| 1. |
- Andersson, Ulrika, et al.
(författare)
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A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk
- 2010
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Ingår i: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 12, s. 17-17
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Tidskriftsartikel (refereegranskat)abstract
- Glioma is the most common type of adult brain tumor and glioblastoma, its most aggressive form, has a dismal prognosis. Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR, ERBB2, ERBB3, ERBB4) family, and the vascular endothelial growth factor receptor (VEGFR), play a central role in tumor progression. We investigated the genetic variants of EGFR, ERBB2, VEGFR and their ligands, EGF and VEGF on glioma and glioblastoma risk. In addition, we evaluated the association of genetic variants of a newly discovered family of genes known to interact with EGFR: LRIG2 and LRIG3 with glioma and glioblastoma risk. Methods. We analyzed 191 tag single nucleotide polymorphisms (SNPs) capturing all common genetic variation of EGF, EGFR, ERBB2, LRIG2, LRIG3, VEGF and VEGFR2 genes. Material from four case-control studies with 725 glioma patients (329 of who were glioblastoma patients) and their 1 610 controls was used. Haplotype analyses were conducted using SAS/Genetics software. Results. Fourteen of the SNPs were significantly associated with glioma risk at p< 0.05, and 17 of the SNPs were significantly associated with glioblastoma risk at p< 0.05. In addition, we found that one EGFR haplotype was related to increased glioblastoma risk at p=0.009, Odds Ratio [OR] = 1.67 (95% confidence interval (CI): 1.14, 2.45). The Bonferroni correction made all p-values non-significant. One SNP, rs4947986 next to the intron/exon boundary of exon 7 in EGFR, was validated in an independent data set of 713 glioblastoma and 2 236 controls, [OR] = 1.42 (95% CI: 1.06,1.91). Discussion. Previous studies show that regulation of the EGFR pathway plays a role in glioma progression but the present study is the first to find that certain genotypes of the EGFR gene may be related to glioblastoma risk. Further studies are required to reinvestigate these findings and evaluate the functional significance.
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| 2. |
- Andersson, Ulrika, et al.
(författare)
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MNS16A minisatellite genotypes in relation to risk of glioma and meningioma and to glioblastoma outcome.
- 2009
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Ingår i: International journal of cancer. Journal international du cancer. - : Wiley. - 1097-0215 .- 0020-7136. ; 125:4, s. 968-972
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Tidskriftsartikel (refereegranskat)abstract
- The human telomerase reverse transcriptase (hTERT) gene is upregulated in a majority of malignant tumours. A variable tandem repeat, MNS16A, has been reported to be of functional significance for hTERT expression. Published data on the clinical relevance of MNS16A variants in brain tumours have been contradictory. The present population-based study in the Nordic countries and the United Kingdom evaluated brain-tumour risk and survival in relation to MNS16A minisatellite variants in 648 glioma cases, 473 meningioma cases and 1,359 age, sex and geographically matched controls. By PCR-based genotyping all study subjects with fragments of 240 or 271 bp were judged as having short (S) alleles and subjects with 299 or 331 bp fragments as having long (L) alleles. Relative risk of glioma or meningioma was estimated with logistic regression adjusting for age, sex and country. Overall survival was analysed using Kaplan-Meier estimates and equality of survival distributions using the log-rank test and Cox proportional hazard ratios. The MNS16A genotype was not associated with risk of occurrence of glioma, glioblastoma (GBM) or meningioma. For GBM there were median survivals of 15.3, 11.0 and 10.7 months for the LL, LS and SS genotypes, respectively; the hazard ratio for having the LS genotype compared with the LL was significantly increased HR 2.44 (1.56-3.82) and having the SS genotype versus the LL was nonsignificantly increased HR 1.46 (0.81-2.61). When comparing the LL versus having one of the potentially functional variants LS and SS, the HR was 2.10 (1.41-3.1). However, functionality was not supported as there was no trend towards increasing HR with number of S alleles. Collected data from our and previous studies regarding both risk and survival for the MNS16A genotypes are contradictory and warrant further investigations.
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| 3. |
- Atkins, Isabelle, et al.
(författare)
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Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma
- 2019
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 79:8, s. 2065-2071
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 x 10(-6), candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 x 10(-6)). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis.Significance: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.
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| 4. |
- Bethke, Lara, et al.
(författare)
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CASP8 D302H and meningioma risk : an analysis of five case-control series
- 2009
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Ingår i: Cancer Letters. - Clare : Elsevier. - 0304-3835 .- 1872-7980. ; 273:2, s. 312-315
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Tidskriftsartikel (refereegranskat)abstract
- Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma.
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| 5. |
- Bethke, Lara, et al.
