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- Ostrom, Quinn T., et al.
(författare)
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Evaluating glioma risk associated with extent of European admixture in African-Americans and Latinos
- 2018
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 78:13
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Glioma incidence is highest in non-Hispanic Whites, where it occurs ~2x as frequently compared with other race/ethnicity groups. Glioma GWAS to date have included European ancestry populations only, and it is unknown whether variants identified by these analyses are associated with glioma in non- European ancestry populations. African Americans and Hispanics are admixed populations with varying proportions of European ancestry. While global ancestry may be similar within admixed groups, the proportion of European ancestry at each allele can vary across the genome. As glioma is more common in European ancestry populations, the presence of increased local European ancestry in these admixed populations could be used to identify glioma risk loci. Here we assessed whether excess European ancestry at established risk loci (Melin et al, Nature Genetics, 2017) was associated with glioma risk in non-European ancestry populations. Global ancestry was estimated using fastStructure, and local ancestry was estimated using RFMix. Both methods used 1,000 genomes project reference populations (African: YRI; European: CEU; East Asian: CHB/JPT; and Native American: CLM/PEL/MXL). We evaluated differences in local European ancestry between cases and controls using logistic regression conditioned on global European ancestry within 500kb of 25 previously identified risk variants among individuals with ≥50% African ancestry, and ≥30% Native American ancestry for all gliomas, and for grade IV glioblastoma (GBM) and grade II-III non-GBM. There were 347 individuals (184 cases and 163 controls) with ≥50% global African ancestry, and 277 individuals (153 cases and 124 controls) with ≥30% global American ancestry. There was no significant difference in proportion of global European ancestry between cases and controls with ≥50% global African ancestry (cases: 18.2%, controls: 17.7%, p=0.6834), and no significant difference in proportion of global European ancestry between cases and controls with ≥30% global American ancestry (cases: 51.1%, controls: 49.0%, p=0.2123). Among individuals with >50% African ancestry, we observed a nominally significant association between all glioma and increased local European ancestry at 7p11.2 (EGFR, pmin=0.0070) and between GBM and increased local European ancestry at 22q13.1 (CSNK1E, pmin=0.0098), both near SNPs previously associated with glioblastoma in majority European-ancestry populations. The dataset used for this analysis represents the largest collection of genotyped non-European glioma cases. These results suggest that glioma risk in African Americans may be associated with an increased local European ancestry variants at glioma risk loci previously identified in majority European ancestry populations (7p11.2 and 22q13.1).
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| 3. |
- Jacobs, Daniel I., et al.
(författare)
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Elucidating the molecular pathogenesis of familial glioma
- 2018
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 78:13
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)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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| 4. |
- Melin, Beatrice, et al.
(författare)
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Familial Factors and Inherited Susceptibility to Glioma
- 2011
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Ingår i: Principles & Practice of Neuro-Oncology. - New York : Demos Medical Publications, LLC. - 9781933864785 - 9781617050145 ; , s. 14-17
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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