Survey of familial glioma and role of germline p16 INK4A /p14 ARF and p53 mutation
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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 (http://braintumor.epigenetic.org/). 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.
Keywordsp16INK4A/p14ARF p53 Mutation Familial glioma
We are grateful to all patients, their clinicians and other individuals for their participation in this study. Work was undertaken with grant support from NIH R01 CA119215 01, American Brain Tumor Association, and National Brain Tumor Society and the Tug McGraw Foundation. Work in the Houlston laboratory is supported by Cancer Research UK (Bobby Moore C1298/A8362).
We acknowledge the following Gliogene Consortium members; Phyllis Adatto, Fabian Morice (MADCC); Lisa Calvocoressi, Kate Saunders (BW); Karen Devine, Gene Barnett, Cathy Brewer, Elizabeth Ennis (Case); Stacy Murray (Duke); Mitchel Berger, Susan Chang, Michael Prados, Terri Rice (UCSF); Christina Corpuz, Erika Florendo, Steven Rosenfeld (Columbia University); Candice Zahora (UIC); Jan C Buckner, Caterina Giannini, Brian P O’Neill, Deb Sprau (Mayo Clinic); Lisa M. DeAngelis, Erica Schubert, Sharon Bayuga (MSK); Pat Lada (NorthShore University HealthSystem); Deborah T. Blumenthal (Gertner Institute); Zvi Ram (Tel-Aviv University); Hans Bolander, Gudrun Byström, Roger Henriksson, Guiseppe Stragliotti and Fredrik Wiklund (Umeå University).