An activating germline IDH1 variant associated with a tumor entity characterized by unilateral and bilateral chondrosarcoma of the mastoid
Patrick R. Blackburn,
Jodi M. Carter,
Devin Oglesbee,
Jennifer J. Westendorf,
Brian A. Neff,
Damian Stichel,
David W. Tsen,
Ralitza H. Gavrilova,
Pieter Wesseling,
Andreas von Deimling,
Thomas R. Caulfield,
Eric W. Klee,
Stefan Pusch,
Carrie Y. Inwards
Affiliations
Patrick R. Blackburn
Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
Jodi M. Carter
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Corresponding author
Devin Oglesbee
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA
Jennifer J. Westendorf
Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
Brian A. Neff
Department of Otolaryngology-Head and Neck Surgery, Mayo Clinic, Rochester, MN 55905, USA
Damian Stichel
German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg 69120, Germany
David W. Tsen
Department of Otolaryngology, Essentia Health, Fargo, ND 58103, USA
Ralitza H. Gavrilova
Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Pieter Wesseling
Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam 1081 HV, the Netherlands; Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam 1081 HV, the Netherlands; Department of Pathology, Princess Máxima Center for Pediatric Oncology and University Medical Center Utrecht 3584 EA, the Netherlands
Andreas von Deimling
German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg 69120, Germany
Thomas R. Caulfield
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA; Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, FL 32224, USA; Department of Cancer Biology, Mayo Clinic Florida, Jacksonville, FL 32224, USA
Eric W. Klee
Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA
Stefan Pusch
German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg 69120, Germany; Corresponding author
Carrie Y. Inwards
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
Summary: Chondrogenic tumors involving the temporal bone are rare and typically arise spontaneously with unilateral presentation. Somatic IDH mutations are common in these tumors, but germline inheritance has not been documented to our knowledge. We describe familial chondrosarcoma, grade 1, of the mastoid with unilateral presentation in the mother and bilateral presentation in each of her two children. Each individual presented with headaches, facial paresis, and conductive hearing loss between the ages of 9–12. Exome sequencing of all three affected family members identified a shared germline heterozygous c.299G>A (p.Arg100Gln) missense variant in IDH1. The p.Arg100Gln variant has only rarely been observed as a somatic mutation in glial tumors, and previous in vitro experiments have shown that p.Arg100Gln produces small amounts of the oncometabolite D-2-hydroxyglutarate (D2HG). Biochemical testing in all three affected family members on urine and plasma was unable to detect increases in D2HG in these sample types. Due to insufficient tumor for methylation studies, we performed genome-wide methylation analysis of an IDH1 p.Arg100Gln mutant brain tumor from an unrelated individual to functionally evaluate this variant. These studies demonstrated a global hypermethylation phenotype consistent with other known isocitrate dehydrogenase (IDH) mutant brain tumors, suggesting that this variant has neomorphic activity despite low-level production of D2HG. The bones of the facial skeleton are formed by membranous ossification and we hypothesize that abnormal embryonic cartilage that rests within the suture lines may be involved in this tumor entity. Testing of additional individuals with similar presentations is needed to confirm this finding and clarify the associated phenotypes.
