LOGGIC Core BioClinical Data Bank: Added clinical value of RNA-Seq in an international molecular diagnostic registry for pediatric low-grade glioma patients

doi:10.1093/neuonc/noad078

. 2023 Apr 19:noad078.

doi: 10.1093/neuonc/noad078. Online ahead of print.

LOGGIC Core BioClinical Data Bank: Added clinical value of RNA-Seq in an international molecular diagnostic registry for pediatric low-grade glioma patients

Emily C Hardin^{1

2

3

4

5}, Simone Schmid⁶, Alexander Sommerkamp^{1

5

7}, Carina Bodden^{1

2

5}, Anna-Elisa Heipertz^{1

2

3

4

5}, Philipp Sievers^{8

9}, Andrea Wittmann^{1

5

7}, Till Milde^{1

2

3

5}, Stefan M Pfister^{1

3

5

10}, Andreas von Deimling^{8

9}, Svea Horn¹¹, Nina A Herz¹¹, Michèle Simon^{11

12}, Ashwyn A Perera^{1

4

5

7}, Amedeo Azizi¹³, Ofelia Cruz¹⁴, Sarah Curry¹⁵, An Van Damme¹⁶, Miklos Garami¹⁷, Darren Hargrave¹⁸, Antonis Kattamis¹⁹, Barbara Faganel Kotnik²⁰, Päivi Lähteenmäki²¹, Katrin Scheinemann^{22

23

24}, Antoinette Y N Schouten-van Meeteren²⁵, Astrid Sehested²⁶, Elisabetta Viscardi²⁷, Ole Mikal Wormdal²⁸, Michal Zapotocky²⁹, David S Ziegler^{30

31

32}, Arend Koch⁶, Pablo Hernáiz Driever^{11

12}, Olaf Witt^{1

2

3

5}, David Capper^{6

33}, Felix Sahm^{8

9}, David T W Jones^{1

5

7}, Cornelis M van Tilburg^{1

2

3

5}

Affiliations

¹ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
² Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK).
³ Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
⁴ Heidelberg Medical Faculty, University of Heidelberg, Germany.
⁵ National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁶ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Berlin, Germany.
⁷ Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸ Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁰ Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, HIT-LOGGIC German Registry for children and adolescents with low-grade glioma, Berlin, Germany.
¹² Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology/Hematology, Berlin, Germany.
¹³ Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
¹⁴ Neuro-Oncology Unit, Pediatric Cancer Center, Hospital Sant Joan de Deu, Barcelona, Spain.
¹⁵ Department of Haematology & Oncology, Children's Health Ireland at Crumlin, Dublin, Ireland.
¹⁶ Department of Pediatric Hematology and Oncology, Saint Luc University Hospital, Brussels, Belgium.
¹⁷ 2nd Department of Pediatrics, Semmelweis University, 1094 Budapest, Hungary.
¹⁸ Great Ormond Street Hospital for Children NHS Trust London, London, UK.
¹⁹ First Department of Paediatrics, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens, Athens 11527, Greece.
²⁰ University Medical Centre Ljubljana (UMC), University Children's Hospital, Department of Haematology and Oncology, Ljubljana, Slovenia.
²¹ Turku University and University Hospital, FI20521 Turku, Finland; Swedish Childhood Cancer Registry, Karolinska Institutet, Stockholm, Sweden.
²² Division of Pediatric Oncology - Hematology, Department of Pediatrics, Kantonsspital Aarau, Aarau, Switzerland.
²³ Department of Health Sciences and Medicine, University of Lucerne, Switzerland.
²⁴ Department of Paediatrics, McMaster Children's Hospital and McMaster University, Hamilton, Canada.
²⁵ Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
²⁶ Department of Paediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, Copenhagen, Denmark.
²⁷ Pediatric Oncology Unit, Padova University, Padova, Italy.
²⁸ Section of Pediatric Oncology, UNN University Hospital of Northern Norway, Tromsø, Norway.
²⁹ Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
³⁰ Kids Cancer Centre, Sydney Children's Hospital, High St, Randwick, NSW, Australia.
³¹ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, Australia.
³² School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
³³ German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.

PMID: 37075810
DOI: 10.1093/neuonc/noad078

LOGGIC Core BioClinical Data Bank: Added clinical value of RNA-Seq in an international molecular diagnostic registry for pediatric low-grade glioma patients

Emily C Hardin et al. Neuro Oncol. 2023.

. 2023 Apr 19:noad078.

doi: 10.1093/neuonc/noad078. Online ahead of print.

