Neuroblastoma Exploring high-risk neuroblastoma by sequencing technology

Exploring high-risk neuroblastoma by sequencing technology

 

Dr. Lars O. Baumbusch and Prof. Klaus Beiske

Norwegian Pediatric Cancer Sequencing Consortium (NPCSC)

 

Next generation sequencing will be the basis for personalized cancer medicine in the near future, in particular for heterogenic diseases with multi-modal therapy applications. Neuroblastoma (NB) comprises a group of extremely heterogenic tumors, making the disease to one of the major challenges in pediatric oncology. Disseminated tumor cells in the bone marrow and circulating tumor cells in the peripheral blood are predictive and prognostic indicators of poor prognosis in children with high-risk NB. Molecular profiling these cells by next generation sequencing may provide means about the clonal evolution of the tumor. Several studies provide evidence that non-coding RNAs play an important role in the development and progression of NB. Integrative analyses of copy number alterations and corresponding changes in expression by RNA sequencing will offer new insights to the regulatory features of NB. Circulating cell-free DNA (cfDNA) has been introduced as novel non-invasive monitoring tool. We wish to sequence cfDNAs to gain supplementary information about tumor burden, mutation characterization, and therapy resistance in NB. We are convinced that comparative analysis of the primary tumor and in relation to residual tissue, micrometastases, and cfDNA reveals a promising strategy to unveil novel insight about the heterogeneity, tumor evolution and biology of NB - improving the therapy prospects for children fighting NB. 

A PhD postion is available in this project from 01.08.2015.

Pediatric cancer

Research team members

Oslo University Hospital (OUS) is responsible for The Norwegian Pediatric Cancer Sequencing Project. The project will be organized by a consortium, consisting of a steering group and a scientific advisory board. The steering committee will be responsible for administration and milestones, and host yearly workshops for updates and discussions on further development. The scientific advisory board will contribute to the over-all strategy of the project, and may contribute with its own subprojects. The consortium will include  members of all main involved departments of OUS, including the Dpts of Pathology, Pediatrics, Pediatric oncology, Medical Genetics (the National Sequencing Center), as well as representatives from the other Norwegian University Hospitals.

Research goals and strategy

The main aim of the Norwegian Pediatric Cancer Sequencing Project is to establish a targeted exome sequencing work-up and strategy for genome guided treatment in pediatric cancer patients. The project will stimulate development of genetic sequencing in pediatric cancer diagnostics, improve treatment decisions based on genetic sequencing technology, develop tests that optimize individualized treatment, with the overall goal of increasing survival rates and optimizing life quality in children with cancer.

Current research projects

The intention is to establish the Norwegian Pediatric Cancer Sequencing Consortium (NPCSC), a national platform for pediatric cancer diagnostics and personalized treatment guided by comprehensive genetic profiling of pediatric cancer tissue.

In 2014, we received funding from HSØ for a PhD prosject Exploring high-risk neuroblastoma by sequencing technology.

Main national and international collaborators

Finally, the implementation of the project relies on close collaboration with national and international research groups such as the Nordic Organization of Pediatric Hematology and Oncology, the Neuroblastoma Research Group at the University in Tromsø, The Intepret Research Group at OUS, and the Departments of Genetics and Medicine and the Dpt of Child Oncology, both at University of North Carolina at Chapel Hill, USA.

Financial support

Several grant applications for funding have been sent to the Norwegian Research Council (NFR), The Norwegian Cancer Society (NCS), and others sources.

Selected publications

Infections and immunology

Research team members

Tore G. Abrahamsen (group leader), Dina Aresvik, Kiran Aftab Gul, Torstein Øverland, Lars O. Baumbusch, Kari Lima, and Rolf D. Pettersen.


Research goals and strategy

The research team of infections and immunology is currently working on general immune response, the use of antibiotics, bacterial resistance development, and primary immune deficiency, including the DiGeorge syndrome. The aim is to encourage the basic understanding of disease mechanisms and thus providing improved diagnosis and treatment of severe infections in children and patients with congenital immune diseases. The establishment of biobanks and quality management are also central for this work of this team. The research group also runs a Resource Centre for the DiGeorge syndrome.

 

Background

The 22q11.2 deletion syndrome (DS) is the second most common childhood genetic disorder, behind Down's syndrome, with an estimated incidence of 1 in 4000 births. Patients with the 22q11.2 DS have a hemizygous deletion which usually (in about 90%) has a size of 3 Mb containing approximately 30 genes, whereas 8% have a smaller deletion of 1,5 Mb with 24 genes. The phenotype is highly variable and the size of the deletion does not predict end organ effects or disease severity. These patients may suffer from disorders of many organ systems, but cardiac malformations, thymic hypoplasia/aplasia, hypoparathyroidism, cleft palate and psychiatric disorders are most frequent.  In addition, the incidence of autoimmune diseases is high.

