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Dahlin, Anna M.
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Publications (10 of 23) Show all publications
Dahlin, A. M., Wibom, C., Andersson, U., Hougaard, D. M., Bybjerg-Grauholm, J., Deltour, I., . . . Melin, B. S. (2019). Genetic Variants in the 9p21.3 Locus Associated with Glioma Risk in Children, Adolescents, and Young Adults: A Case-Control Study. Cancer Epidemiology, Biomarkers and Prevention, 28(7), 1252-1258
Open this publication in new window or tab >>Genetic Variants in the 9p21.3 Locus Associated with Glioma Risk in Children, Adolescents, and Young Adults: A Case-Control Study
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2019 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 28, no 7, p. 1252-1258Article in journal (Refereed) Published
Abstract [en]

Background: Genome-wide association studies have identified germline genetic variants in 25 genetic loci that increase the risk of developing glioma in adulthood. It is not known if these variants increase the risk of developing glioma in children and adolescents and young adults (AYA). To date, no studies have performed genome-wide analyses to find novel genetic variants associated with glioma risk in children and AYA.

Methods: We investigated the association between 8,831,628 genetic variants and risk of glioma in 854 patients diagnosed up to the age of 29 years and 3,689 controls from Sweden and Denmark. Recruitment of patients and controls was population based. Genotyping was performed using Illumina BeadChips, and untyped variants were imputed with IMPUTE2. We selected 41 established adult glioma risk variants for detailed investigation.

Results: Three adult glioma risk variants, rs634537, rs2157719, and rs145929329, all mapping to the 9p21.3 (CDKN2B-AS1) locus, were associated with glioma risk in children and AYA. The strongest association was seen for rs634537 (odds ratioG = 1.21; 95% confidence interval = 1.09–1.35; P = 5.8 × 10−4). In genome-wide analysis, an association with risk was suggested for 129 genetic variants (P <1 × 10−5).

Conclusions: Carriers of risk alleles in the 9p21.3 locus have an increased risk of glioma throughout life. The results from genome-wide association analyses require validation in independent cohorts.

Impact: Our findings line up with existing evidence that some, although not all, established adult glioma risk variants are associated with risk of glioma in children and AYA. Validation of results from genome-wide analyses may reveal novel susceptibility loci for glioma in children and AYA.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2019
National Category
Cancer and Oncology Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-162886 (URN)10.1158/1055-9965.EPI-18-1026 (DOI)000481682500019 ()31040135 (PubMedID)
Available from: 2019-09-04 Created: 2019-09-04 Last updated: 2019-09-04Bibliographically approved
Andersson, U., Degerman, S., Dahlin, A. M., Wibom, C., Johansson, G., Bondy, M. L. & Melin, B. S. (2019). The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking. Cancer Causes and Control, 30(2), 177-185
Open this publication in new window or tab >>The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking
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2019 (English)In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 30, no 2, p. 177-185Article in journal (Refereed) Published
Abstract [en]

Purpose: Previous studies have suggested an association between relative leukocyte telomere length (rLTL) and glioma risk. This association may be influenced by several factors, including allergies, BMI, and smoking. Previous studies have shown that individuals with asthma and allergy have shortened relative telomere length, and decreased risk of glioma. Though, the details and the interplay between rLTL, asthma and allergies, and glioma molecular phenotype is largely unknown. Methods: rLTL was measured by qPCR in a Swedish population-based glioma case–control cohort (421 cases and 671 controls). rLTL was related to glioma risk and health parameters associated with asthma and allergy, as well as molecular events in glioma including IDH1 mutation, 1p/19q co-deletion, and EGFR amplification. Results: Longer rLTL was associated with increased risk of glioma (OR = 1.16; 95% CI 1.02–1.31). Similar to previous reports, there was an inverse association between allergy and glioma risk. Specific, allergy symptoms including watery eyes was most strongly associated with glioma risk. High body mass index (BMI) a year prior diagnosis was significantly protective against glioma in our population. Adjusting for allergy, asthma, BMI, and smoking did not markedly change the association between longer rLTL and glioma risk. rLTL among cases was not associated with IDH1 mutation, 1p/19q co-deletion, or EGFR amplification, after adjusting for age at diagnosis and sex. Conclusions: In this Swedish glioma case–control cohort, we identified that long rLTL increases the risk of glioma, an association not confounded by allergy, BMI, or smoking. This highlights the complex interplay of the immune system, rLTL and cancer risk.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Glioma, Relative leukocyte telomere length (rLTL), Allergy, BMI, Smoking, IDH1, 1p/19q, EGFR
National Category
Cancer and Oncology Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-157597 (URN)10.1007/s10552-018-1120-2 (DOI)000459153800007 ()30560391 (PubMedID)
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-03-28Bibliographically approved
Andersson, U., Degerman, S., Dahlin, A., Brannstrom, T., Roos, G. & Melin, B. S. (2017). TELOMERE LENGTH, ALLERGIES AND RISK OF GLIOMA. Paper presented at 5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), MAY 04-07, 2017, Zurich, SWITZERLAND. Neuro-Oncology, 19(Supplement: 3), 23-23, Article ID Meeting Abstract: P01.03.
Open this publication in new window or tab >>TELOMERE LENGTH, ALLERGIES AND RISK OF GLIOMA
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2017 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 19, no Supplement: 3, p. 23-23, article id Meeting Abstract: P01.03Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-136984 (URN)000402732900081 ()
Conference
5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), MAY 04-07, 2017, Zurich, SWITZERLAND
Available from: 2017-06-30 Created: 2017-06-30 Last updated: 2018-06-09Bibliographically approved
Ghasimi, S., Wibom, C., Dahlin, A. M., Brännström, T., Golovleva, I., Andersson, U. & Melin, B. (2016). Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma. Journal of Neuro-Oncology, 127(3), 483-492
Open this publication in new window or tab >>Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma
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2016 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 127, no 3, p. 483-492Article in journal (Refereed) Published
Abstract [en]

