title: New insights into the genetics of glioblastoma multiforme by familial exome sequencing.
abstract: Glioblastoma multiforme (GBM) is the most aggressive and malignant subtype of human brain tumors. While a family clustering of GBM has long been acknowledged, relevant hereditary factors still remained elusive. Exome sequencing of families offers the option to discover respective genetic factors.We sequenced blood samples of one of the rare affected families: while both parents were healthy, both children were diagnosed with GBM. We report 85 homozygous non-synonymous single nucleotide variations (SNVs) in both siblings that were heterozygous in the parents. Beyond known key players for GBM such as ERBB2, PMS2, or CHI3L1, we identified over 50 genes that have not been associated to GBM so far. We also discovered three accumulative effects potentially adding to the tumorigenesis in the siblings: a clustering of multiple variants in single genes (e.g., PTPRB, CROCC), the aggregation of affected genes on specific molecular pathways (e.g., Focal adhesion or ECM receptor interaction) and genomic proximity (e.g., chr22.q12.2, chr1.p36.33). We found a striking accumulation of SNVs in specific genes for the daughter, who developed not only a GBM at the age of 12 years but was subsequently diagnosed with a pilocytic astrocytoma, a common acute lymphatic leukemia and a diffuse pontine glioma.The reported variants underline the relevance of genetic predisposition and cancer development in this family and demonstrate that GBM has a complex and heterogeneous genetic background. Sequencing of other affected families will help to further narrow down the driving genetic causes for this disease.
authors.affiliation: Clinical Bioinformatics, University of Saarland, Saarbrücken, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Backes
authors.affiliation: Institute of Human Genetics, University of Saarland, Medical School, Homburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Harz
authors.affiliation: Institute of Human Genetics, University of Saarland, Medical School, Homburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Fischer
authors.affiliation: Institute of Human Genetics, University of Saarland, Medical School, Homburg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Schmitt
authors.affiliation: Institute of Human Genetics, University of Saarland, Medical School, Homburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Ludwig
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Haus Niemannsweg, Kiel, Germany.
authors.forename: Britt-Sabina
authors.initials: BS
authors.lastname: Petersen
authors.affiliation: Clinical Bioinformatics, University of Saarland, Saarbrücken, Germany.|Institute of Human Genetics, University of Saarland, Medical School, Homburg, Germany.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Mueller
authors.affiliation: Department of Pathology, University of Saarland, Medical School, Building, Homburg, Germany.
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany.
authors.forename: Nadine M
authors.initials: NM
authors.lastname: Wolf
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.affiliation: Pediatric Hematology and Oncology, University of Saarland, Medical School, Homburg, Germany.
authors.forename: Rhoikos
authors.initials: R
authors.lastname: Furtwängler
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Haus Niemannsweg, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Pathology, University of Saarland, Medical School, Building, Homburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Bohle
authors.affiliation: Institute of Human Genetics, University of Saarland, Medical School, Homburg, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Henn
authors.affiliation: Pediatric Hematology and Oncology, University of Saarland, Medical School, Homburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Graf
authors.affiliation: Clinical Bioinformatics, University of Saarland, Saarbrücken, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Keller
authors.affiliation: Institute of Human Genetics, University of Saarland, Medical School, Homburg, Germany.
authors.forename: Eckart
authors.initials: E
authors.lastname: Meese
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D001932:Brain Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D005909:Glioblastoma / Q000097:blood / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree
chemical_list: D004273:DNA, Neoplasm
keywords: bioinformatics; glioblastoma multiforme; next generation sequencing