(författare)
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Comprehensive analysis of DNA repair gene variants and risk of meningioma
- 2008
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:4, s. 270-276
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Tidskriftsartikel (refereegranskat)abstract
- Background: Meningiomas account for up to 37% of all primary brain tumors. Genetic susceptibility to meningioma is well established, with the risk among relatives of meningioma patients being approximately threefold higher than that in the general population. A relationship between risk of meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility.Methods: We analyzed 1127 tagging single-nucleotide polymorphisms (SNPs) that were selected to capture most of the common variation in 136 DNA repair genes in five case–control series (631 case patients and 637 control subjects) from four countries in Europe. We also analyzed 388 putative functional SNPs in these genes for their association with meningioma. All statistical tests were two-sided.Results: The SNP rs4968451, which maps to intron 4 of the gene that encodes breast cancer susceptibility gene 1–interacting protein 1, was consistently associated with an increased risk of developing meningioma. Across the five studies, the association was highly statistically significant (trend odds ratio = 1.57, 95% confidence interval = 1.28 to 1.93; Ptrend = 8.95 × 10−6; P = .009 after adjusting for multiple testing).Conclusions: We have identified a novel association between rs4968451 and meningioma risk. Because approximately 28% of the European population are carriers of at-risk genotypes for rs4968451, the variant is likely to make a substantial contribution to the development of meningioma.
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| 6. |
- Bethke, Lara, et al.
(författare)
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Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma
- 2008
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 17:6, s. 800-805
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Tidskriftsartikel (refereegranskat)abstract
- Much of the variation in inherited risk of glioma is likely to be explained by combinations of common low risk variants. The established relationship between glioma risk and exposure to ionizing radiation led us to examine whether variants in the DNA repair genes contribute to disease susceptibility. We evaluated 1127 haplotype-tagging single-nucleotide polymorphisms (SNPs) supplemented with 388 putative functional SNPs to capture most of the common variation in 136 DNA repair genes, in five unique case–control series from four different countries (1013 cases, 1016 controls). We identified 16 SNPs associated with glioma risk at the 1% significance level. The highest association observed across the five independent case–control datasets involved rs243356, which maps to intron 3 of CHAF1A (trend odds ratio, 1.32; 95% confidence interval 1.14–1.54; P = 0.0002; false-positive report probability = 0.055, based on a prior probability of 0.01). Our results provide additional support for the hypothesis that low penetrance variants contribute to the risk of developing glioma and suggest that a genetic variant located in or around the CHAF1A gene contributes to disease risk.
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| 7. |
- Bethke, Lara, et al.
(författare)
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Functional polymorphisms in folate metabolism genes influence the risk of meningioma and glioma
- 2008
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 17:5, s. 1195-1202
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Tidskriftsartikel (refereegranskat)abstract
- Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk.
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| 8. |
- Bethke, Lara, et al.
(författare)
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The Common D302H Variant of CASP8 Is Associated with Risk of Glioma
- 2008
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 17:4, s. 987-989
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Tidskriftsartikel (refereegranskat)abstract
- Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and, hence, a defense against cancer. We tested the hypothesis that the CASP8 polymorphism D302H influences risk of glioma through analysis of five series of glioma case patients and controls (n = 1,005 and 1,011, respectively). Carrier status for the rare allele of D302H was associated with a 1.37-fold increased risk (95% confidence interval, 1.10-1.70; P = 0.004). The association of CASP8 D302H with glioma risk indicates the importance of inherited variation in the apoptosis pathway in susceptibility to this form of primary brain tumor.
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| 9. |
- Clendenen, Tess V., et al.
(författare)
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Breast Cancer Risk Factors and Circulating Anti-Müllerian Hormone Concentration in Healthy Premenopausal Women
- 2021
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 106:11, s. E4542-E4553
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Tidskriftsartikel (refereegranskat)abstract
- Context: We previously reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies.Objective: This study assessed whether risk factors for breast cancer are correlates of AMH concentration.Methods: This cross-sectional study included 3831 healthy premenopausal women (aged 21-57, 87% aged 35-49) from 10 cohort studies among the general population.Results: Adjusting for age and cohort, AMH positively associated with age at menarche (P < 0.0001) and parity (P = 0.0008) and inversely associated with hysterectomy/partial oophorectomy (P = 0.0008). Compared with women of normal weight, AMH was lower (relative geometric mean difference 27%, P < 0.0001) among women who were obese. Current oral contraceptive (OC) use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, P < 0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, P = 0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40 vs ≥40), associations of AMH with body mass index and OCs were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to women ≥40 (P-interaction < 0.05).Conclusion: This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and it suggests that most associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.
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| 10. |
- Clendenen, Tess V., et al.
(författare)
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Breast cancer risk prediction in women aged 35-50 years : impact of including sex hormone concentrations in the Gail model
- 2019
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Ingår i: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background: Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Mullerian hormone (AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35-50.Methods: In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers.Results: The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer.Conclusions: AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35-50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history.
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