Less than 1% of patients with 22q11.2 DS have true thymic aplasia requiring an urgent transplant. The majority of the patients has an immunodeficiency with mild to moderate deficit in T cell number and possibly also function. The clinical problems including the immunodeficiency in 22q11.2 DS are age dependent. This may be due to the fact that the greatest T-cell deficit occurs in the neonatal period.  Interestingly, the physiologic, age-related decrease in T-cell numbers is slower in the patients than in healthy controls. It has been shown that compared to controls conversion of naïve to memory T-cells is accelerated in patients with 22q11.2 DS. Spontaneous apoptosis of both CD4+ and CD8+ T-cells from one patient with DiGeorge syndrome has been described.

The incidence of autoimmunity is increased in 22q11.2 DS and occurs in up to 10% of the patients. These diseases occur particularly in the older patient population. For example, autoimmune cytopenias, juvenile rheumatoid arthritis, autoimmune endocrinopathy, autoimmune hemolytic anemia, celiac disease and inflammatory bowl disease have been reported. 

 

Objectives/ Aims

The aim of our study is to explain the clinical course of patients with 22q11.2 DS, particularly the development of autoimmune diseases.


Current research projects

  • T-cells, autoimmunity and inflammation in 22q11.2 deletion syndrome (DiGeorge syndrome)
  • Newborn screening for severe combined immunodeficiency (SCID)
  • Immunological studies of patients with DiGeorge syndrome and its variants


Main national and international collaborators

  • Liv Osnes, Børre Fevang, and Tom Eirik Mollnes.
  • Avdeling for genetikk, OUS
  • Immunologisk institutt, UiO
  • Avdeling for medisinsk biokjemi, UiO


Financial support

South-Eastern Norway Regional Health Authority, Renée og Bredo Grimsgaard's Stiftelse, and Legatet til Henrik Homans Minde.


Selected publications for 2012

  • Nordgarden H, Lima K, Skogedal N, Følling I, Storhaug K, Abrahamsen TG Dental developmental disturbances in 50 individuals with the 22q11.2 deletion syndrome; relation to medical conditions? Acta Odontol Scand 2012, 70 (3), 194-201.

 

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Pediatric Liver Kidney Alimentary Nutrition and Transplantation Research Group

 Research team members

Runar Almaas (group leader), Beint Sigmund Bentsen, Anna Bjerre, Marianne Bratlie, Svanhildur Haflidadottir, Gaute Reier Jenssen, Janne Kvammen, Anine Lie, Gøri Perminow, Jarle Rugtveit, Truls Sanengen, Ingrid H Sparr, Rut Anne Thomassen, Hjørdis Thorsteinsdottir, Karianne Vegheim, Niklas Westerberg, and Anniken B Østensen.

Research goals and strategy

PELIKANTRA was created in 2011 with members from several sections at the Department of Pediatrics at Oslo University Hospital. We are working with gastroenterology, nutrition, nephrology, hepatology, and organ transplantation. Our research is conducted both at Department of Pediatrics at Ullevål and Rikshospitalet and at Department of Pediatric Research. We are cooperating with several research groups. PELIKANTRA does both clinical science and basic science and takes a special interest in putting clinical relevant projects into the laboratory. Several of the projects relate to the life after organ transplantation. Other areas of interest are inflammatory bowel disease, enteral and parenteral nutrition, and cholestasis.

Current research projects

  • IBSEN-II (Inflammatory Bowel South Eastern Norway-II): Children and adolescents presenting with inflammatory bowel disease was included in 2005-2007. We are studying clinical presentation, biochemical markers, and biopsies at diagnosis and after 2 years of treatment.
  • EARLY-IBD: Prospective international multicenter study of presentation of inflammatory bowel disease.
  • Transplantation and allergy: There are several reports of increased incidence of allergy in liver transplanted children. We are investigating how liver transplanted children are affected by different allergies and whether allergies are associated with certain risk factors.
  • Hypoxic hepatocyte damage: In the transplanted liver thrombosis of the hepatic artery may cause hypoxic-ischemic damage of the liver. We are investigating mechanisms of hypoxic-ischemic hepatocyte damage and how pharmacological treatment can affect the extent of hypoxic-ischemic hepatocyte damage.  A model with combined oxygen and glucose deprivation in hepatocytes is used. Another field of interest is development and mechanisms of cholestasis and hepatobiliary transport systems are investigated in hepatocytes.
  • Fecal calprotectin: Fecal calprotectin is a marker of inflammatory activity in inflammatory bowel disease. Several parallel methods of analysis of calprotectin exist and we compare and relate different methods to endoscopic findings in children with and without inflammatory bowel disease.

