Survey of familial glioma and role of germline p16 INK4A /p14 ARF and p53 mutation

Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK.
Familial Cancer (Impact Factor: 1.98). 05/2010; 9(3):413-21. DOI: 10.1007/s10689-010-9346-5
Source: PubMed


There is increasing recognition of familial propensity to glioma as a distinct clinical entity beyond a few rare syndromes; however its genetic basis is poorly understood. The role of p16(INK4A)/p14(ARF) and p53 mutations in sporadic glioma provides a strong rationale for investigating germline mutations in these genes as a cause of familial glioma. To survey the familial glioma phenotype and examine the contribution of germline mutation in p16(INK4A)/p14(ARF) and p53 to the disease we have analyzed a series of 101 index familial cases collected through the GLIOGENE Consortium ( There was little evidence for within family correlations for tumour histology, suggesting generic susceptibility to glial tumors. We did not detect any functional mutations in p16(INK4A) or p14(ARF). One index case with glioblastoma multiforme (GBM) diagnosed at age 54 and had a family history comprised of a paternal aunt with GBM at age 55, carried the p53 R158H mutation, which is predicted to be functional and has previously been implicated as a cause of Li-Fraumeni syndrome. Our findings provide no evidence that p16(INK4A)/p14(ARF) and p53 mutations contribute significantly to familial glioma.

Download full-text


Available from: Dora Il'yasova
  • [Show abstract] [Hide abstract]
    ABSTRACT: Some cancers are involved in inherited genetic syndromes. These genetic diseases are suspected of being involved in approximately 1% of gliomas. Few data are available on glioblastomas and their characteristics among these diseases. Familial syndromes known to predispose individuals to glioblastoma are neurofibromatosis type 1, Li-Fraumeni's syndrome, tuberous sclerosis, and Turcot's syndrome. This review discusses glioblastomas related to these diseases and the current knowledge on the statistical, clinical, and molecular biology data. Non-syndromic glioma families are discussed: a better understanding of molecular abnormalities in these groups should help understand the mechanisms of gliomagenesis. A case of malignant glioma requires the physician to actively search for the possibility of inherited factors and eventually suggest genetic counseling.
    No preview · Article · Dec 2010 · Neurochirurgie
  • [Show abstract] [Hide abstract]
    ABSTRACT: A small percentage of gliomas are caused by inheritance in cancer syndromes but there is also a general familial aggregation of glioma. Recently, low penetrant genes associated with glioma risk have been identified. Seven independent chromosomal loci have robustly been associated with glioma risk: 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A-CDKN2B), 20q13.33 (rs6010620, RTEL1), and 11q23.3 (rs498872, PHLDB1), and two loci at 7p11.2 (rs11979158 and rs2252586, EGFR). Several of these genes are obvious candidates in their role for chromosomal integrity and glioma progression. Moreover, all loci but the EGFR and CDKN2A genes display a pattern of association to certain glioma subtypes. The causes of glioma have until recently been unknown for most cases, partly due to lack of statistically powered studies enabling subclassification of glioma subtypes. The novel chromosomal loci associated with different glioma subtypes have provided us with an additional understanding of causes of glioma. All low penetrant genes contribute with a modest increased risk and cannot by themselves be used for risk prediction. Nevertheless, they could provide a tool to understand the underlying biology of glioma progression and to be used in future studies of gene-environment studies of specific glioma subtypes.
    No preview · Article · Aug 2011 · Current opinion in oncology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gliomas make up approximately 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. Despite the frequency of gliomas, the etiology of these tumors remains largely unknown. Diffuse gliomas, including astrocytomas and oligodendrogliomas, belong to a single pathologic class but have very different histologies and molecular etiologies. Recent genomic studies have identified separate molecular subtypes within the glioma classification that appear to correlate with biological etiology, prognosis, and response to therapy. The discovery of these subtypes suggests that molecular genetic tests are and will be useful, beyond classical histology, for the clinical classification of gliomas. While a familial susceptibility to glioma has been identified, only a small percentage of gliomas are thought to be due to single-gene hereditary cancer syndromes. Through the use of linkage studies and genome-wide association studies, multiple germline variants have been identified that are beginning to define the genetic susceptibility to glioma.
    No preview · Article · Dec 2012 · Cancer Genetics
Show more