Authors

Affiliations

¹ Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
² Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK).
³ Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.
⁴ Heidelberg Medical Faculty, University of Heidelberg, Germany.
⁵ National Center for Tumor Diseases (NCT), Heidelberg, Germany.
⁶ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Berlin, Germany.
⁷ Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸ Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁰ Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, HIT-LOGGIC German Registry for children and adolescents with low-grade glioma, Berlin, Germany.
¹² Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Pediatric Oncology/Hematology, Berlin, Germany.
¹³ Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
¹⁴ Neuro-Oncology Unit, Pediatric Cancer Center, Hospital Sant Joan de Deu, Barcelona, Spain.
¹⁵ Department of Haematology & Oncology, Children's Health Ireland at Crumlin, Dublin, Ireland.
¹⁶ Department of Pediatric Hematology and Oncology, Saint Luc University Hospital, Brussels, Belgium.
¹⁷ 2nd Department of Pediatrics, Semmelweis University, 1094 Budapest, Hungary.
¹⁸ Great Ormond Street Hospital for Children NHS Trust London, London, UK.
¹⁹ First Department of Paediatrics, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens, Athens 11527, Greece.
²⁰ University Medical Centre Ljubljana (UMC), University Children's Hospital, Department of Haematology and Oncology, Ljubljana, Slovenia.
²¹ Turku University and University Hospital, FI20521 Turku, Finland; Swedish Childhood Cancer Registry, Karolinska Institutet, Stockholm, Sweden.
²² Division of Pediatric Oncology - Hematology, Department of Pediatrics, Kantonsspital Aarau, Aarau, Switzerland.
²³ Department of Health Sciences and Medicine, University of Lucerne, Switzerland.
²⁴ Department of Paediatrics, McMaster Children's Hospital and McMaster University, Hamilton, Canada.
²⁵ Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
²⁶ Department of Paediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, Copenhagen, Denmark.
²⁷ Pediatric Oncology Unit, Padova University, Padova, Italy.
²⁸ Section of Pediatric Oncology, UNN University Hospital of Northern Norway, Tromsø, Norway.
²⁹ Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
³⁰ Kids Cancer Centre, Sydney Children's Hospital, High St, Randwick, NSW, Australia.
³¹ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, Australia.
³² School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
³³ German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.

PMID: 37075810
DOI: 10.1093/neuonc/noad078

Abstract

Background: The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data to support treatment decisions and interventional trial participation. Hence, the question arises whether implementation of RNA sequencing (RNA-Seq) using Fresh Frozen (FrFr) tumor tissue in addition to gene panel and DNA methylation analysis improves diagnostic accuracy and provides additional clinical benefit.

Methods: Analysis of patients age 0 to 21 years, enrolled in Germany between 04/2019 and 02/2021, and for whom FrFr tissue was available. Central reference histopathology, immunohistochemistry, 850k DNA methylation analysis, gene panel sequencing and RNA-Seq were performed.

Results: FrFr tissue was available in 178/379 enrolled cases. RNA-Seq was performed on 125 of these samples. We confirmed KIAA1549::BRAF-fusion (n=71), BRAF V600E-mutation (n=12) and alterations in FGFR1 (n=14) as the most frequent alterations, among other common molecular drivers (n=12). . N=16 cases (13%) presented rare gene fusions (e.g. TPM3::NTRK1, EWSR1::VGLL1, SH3PXD2A::HTRA1, PDGFB::LRP1, GOPC::ROS1). In n=27 cases (22%), RNA-Seq detected a driver alteration not otherwise identified (22/27 actionable). The rate of driver alteration detection was hereby increased from 75% to 97%. Furthermore, FGFR1 ITD (n=6) were only detected by RNA-Seq using current bioinformatics pipelines, leading to a change in analysis protocols.

Conclusions: The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified.

Keywords: RNA sequencing; actionable drivers; molecular profiling; pLGG; rare gene fusions.

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The 'LOGGIC' of RNA-sequencing in enhancing diagnoses of pediatric low-grade gliomas.
Apfelbaum A, Bandopadhayay P. Apfelbaum A, et al. Neuro Oncol. 2023 Aug 2:noad142. doi: 10.1093/neuonc/noad142. Online ahead of print. Neuro Oncol. 2023. PMID: 37531270 No abstract available.

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Sigaud R, Albert TK, Hess C, Hielscher T, Winkler N, Kocher D, Walter C, Münter D, Selt F, Usta D, Ecker J, Brentrup A, Hasselblatt M, Thomas C, Varghese J, Capper D, Thomale UW, Hernáiz Driever P, Simon M, Horn S, Herz NA, Koch A, Sahm F, Hamelmann S, Faria-Andrade A, Jabado N, Schuhmann MU, Schouten-van Meeteren AYN, Hoving E, Brummer T, van Tilburg CM, Pfister SM, Witt O, Jones DTW, Kerl K, Milde T. Sigaud R, et al. Nat Commun. 2023 Jul 27;14(1):4533. doi: 10.1038/s41467-023-40235-8. Nat Commun. 2023. PMID: 37500667 Free PMC article.

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LOGGIC Core BioClinical Data Bank: Added clinical value of RNA-Seq in an international molecular diagnostic registry for pediatric low-grade glioma patients

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LOGGIC Core BioClinical Data Bank: Added clinical value of RNA-Seq in an international molecular diagnostic registry for pediatric low-grade glioma patients

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