription, and chromatin state shows a new cancer risk factor in human populations.

  Study phs000830

• Novel mutations in TOP2A in gliomas

  High grade gliomas (HGGs) are aggressive, primary brain tumors with poor clinical outcomes. To better understand glioma pathobiology and find potential therapeutic susceptibilities, we designed a custom- panel 664 cancer- and epigenetics-related genes and employed targeted next generation sequencing to study the genomic landscape of somatic and germline variants in 182 glioma samples of different malignancy grades. Besides known alterations in TP53, IDH1, ATRX, EGFR genes, we found several novel variants that can be potential drivers in gliomas. In four patients from the Polish glioma cohort, we identified a novel recurrent mutation in the TOP2A gene coding for Topoisomerase 2A in glioblastomas (GBM, WHO grade IV gliomas). The mutation results in a substitution of glutamic acid (E) 948 to glutamine (Q) of TOP2 A and we predicted this E948Q substitution may affect DNA binding and a TOP2A enzymatic activity.

  Study EGAS00001004556

• Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

  We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway and re-expression of epigenetically silenced endogenous retrovirus. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.

  Study phs001038

• The landscape of somatic mutations in epigenetic regulators across 1000 pediatric cancer genomes

  To define the frequency and pattern of somatic mutations in epigenetic regulators in pediatric cancer, we sequenced 633 genes, encoding the majority of proteins involved in patterning the epigenome, in 1000 pediatric tumors spanning 21 different cancer subtypes. This analysis establishes an epigenetic landscape of pediatric cancer, which expands the knowledge for potential therapeutic targets and for developing personalized therapy.

  Study EGAS00001000449

• Kids First: Genomics of Orofacial Clefts in the Philippines

  Orofacial clefts (OFCs) are the most common craniofacial structural birth defect in humans caused by incomplete formation of the upper lip and/or the palate. Over 4,000 children in the Philippines are born with an OFC every year, and the Filipino OFC birth prevalence rate of 1 in 500 live births is one of the highest in the world. Genome-wide association studies support a multifactorial etiology for OFCs, but common variants only account for up to ~25% of the heritable risk in any one population. Sequencing studies in diverse populations is essential to fully understand the genetic architecture of OFCs. The study goals of the Kids First project are to sequence a collection of case-parent trios from the Philippines, in order to identify de novo mutations and inherited rare variants, and understand the population differences in common variant signals in the Philippines versus other populations. Approximately 373 trios from the Philippines were selected for whole genome sequencing (WGS) as part of this Gabriella Miller Kids First project.

  Study phs002595

• Altered enhancer-promoter interaction leads to MNX1 expression in pediatric acute myeloid leukemia with t(7;12)(q36;p13)

  Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between breakpoint partners (MNX1 and ETV6) has only been reported in a subset of cases. However, a universal feature is the strong transcript and protein expression of MNX1, a homeobox transcription factor that is normally not expressed in hematopoietic cells. Here, we map the translocation breakpoints on chromosomes 7 and 12 in affected patients to a region proximal to MNX1 and either introns 1 or 2 of ETV6. The frequency of MNX1 overexpression in pediatric AML (n=1556, own and published data) is 2.4% and occurs predominantly in t(7;12)(q36;p13) AML. Chromatin interaction assays in a t(7;12)(q36;p13) iPSC cell line model unravel an enhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Our data suggest that enhancer-hijacking is a more common and overlooked mechanism for structural rearrangement-mediated gene activation in AML.

  Study EGAS50000000130

• RTEL1 mutation as a modifier of Dyskeratosis Congenita in a family with a Telomerase RNA (hTR) template mutation and variant telomeric repeats

  Vertebrate telomeres, the sequences protecting the end of linear chromosomes, are composed of conserved hexameric GGTTAG repeats. Here we present a C50>A telomerase RNA template mutation that results in the incorporation of the variant telomeric repeat GTTTAG in a family with dyskeratosis congenita primarily presenting as idiopathic pulmonary fibrosis. The mutant telomerase is characterized by decreased processivity in direct telomerase activity assays and in vivo based on data from Illumina next-generation whole genome sequencing and Oxford Nanopore Technologies long-read telomere sequencing. The latter provided positional mutant repeat information that revealed the inheritance and maintenance of proximal mutant repeats in individuals who did not inherit the template mutation. Additionally, we describe an RTEL1 nonsense mutation that is associated with very short telomeres in progeny harboring wild-type telomerase and inherited mutant telomeric repeats in the absence of overt clinical phenotypes. In contrast, co-inheritance of the RTEL1 nonsense and TERC r.C50>A mutations coincided with severe early-onset DC phenotypes in two individuals.

  Study EGAS50000001644

• BLUEPRINT DNA methylation profiles of graft donors in allogenic hematopoietic stem cell transplantation

  Allogenic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. We investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in HLA-matched sibling recipients prior to HSCT. We measured genome-wide DNA methylation levels in peripheral blood of 91 HSCT donors using Illumina Infinium HumanMethylation450 BeadChips. We showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We identified distinct DNA methylation marks in graft donors that are associated with aGVHD severity status in recipients. Together, our findings suggest that ‘epigenetic matching’ of HSCT donor-recipient pairs in a clinical setting may be used in conjunction with genetic matching to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome.

  Study EGAS00001001287

• Combined Metabolic Activators Reduces Liver Fat in Nonalcoholic Fatty Liver Disease Patients

  Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMA) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomics data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host-microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.

  Study EGAS00001005616