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Sökning: WFRF:(Bainbridge Matthew N.)

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1.
  • Andersson, Ulrika, et al. (författare)
  • Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer
  • 2014
  • Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 16:10, s. 1333-1340
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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2.
  • Bainbridge, Matthew N, et al. (författare)
  • Germline mutations in shelterin complex genes are associated with familial glioma
  • 2015
  • Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 107:1
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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3.
  • Jalali, Ali, et al. (författare)
  • Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene Consortium
  • 2015
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 5, s. 8278-
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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4.
  • Jacobs, Daniel I., et al. (författare)
  • Elucidating the molecular pathogenesis of familial glioma
  • 2018
  • Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 78:13
  • Tidskriftsartikel (övrigt vetenskapligt)abstract
    • In recent years, the molecular characterization of sporadically arising diffuse gliomas has identified recurrent driving alterations and delineated molecularly and clinically distinct subclasses of disease. However, less is known about the molecular nature of gliomas that are familial in origin. To address this question, we integrated germline and somatic genomic data to characterize the molecular pathogenesis of 20 tumors arising in unrelated individuals with a family history of glioma collected through the Gliogene International Consortium. METHODS: FFPE tumor specimens were sectioned and reviewed to localize neoplastic tissue for DNA extraction. Library preparation, exome plus targeted capture, and paired-end sequencing on the Illumina HiSeq 2000 platform was performed at the Baylor College of Medicine Human Genome Sequencing Center. Single-nucleotide variants and indels were called with respect to germline DNA sequencing data for each case using MuTect2. Copy number profiling was performed on the Illumina HumanOmniExpress BeadChip and analyzed using GenomeStudio v2.0. Genotypes at known glioma risk polymorphisms were determined from germline DNA profiled on the Illumina Infinium OncoArray and rare, predicted deleterious germline mutations were identified from germline whole-exome sequencing data. RESULTS: Tumor exome sequencing was completed at an average read depth of 116X and we detected a median of 54 non-silent somatic mutations per tumor across the 20 tumors profiled. All three molecular subtypes of sporadic glioma were represented, including IDH-mutant, 1p/19q codeleted (n=3), IDH-mutant, 1p/19q intact (n=7), and IDH-wildtype tumors (n=10). Characteristic subtype-specific mutations and copy number alterations (e.g., TP53 and ATRX mutations among IDH-mutant, 1p/19q intact tumors) were observed, and the frequencies of recurrent alterations were comparable to sporadic glioma cases analyzed by The Cancer Genome Atlas. Notably, all 20 cases had alterations in genes regulating telomere length; 17 had acquired mutations in ATRX or the TERT promoter as typically seen in sporadic glioma, while three instead had germline mutations in telomere shelterin complex genes POT1 or TERF2. Frequencies of known common glioma risk alleles were similar to those among sporadic cases and correlations between risk alleles and specific somatic mutations were not observed. CONCLUSIONS: This study illustrates: 1) the complementarity of inherited and acquired alterations in driving gliomagenesis in some individuals with a familial predisposition to the disease; and 2) that the molecular characteristics of familial tumors profiled largely recapitulate what is known about sporadic glioma. In the majority of cases, the source of germline genetic susceptibility is not known but does not appear to be conferred by common risk polymorphisms.
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5.
  • Ruiz, Vanessa Y., et al. (författare)
  • Molecular subtyping of tumors from patients with familial glioma
  • 2018
  • Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 20:6, s. 810-817
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. Single-gene mutation syndromes account for some familial glioma (FG); however, they make up only a small fraction of glioma families. Gliomas can be classified into 3 major molecular subtypes based on isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion. We hypothesized that the prevalence of molecular subtypes might differ in familial versus sporadic gliomas and that tumors in the same family should have the same molecular subtype. Methods. Participants in the FG study (Gliogene) provided samples for germline DNA analysis. Formalin-fixed, paraffin-embedded tumors were obtained from a subset of FG cases, and DNA was extracted. We analyzed tissue from 75 families, including 10 families containing a second affected family member. Copy number variation data were obtained using a first-generation Affymetrix molecular inversion probe (MIP) array. Results. Samples from 62 of 75 (83%) FG cases could be classified into the 3 subtypes. The prevalence of the molecular subtypes was: 30 (48%) IDH-wildtype, 21 (34%) IDH-mutant non-codeleted, and 11 (19%) IDH-mutant and 1p/19q codeleted. This distribution of molecular subtypes was not statistically different from that of sporadic gliomas (P = 0.54). Of 10 paired FG samples, molecular subtypes were concordant for 7 (kappa = 0.59): 3 IDH-mutant non-codeleted, 2 IDH-wildtype, and 2 IDH-mutant and 1p/19q codeleted gliomas. Conclusions. Our data suggest that within individual families, patients develop gliomas of the same molecular subtype. However, we did not observe differences in the prevalence of the molecular subtypes in FG compared with sporadic gliomas. These observations provide further insight into the distribution of molecular subtypes in FG.
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