LGG-06_Michael Fisher
LGG-06 COMPREHENSIVE GENOMIC CHARACTERIZATION AND INTEGRATED CLINICAL ANALYSIS OF LOW-GRADE GLIOMAS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1
Contact Presenter
Michael Fisher1, David Jones2,3, Yimei Li4, Xiaofan Guo5, Poonam Sonawane1, Angela Waanders6, Joanna Phillips7, William Weiss7, Adam Resnick1, Sara Gosline8, Jineta Banerjee8, Justin Guinney8, Astrid Gnekow9, Daniela Kandels9, Nicholas Foreman10, Andrey Korshunov11, Marina Ryzhova12, Luca Massimi13, Sri Gururangan14, Mark Kieran15, Zhihong Wang16, Maryam Fouladi17, Mariko Sato18, Ingrid Øra19, Stefan Holm20, Stephen Markham1, Pengbo Beck2,3, Natalie Jäger2,3, Andrea Wittmann2, Alexander Sommerkamp2,3, Felix Sahm11, Stefan Pfister2,3, David Gutmann5;
1The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 2Hopp Children’s Cancer Center, Heidelberg, Germany. 3German Cancer Research Center (DKFZ), Heidelberg, Germany. 4University of Pennsylvania, Philadelphia, PA, USA. 5Washington University School of Medicine, St. Louis, MO, USA. 6Lurie Children’s Hospital, Chicago, IL, USA. 7University of California, San Francisco, San Francisco, CA, USA. 8Sage Bionetworks, Seattle, WA, USA. 9University Augsburg, Augsburg, Germany. 10University of Colorado, Denver, CO, USA. 11Heidelberg University, Heidelberg, Germany. 12NN Burdenko Neurosurgical Research Centre, Moskow, Russian Federation. 13A. Gemelli Hospital, Rome, Italy. 14UF Health Shands Hospital, Gainesville, FL, USA. 15Bristol Myers Squibb, Lawrenceville, NJ, USA. 16Children’s Hospital of Richmond, Richmond, VA, USA. 17Nationwide Children’s Hospital, Columbus, OH, USA. 18University of Iowa Stead Family Children's Hospital, Iowa City, IA, USA. 19Lund University, Lund, Sweden. 20Karolinska University Hospital, Stockholm, Sweden
BACKGROUND: Low-grade gliomas (LGGs) arising in children with neurofibromatosis type 1 (NF1) are usually not biopsied. To identify secondary genetic alterations or molecular features that may contribute to pathogenesis and correlate with clinical behavior, we initiated a comprehensive molecular and clinical analysis of pediatric NF1-LGGs. METHODS: NF1-LGGs were analysed by whole-genome sequencing (31), targeted gene panel sequencing (9), RNAseq transcriptomal profiling (33) and genome-wide DNA methylation analysis (67). Clinical annotation was available for 48 subjects. RESULTS: Most LGGs harbored bi-allelic NF1 inactivation as the sole genetic abnormality, but 11% had additional alterations (FGFR1 mutation, n=3; PIK3CA mutation, n=2; homozygous 9p21 deletion, n=2; MYB:QKI fusion, n=1; SETD2 mutation, n=1; EGFR amplification, n=1). FGFR1 mutation conferred additional growth advantage in multiple complementary murine Nf1 models. 88% of NF1-LGGs resembled sporadic pilocytic astrocytoma (PA) by methylation, higher than that based on histology. Non-PA methylation patterns included low-grade glial/glioneuronal tumors, rosette-forming glioneuronal tumors, MYB/MYBL1-altered glioma, and high-grade astrocytoma with piloid features (2 tumors histologically diagnosed as LGG). In total, 18% of samples were classified as non-PA and/or harbored an additional non-NF1 mutation. Non-PA methylation class tumors were more likely to harbor an additional non-NF1 mutation (p=0.005). 7.7% of optic pathway hypothalamic gliomas (OPHGs) had other mutations or were not classified by methylation as PA, compared with 20.6% of NF1-LGGs arising elsewhere. There was no difference based on age for the presence of an additional non-NF1 mutation or non-PA methylation class. CONCLUSIONS: Given the overall low occurrence of non-NF1 mutations or non-PA methylation class tumors in this series, routine clinical biopsy of typically-appearing NF1-LGG may not be indicated, particularly for children with OPHG. Biopsy should be considered for non-OPHG tumors refractory to conventional treatment. As additional agents are developed and treatment strategies evolve, the rationale for biopsy of NF1-LGG may become stronger.