During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B, PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations.

Keywords
CDKN2A/B, EGFR, RTEL1, SNP, FISH, ASCAT
National Category
Cancer and Oncology Neurology
Identifiers
urn:nbn:se:umu:diva-121460 (URN)10.1007/s11060-016-2066-4 (DOI)000374463800009 ()26839018 (PubMedID)
Available from: 2016-06-22 Created: 2016-06-02 Last updated: 2018-06-07Bibliographically approved
Heimberger, A., Liu, Y., Gabrusiewicz, K., Amirian, E. S., Tsavachidis, S., Armstrong, G., . . . Bondy, M. (2016). POLYMORPHISMS IN MYELOID-ASSOCIATED GENES PREDICT GLIOMA SURVIVAL. Paper presented at 21st Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology, NOV 17-20, 2016, Scottsdale, AZ. Neuro-Oncology, 18, 58-58
Open this publication in new window or tab >>POLYMORPHISMS IN MYELOID-ASSOCIATED GENES PREDICT GLIOMA SURVIVAL
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2016 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, p. 58-58Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2016
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-134840 (URN)10.1093/neuonc/now212.239 (DOI)000398604101175 ()
Conference
21st Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology, NOV 17-20, 2016, Scottsdale, AZ
Note

Supplement: 6, Meeting Abstract: EPID-13

Available from: 2017-05-23 Created: 2017-05-23 Last updated: 2018-06-09Bibliographically approved
Späth, F., Andersson, U., Dahlin, A. M., Langseth, H., Hovig, E., Johannesen, T. B., . . . Melin, B. (2016). Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study. Tumor Biology, 37(8), 11065-11072
Open this publication in new window or tab >>Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study
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2016 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 11065-11072Article in journal (Refereed) Published
Abstract [en]

Genetic variants have been associated with the risk of developing glioma, but functional mechanisms on disease phenotypic traits remain to be investigated. One phenotypic trait of glioblastoma is the mutation and amplification of the epidermal growth factor receptor (EGFR) gene. We investigated associations between pre-diagnostic serum protein concentrations of EGFR and ErbB2, both members of the EGFR family, and future risk of glioma. Further, we studied if EGFR glioma risk variants were associated with EGFR and ErbB2 serum levels. We assessed the associations between genetic glioma risk variants and serum concentrations of EGFR and ErbB2, as measured in pre-diagnostic cohort serum samples of 593 glioma patients and 590 matched cancer-free controls. High serum EGFR and ErbB2 levels were associated with risk of developing glioblastoma (P = 0.008; OR = 1.58, 95 % CI = 1.13-2.22 and P = 0.017, OR = 1.63, 95 % CI = 1.09-2.44, respectively). High serum ErbB2 concentration was also associated with glioma risk overall (P = 0.049; OR = 1.39, 95 % CI = 1.00-1.93). Glioma risk variants were not associated with high serum protein abundance. In contrast, the EGFR risk variant rs4947986 (T) was correlated with decreased EGFR serum levels (study cohort P = 0.024 and controls P = 0.009). To our knowledge, this is the first study showing an association of EGFR and ErbB2 serum levels with glioma more than a decade before diagnosis, indicating that EGFR and ErbB2 serum proteins are important in early gliomagenesis. However, we did not find evidence that glioma risk variants were associated with high pre-diagnostic serum concentrations of EGFR and ErbB2.

