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.

Protein tyrosine phosphatase PTPRB regulates Src phosphorylation and tumour progression in NSCLC

“…Compared to its family members, little is known about the function of PTPRB in the tumorigenesis process. A few recent studies have identified mutations in this gene in angiosarcoma, melanoma, GBM and more recently in premalignant colonic epithelial cells, suggestive of its potential role as a tumour suppressor in these cancer types . In our study, we investigated the potential tumour suppressive function of PTPRB in NSCLC by ectopically expressing this protein in A549 and H1299 cells, followed by tumorigenic assays.…”

“…13 In addition, familial exome sequencing identified polymorphism of PTPRB gene in glioblastoma multiforme (GBM) individuals. 14 These observations suggest that PTPRB may function as a tumour suppressor in carcinogenesis and cancer development. However, it remains largely unknown whether mutations in this gene directly contribute to carcinogenesis in these cancer types.…”

“…Recent studies have discovered recurrent mutations in PTPRB in angiosarcoma and a large number of truncation mutations of this gene in metastatic melanoma . In addition, familial exome sequencing identified polymorphism of PTPRB gene in glioblastoma multiforme (GBM) individuals . These observations suggest that PTPRB may function as a tumour suppressor in carcinogenesis and cancer development.…”

Geographical distribution of complement receptor type 1 variants and their associated disease risk

“…Further studies are warranted with increased sample sizes, to determine the role of CR1 in disease associations and pathogenesis mechanisms. [38] Malaria [36,37,40,42] Tuberculosis [46] Leprosy [47] rs17047661 (4841A>G) Sl1/Sl2 R1601G Sickle cell trait [38] Malaria [36,37,39,41,42,48] Tuberculosis [46] rs4844609 (4868T>A) Sl4/Sl5 T1610S Alzheimer disease [49][50][51][52] Cognitive decline [53,54] rs6691117 (4883A>G) KCAM +/-I1615V Erythrocyte Sedimentation Rate [55] Alzheimer Disease [56] Gastric cancer [57] Lung cancer [58] Glioblastoma multiforme [59]…”

Pinpointing a potential role for CLEC12B in cancer predisposition through familial exome sequencing

“…Recent advances in DNA sequencing technology and associated bioinformatics enable the identification of novel predisposition genes . Early age of onset, syndromic features, multifocal primary tumors, associated primary immunodeficiency, and familial clustering are key features of hereditary susceptibility to cancer.…”