Contact Presenter
Michael Fisher1, David Jones2,3, Yimei Li4, Xiaofan Guo5, Poonam Sonawane1, Angela Waanders6, Joanna Phillips7, William Weiss7, Adam Resnick1, Sara Gosline8, Jineta Banerjee8, Justin Guinney8, Astrid Gnekow9, Daniela Kandels9, Nicholas Foreman10, Andrey Korshunov11, Marina Ryzhova12, Luca Massimi13, Sri Gururangan14, Mark Kieran15, Zhihong Wang16, Maryam Fouladi17, Mariko Sato18, Ingrid Øra19, Stefan Holm20, Stephen Markham1, Pengbo Beck2,3, Natalie Jäger2,3, Andrea Wittmann2, Alexander Sommerkamp2,3, Felix Sahm11, Stefan Pfister2,3, David Gutmann5;
1The Children’s Hospital of Philadelphia, Philadelphia, PA, USA. 2Hopp Children’s Cancer Center, Heidelberg, Germany. 3German Cancer Research Center (DKFZ), Heidelberg, Germany. 4University of Pennsylvania, Philadelphia, PA, USA. 5Washington University School of Medicine, St. Louis, MO, USA. 6Lurie Children’s Hospital, Chicago, IL, USA. 7University of California, San Francisco, San Francisco, CA, USA. 8Sage Bionetworks, Seattle, WA, USA. 9University Augsburg, Augsburg, Germany. 10University of Colorado, Denver, CO, USA. 11Heidelberg University, Heidelberg, Germany. 12NN Burdenko Neurosurgical Research Centre, Moskow, Russian Federation. 13A. Gemelli Hospital, Rome, Italy. 14UF Health Shands Hospital, Gainesville, FL, USA. 15Bristol Myers Squibb, Lawrenceville, NJ, USA. 16Children’s Hospital of Richmond, Richmond, VA, USA. 17Nationwide Children’s Hospital, Columbus, OH, USA. 18University of Iowa Stead Family Children's Hospital, Iowa City, IA, USA. 19Lund University, Lund, Sweden. 20Karolinska University Hospital, Stockholm, Sweden
BACKGROUND: Low-grade gliomas (LGGs) arising in children with neurofibromatosis type 1 (NF1) are usually not biopsied. To identify secondary genetic alterations or molecular features that may contribute to pathogenesis and correlate with clinical behavior, we initiated a comprehensive molecular and clinical analysis of pediatric NF1-LGGs. METHODS: NF1-LGGs were analysed by whole-genome sequencing (31), targeted gene panel sequencing (9), RNAseq transcriptomal profiling (33) and genome-wide DNA methylation analysis (67). Clinical annotation was available for 48 subjects. RESULTS: Most LGGs harbored bi-allelic NF1 inactivation as the sole genetic abnormality, but 11% had additional alterations (FGFR1 mutation, n=3; PIK3CA mutation, n=2; homozygous 9p21 deletion, n=2; MYB:QKI fusion, n=1; SETD2 mutation, n=1; EGFR amplification, n=1). FGFR1 mutation conferred additional growth advantage in multiple complementary murine Nf1 models. 88% of NF1-LGGs resembled sporadic pilocytic astrocytoma (PA) by methylation, higher than that based on histology. Non-PA methylation patterns included low-grade glial/glioneuronal tumors, rosette-forming glioneuronal tumors, MYB/MYBL1-altered glioma, and high-grade astrocytoma with piloid features (2 tumors histologically diagnosed as LGG). In total, 18% of samples were classified as non-PA and/or harbored an additional non-NF1 mutation. Non-PA methylation class tumors were more likely to harbor an additional non-NF1 mutation (p=0.005). 7.7% of optic pathway hypothalamic gliomas (OPHGs) had other mutations or were not classified by methylation as PA, compared with 20.6% of NF1-LGGs arising elsewhere. There was no difference based on age for the presence of an additional non-NF1 mutation or non-PA methylation class. CONCLUSIONS: Given the overall low occurrence of non-NF1 mutations or non-PA methylation class tumors in this series, routine clinical biopsy of typically-appearing NF1-LGG may not be indicated, particularly for children with OPHG. Biopsy should be considered for non-OPHG tumors refractory to conventional treatment. As additional agents are developed and treatment strategies evolve, the rationale for biopsy of NF1-LGG may become stronger.