Keywords
Glioma, SNP, Serum EGFR, Serum ErbB2, Pre-diagnostic
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-126327 (URN)10.1007/s13277-015-4742-y (DOI)000382672900107 ()26906551 (PubMedID)
Available from: 2016-11-01 Created: 2016-10-03 Last updated: 2019-02-14Bibliographically approved
Dahlin, A. M., Wibom, C., Ghasimi, S., Brännström, T., Andersson, U. & Melin, B. (2016). Relation between Established Glioma Risk Variants and DNA Methylation in the Tumor. PLoS ONE, 11(10), Article ID e0163067.
Open this publication in new window or tab >>Relation between Established Glioma Risk Variants and DNA Methylation in the Tumor
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0163067Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies and candidate gene studies have identified several genetic variants that increase glioma risk. The majority of these variants are non-coding and the mechanisms behind the increased risk in carriers are not known. In this study, we hypothesize that some of the established glioma risk variants induce aberrant DNA methylation in the developing tumor, either locally (gene-specific) or globally (genome-wide). In a pilot data set including 77 glioma patients, we used Illumina beadchip technology to analyze genetic variants in blood and DNA methylation in matched tumor samples. To validate our findings, we used data from the Cancer Genome Atlas, including 401 glioblastoma patients. Consensus clustering identified the glioma CpG island methylator phenotype (gCIMP) and two additional subgroups with distinct patterns of global DNA methylation. In the pilot dataset, gCIMP was associated with two genetic variants in CDKN2B-AS1, rs1412829 and rs4977756 (9p21.3, p = 8.1 x 10(-7) and 4.8 x 10(-5), respectively). The association was in the same direction in the TCGA dataset, although statistically significant only when combining individuals with AG and GG genotypes. We also investigated the relation between glioma risk variants and DNA methylation in the promoter region of genes located within 30 kb of each variant. One association in the pilot dataset, between the TERT risk variant rs2736100 and lower methylation of cg23827991 (in TERT; p = 0.001), was confirmed in the TCGA dataset (p = 0.001). In conclusion, we found an association between rs1412829 and rs4977756 (9p21.3, CDKN2B-AS1) and global DNA methylation pattern in glioma, for which a trend was seen also in the TCGA glioblastoma dataset. We also found an association between rs2736100 (in TERT) and levels of methylation at cg23827991 (localized in the same gene, 3.3 kbp downstream of the risk variant), which was validated in the TCGA dataset. Except for this one association, we did not find strong evidence for gene-specific DNA methylation mediated by glioma risk variants.

Place, publisher, year, edition, pages
Public library science, 2016
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-130026 (URN)10.1371/journal.pone.0163067 (DOI)000389046900002 ()
Available from: 2017-01-11 Created: 2017-01-11 Last updated: 2018-06-09Bibliographically approved
Dahlin, A. M., Hollegaard, M. V., Wibom, C., Andersson, U., Hougaard, D. M., Deltour, I., . . . Melin, B. (2015). CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma. Journal of Neuro-Oncology, 125(1), 75-78
Open this publication in new window or tab >>CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma
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2015 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 125, no 1, p. 75-78Article in journal (Refereed) Published
Abstract [en]

Recent studies have described a number of genes that are frequently altered in medulloblastoma tumors and that have putative key roles in the development of the disease. We hypothesized that common germline genetic variations in these genes may be associated with medulloblastoma development. Based on recent publications, we selected 10 genes that were frequently altered in medulloblastoma: CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 (now renamed as KMT2D). Common genetic variants (single nucleotide polymorphisms) annotating these genes (n = 221) were genotyped in germline DNA (neonatal dried blood spot samples) from 243 childhood medulloblastoma cases and 247 control subjects from Sweden and Denmark. Eight genetic variants annotating three genes in the sonic hedgehog signaling pathway; CCND2, PTCH1, and GLI2, were found to be associated with the risk of medulloblastoma (P (combined) < 0.05). The findings were however not statistically significant following correction for multiple testing by the very stringent Bonferroni method. The results do not support our hypothesis that common germline genetic variants in the ten studied genes are associated with the risk of developing medulloblastoma.