Main national and international collaborators

National

  • Avdeling for patologi, OUS
  • Avdeling for helsefag, UiO
  • Akuttavdelingen, OUS
  • Bioteknologisenteret, UiO
  • Immunologisk institutt, OUS
  • Folkehelseinstituttet
  • Radiologisk avdeling, OUS
  • Gastromedisinsk avdeling, Medisinsk klinikk, OUS
  • Klinikk for indremedisin og laboratoriefag, Ahus
  • Professor emeritus Magne K Fagerhol

International

  • IBSEN II study group/Early IBD group leader professor Morten Vatn (internatonal multi-center study)
  • Dr Margarete Fisher-Bosch Institute for Clinical Pharmacology, Robert-Bosch Hospital, Stuttgart, Germany
  • Karolinska University Hospital, Stockholm, Sverige

Financial support

  • Eckbos legater
  • Renée og Bredo Grimsgaards Stiftelse
  • Barnefondet, Oslo universitetssykehus UiO
  • Helse Sør-Øst

Selected publications for 2013

Brun AC, Størdal K, Johannesdottir GB, Fossum V, Bentsen BS, Medhus AW. Nissen fundoplication in children with cerebral palsy: Influence on rate of gastric emptying and postprandial symptoms in relation to protein source in caloric liquid meals. Clin Nutr. 2013;32:619-623.

Wühl E, van Stralen KJ, Verrina E, Bjerre A, Wanner C, Heaf JG, Zurriaga O, Hoitsma A, Niaudet P, Palsson R, Ravani P, Jager KJ, Schaefer F. Timing and outcome of renal replacement therapy in patients with congenital malformations of the kidney and urinary tract. Clin J Am Soc Nephrol. 2013;8(1):67-74.

Haugaa H, Almaas R, Thorgersen EB, Foss A, Line PD, Sanengen T, Bergmann GB, Ohlin P,  Waelgaard, Grindheim G, Pischke  SE, Mollnes TE, Tønnessen TI. Clinical experience with microdialysis catheters in pediatric liver transplants. Liver Transplantation 2013 Mar;19(3):305-1.

Dissertations

Publications 2011 - 2014

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Hypoxia and oxidativ stress

Research team members

Ola Didrik Saugstad (group leader), Rønnaug Solberg, Lars O. Baumbusch, Torkil Benterud, Marianne U. Huun, Cecilie Revhaug, Leonid Pankratov, Anne Gro W Rognlien, Martin Bogale Ystgaard, and Monica Atneosen-Åsegg.

 

Research goals and strategy

Over the past 30 years, considerable research efforts have helped to elucidate the mechanisms of hypoxia and reoxygenation, oxidative stress, and subsequent oxidative damage. The PFI has substantially contributed to change the guidelines for resuscitation of neonates in October 2010; however, more research is required to elucidate the mechanisms and effects of oxidative stress and possible intervention strategies to reduce the potential harmful effects of oxygen. The group has conducted many experimental studies in various animal models (mainly piglets and mice) and in cell models.

The Institute's strategy has been and will be to recruit dedicated scientific professionals for ongoing  studies in our key areas of research and to develop new ideas. The Institute has many local and international partners and is open to visiting scholars. Research group leader Ola Didrik Saugstad received in 2011 three awards for their contributions to neonatal medicine and for his involvement in the public debate about medical ethics, The Landmark Award (American Academy of Pediatrics), Bjornson Prize (along with Marte Wexelsen Goksøyr, Bjornson Academy) and Corresponding member (Deutsche Gesellschaft für Medizin Perinatal).

 

Current research projects

  • Studies of newborn mice to identify whole-genome and transcriptome changes at hypoxia and reoxygenation
  • Studies in newborn mice to investigate toxicity of DNA at reoxygenation after hypoxia
  • Studies on newborn pigs to examine neuroprotective principles
  • Studies in newborn pigs to optimize resuscitation algorithms
  • Studies on brain cells in culture to study the toxic effects of bilirubin on the enzymatic and molecular levels
  • Clinical trials in neonates

 

Main national and international collaborators

  • Many different collaboration partners at the Oslo University Hospital and the University of Oslo, among others, research groups at PFI, Inner Medical Research Institute (Rikshospitalet), Children Medical Centre (OUS HF), Department of Microbiology (OUS HF), Department of Anatomy (OUS HF), Biotechnology Centre (University of Oslo), and the Biology Institute (University of Oslo)
  • University & Polytechnic Hospital La Fe, Valencia, Spania
  • UOC Pediatria Neonatale, Policlinico S. Maria alle Scotte, Siena, Italia
  • Faculté de médecine, Aix-Marseille Université, Marseille, Frankrike
  • Barnemedisinsk klinikk, Karolinska Sjukhuset, Stockholm
  • Børneafdeling, Aalborg Amtssygehus, Universitetet i Aarhus, Danmark

 

Financial support

  • Oslo University Hospital
  • University of Oslo
  • South-Eastern Norway Regional Health Authority
  • The Norwegian Research Council
  • Landsforeningen for uventet barnedød (LUB) (The National Association of unexpected child death)
  • EU/EAAEU/EAA
  • Chiesi Pharma AB

 

 

 

 

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