%0 Journal Article %J J Natl Cancer Inst %D 2015 %T Germline mutations in shelterin complex genes are associated with familial glioma. %A Bainbridge, Matthew N %A Armstrong, Georgina N %A Gramatges, M Monica %A Bertuch, Alison A %A Jhangiani, Shalini N %A Doddapaneni, Harsha %A Lewis, Lora %A Tombrello, Joseph %A Tsavachidis, Spyros %A Liu, Yanhong %A Jalali, Ali %A Plon, Sharon E %A Lau, Ching C %A Parsons, Donald W %A Claus, Elizabeth B %A Barnholtz-Sloan, Jill %A Il'yasova, Dora %A Schildkraut, Joellen %A Ali-Osman, Francis %A Sadetzki, Siegal %A Johansen, Christoffer %A Houlston, Richard S %A Jenkins, Robert B %A Lachance, Daniel %A Olson, Sara H %A Bernstein, Jonine L %A Merrell, Ryan T %A Wrensch, Margaret R %A Walsh, Kyle M %A Davis, Faith G %A Lai, Rose %A Shete, Sanjay %A Aldape, Kenneth %A Amos, Christopher I %A Thompson, Patricia A %A Muzny, Donna M %A Gibbs, Richard A %A Melin, Beatrice S %A Bondy, Melissa L %K Adult %K Aged %K Brain Neoplasms %K Exome %K Female %K Genetic Predisposition to Disease %K Germ-Line Mutation %K Glioma %K Humans %K Male %K Middle Aged %K Oligodendroglioma %K Pedigree %K Shelterin Complex %K Telomere-Binding Proteins %X

Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.

%B J Natl Cancer Inst %V 107 %P 384 %8 2015 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/25482530?dopt=Abstract %R 10.1093/jnci/dju384 %0 Journal Article %J Sci Rep %D 2015 %T Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene Consortium. %A Jalali, Ali %A Amirian, E Susan %A Bainbridge, Matthew N %A Armstrong, Georgina N %A Liu, Yanhong %A Tsavachidis, Spyros %A Jhangiani, Shalini N %A Plon, Sharon E %A Lau, Ching C %A Claus, Elizabeth B %A Barnholtz-Sloan, Jill S %A Il'yasova, Dora %A Schildkraut, Joellen %A Ali-Osman, Francis %A Sadetzki, Siegal %A Johansen, Christoffer %A Houlston, Richard S %A Jenkins, Robert B %A Lachance, Daniel %A Olson, Sara H %A Bernstein, Jonine L %A Merrell, Ryan T %A Wrensch, Margaret R %A Davis, Faith G %A Lai, Rose %A Shete, Sanjay %A Aldape, Kenneth %A Amos, Christopher I %A Muzny, Donna M %A Gibbs, Richard A %A Melin, Beatrice S %A Bondy, Melissa L %K Adult %K Brain Neoplasms %K Chromosomes, Human, Pair 17 %K Family %K Female %K Genetic Linkage %K Genetic Variation %K Glioma %K Humans %K Male %K Middle Aged %K Mutation %K Pedigree %K Sequence Analysis, DNA %K Young Adult %X

Glioma is a rare, but highly fatal, cancer that accounts for the majority of malignant primary brain tumors. Inherited predisposition to glioma has been consistently observed within non-syndromic families. Our previous studies, which involved non-parametric and parametric linkage analyses, both yielded significant linkage peaks on chromosome 17q. Here, we use data from next generation and Sanger sequencing to identify familial glioma candidate genes and variants on chromosome 17q for further investigation. We applied a filtering schema to narrow the original list of 4830 annotated variants down to 21 very rare (<0.1% frequency), non-synonymous variants. Our findings implicate the MYO19 and KIF18B genes and rare variants in SPAG9 and RUNDC1 as candidates worthy of further investigation. Burden testing and functional studies are planned.

%B Sci Rep %V 5 %P 8278 %8 2015 Feb 05 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/25652157?dopt=Abstract %R 10.1038/srep08278 %0 Journal Article %J Neuro Oncol %D 2014 %T Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer. %A Andersson, Ulrika %A Wibom, Carl %A Cederquist, Kristina %A Aradottir, Steina %A Borg, Ake %A Armstrong, Georgina N %A Shete, Sanjay %A Lau, Ching C %A Bainbridge, Matthew N %A Claus, Elizabeth B %A Barnholtz-Sloan, Jill %A Lai, Rose %A Il'yasova, Dora %A Houlston, Richard S %A Schildkraut, Joellen %A Bernstein, Jonine L %A Olson, Sara H %A Jenkins, Robert B %A Lachance, Daniel H %A Wrensch, Margaret %A Davis, Faith G %A Merrell, Ryan %A Johansen, Christoffer %A Sadetzki, Siegal %A Bondy, Melissa L %A Melin, Beatrice S %K Adaptor Proteins, Signal Transducing %K Adult %K Brain Neoplasms %K Breast Neoplasms %K Checkpoint Kinase 2 %K Child, Preschool %K Colonic Neoplasms %K Cyclin-Dependent Kinase Inhibitor p15 %K Cyclin-Dependent Kinase Inhibitor p16 %K Female %K Genetic Predisposition to Disease %K Germ-Line Mutation %K Glioma %K Humans %K Male %K Melanoma %K Middle Aged %K MutL Protein Homolog 1 %K MutS Homolog 2 Protein %K Nuclear Proteins %K Pedigree %K Tumor Suppressor Protein p53 %K Young Adult %X

BACKGROUND: Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers.

METHODS: Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer.The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma.

RESULTS: We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer.

CONCLUSIONS: Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes.

%B Neuro Oncol %V 16 %P 1333-40 %8 2014 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/24723567?dopt=Abstract %R 10.1093/neuonc/nou052 %0 Journal Article %J Cancer Res %D 2011 %T Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium. %A Shete, Sanjay %A Lau, Ching C %A Houlston, Richard S %A Claus, Elizabeth B %A Barnholtz-Sloan, Jill %A Lai, Rose %A Il'yasova, Dora %A Schildkraut, Joellen %A Sadetzki, Siegal %A Johansen, Christoffer %A Bernstein, Jonine L %A Olson, Sara H %A Jenkins, Robert B %A Yang, Ping %A Vick, Nicholas A %A Wrensch, Margaret %A Davis, Faith G %A McCarthy, Bridget J %A Leung, Eastwood Hon-chiu %A Davis, Caleb %A Cheng, Rita %A Hosking, Fay J %A Armstrong, Georgina N %A Liu, Yanhong %A Yu, Robert K %A Henriksson, Roger %A Melin, Beatrice S %A Bondy, Melissa L %K Adolescent %K Adult %K Aged %K Brain Neoplasms %K Child %K Chromosome Mapping %K Family Health %K Female %K Genetic Heterogeneity %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Glioma %K Humans %K Linkage Disequilibrium %K Lod Score %K Male %K Middle Aged %K Pedigree %K Polymorphism, Single Nucleotide %K United States %K Young Adult %X

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma.

%B Cancer Res %V 71 %P 7568-75 %8 2011 Dec 15 %G eng %N 24 %1 https://www.ncbi.nlm.nih.gov/pubmed/22037877?dopt=Abstract %R 10.1158/0008-5472.CAN-11-0013