Keywords
Medulloblastoma, PNET, Primitive neuroectodermal tumors, Genetic association studies, Genetic riation
National Category
Cancer and Oncology Neurology
Identifiers
urn:nbn:se:umu:diva-110559 (URN)10.1007/s11060-015-1891-1 (DOI)000362334800008 ()26290144 (PubMedID)
Available from: 2015-11-10 Created: 2015-10-23 Last updated: 2018-06-07Bibliographically approved
Wibom, C., Späth, F., Dahlin, A. M., Langseth, H., Hovig, E., Rajaraman, P., . . . Melin, B. (2015). Investigation of Established Genetic Risk Variants for Glioma in Prediagnostic Samples from a Population-Based Nested Case-Control Study. Cancer Epidemiology, Biomarkers and Prevention, 24(5), 810-816
Open this publication in new window or tab >>Investigation of Established Genetic Risk Variants for Glioma in Prediagnostic Samples from a Population-Based Nested Case-Control Study
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2015 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, no 5, p. 810-816Article in journal (Refereed) Published
Abstract [en]

Background: Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case-control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included.

Methods: To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research.

Results: We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study.

Conclusions: Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis.

Impact: Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-103722 (URN)10.1158/1055-9965.EPI-14-1106 (DOI)000353702800006 ()25713050 (PubMedID)
Available from: 2015-06-10 Created: 2015-05-28 Last updated: 2018-06-07Bibliographically approved
Wibom, C., Spaeth, F., Dahlin, A., Langseth, H., Hovig, E., Rajaraman, P., . . . Melin, B. (2014). Glioma Gwas Hits - Markers for Risk or for Prognosis?. Paper presented at 11th Congress of the European Association of Neuro-Oncology, Turin, Italy, October 9-12, 2014. Neuro-Oncology, 16(Suppl. 2), ii109-ii110
Open this publication in new window or tab >>Glioma Gwas Hits - Markers for Risk or for Prognosis?
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2014 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, no Suppl. 2, p. ii109-ii110Article in journal, Meeting abstract (Refereed) Published
Abstract [en]

One obstacle to developing new treatments for glioma is the generally poor understanding of glioma aetiology. The only generally accepted environmental risk factor or glioma is ionizing radiation. Glioma aetiology has also been shown to contain a genetic component, in part through observations that individuals in families with a history of glioma have an elevated risk of developing glioma themselves. The genetic component in glioma aetiology has been further substantiated through genome wide association studies (GWAS). These studies have identified associations between a number of common genetic variants and an increased glioma risk. However, the studies have all been of case-control design (i.e. including cases at diagnosis), and as such they presumably suffer from a degree of survival bias. Survival bias risks being introduced in a study when rapidly fatal cases are not included. This is an inherent risk of case-control designs, which is particularly pronounced when studying a disease with very poor prognosis, such as glioma. Ultimately, survival bias may result in erroneous conclusions, as it is impossible to separate associations with prognosis from associations with risk of disease. To accurately confirm previously identified glioma risk variants, and ascertain whether they are associated with risk or with prolonged survival, we investigated these variants in a set of pre-diagnostic serum samples (594 cases and 591 matched controls). Analyses of population based, pre-diagnostic samples eliminates the risk of survival bias, and enables distinction between genetic variants associated with glioma risk (i.e. aetiology) and genetic variants associated with prognosis. The serum samples were acquired through The Janus Serum Bank, a Norwegian population based biobank reserved for cancer research. Variant detection was achieved by means of cycling temperature capillary electrophoresis. Our investigation confirmed the association with glioma risk for the investigated variants within five genomic regions; 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). This is indicative of these variants being truly associated with glioma risk, and thus may impact gliomagenesis. However, previously identified risk variants within the 5p15.33 (TERT) and 7p11.2 (EGFR) could not be positively confirmed by this study. The lack of positive confirmation raises the question whether EGFR and TERT genetic variants are linked with prolonged survival, rather than with glioma aetiology.

Place, publisher, year, edition, pages
Oxford University Press, 2014
Keywords
onkology
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-96968 (URN)10.1093/neuonc/nou174.423 (DOI)000344235700424 ()
Conference
11th Congress of the European Association of Neuro-Oncology, Turin, Italy, October 9-12, 2014
Note

This article appears in: Abstracts from the 11th Congress of the European Association of Neuro-Oncology, Turin, Italy, October 9-12, 2014

Available from: 2014-12-09 Created: 2014-12-05 Last updated: 2018-06-07Bibliographically approved
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