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Melin, Beatrice S.
Alternative names
Publications (10 of 222) Show all publications
Löding, S., Andersson, U., Kaaks, R., Schulze, M. B., Pala, V., Urbarova, I., . . . Melin, B. S. (2023). Altered plasma metabolite levels can be detected years before a glioma diagnosis. JCI Insight, 8(19), Article ID e171225.
Open this publication in new window or tab >>Altered plasma metabolite levels can be detected years before a glioma diagnosis
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2023 (English)In: JCI Insight, ISSN 2379-3708, Vol. 8, no 19, article id e171225Article in journal (Refereed) Published
Abstract [en]

Genetic and metabolic changes in tissue and blood are reported to occur several years before glioma diagnosis. Since gliomas are currently detected late, a liquid biopsy for early detection could affect the quality of life and prognosis of patients. Here, we present a nested case-control study of 550 prediagnostic glioma cases and 550 healthy controls from the Northern Sweden Health and Disease study (NSHDS) and the European Prospective Investigation into Cancer and Nutrition (EPIC) study. We identified 93 significantly altered metabolites related to glioma development up to 8 years before diagnosis. Out of these metabolites, a panel of 20 selected metabolites showed strong disease correlation and a consistent progression pattern toward diagnosis in both the NSHDS and EPIC cohorts, and they separated future cases from controls independently of biological sex. The blood metabolite panel also successfully separated both lower-grade glioma and glioblastoma cases from controls, up to 8 years before diagnosis in patients within the NSHDS cohort and up to 2 years before diagnosis in EPIC. Pathway enrichment analysis detected metabolites related to the TCA cycle, Warburg effect, gluconeogenesis, and cysteine, pyruvate, and tyrosine metabolism as the most affected.

Place, publisher, year, edition, pages
American Society For Clinical Investigation, 2023
Keywords
Brain cancer, Metabolism, Oncology
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-215372 (URN)10.1172/jci.insight.171225 (DOI)37651185 (PubMedID)2-s2.0-85173580693 (Scopus ID)
Funder
Swedish Research Council, 2017-00650Swedish Research Council, 2019-01566Swedish Cancer Society, CAN2018/390Swedish Cancer Society, 19 0370Cancerforskningsfonden i Norrland, AMP 21-1045Cancerforskningsfonden i Norrland, AMP22-1084Sjöberg Foundation, 2020-01-07-08Public Health Agency of Sweden , 2020-2022World Cancer Research Fund InternationalRegion SkåneRegion Västerbotten
Available from: 2023-10-31 Created: 2023-10-31 Last updated: 2023-10-31Bibliographically approved
Edström, S., Numan Hellquist, B., Sandström, M., Sadanandan, S. A., Björkblom, B., Melin, B. S. & Sjöberg, R. L. (2023). Antidepressants and survival in glioma: a registry-based retrospective cohort study. Neuro-Oncology Practice
Open this publication in new window or tab >>Antidepressants and survival in glioma: a registry-based retrospective cohort study
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2023 (English)In: Neuro-Oncology Practice, ISSN 2054-2577, E-ISSN 2054-2585Article in journal (Refereed) Accepted
Abstract [en]

Background: Depression and treatment with antidepressant medication is common in patients with malignant glioma. However, the extent to which antidepressants may affect the disease is not fully understood. Therefore, the purpose of the present study was to investigate possible associations between treatment with antidepressant medication and survival in glioma patients.

Methods: We performed a registry-based cohort study including 1231 patients with malignant glioma (WHO grade 2, 3 and 4) having undergone surgery, and 6400 matched controls without glioma. All data was extracted from the RISK North database, which contains information from multiple national population-based registries in Sweden.

Results: Treatment with antidepressants is more common in patients with malignant glioma (27%), compared to controls (16%), p<.001. Treatment with antidepressants after surgery for glioma was significantly associated with poorer survival. These effects were observed both for selective serotonin reuptake inhibitors (SSRIs) and non-SSRIs. In grade 4 glioma, SSRI treatment was associated with a HR of 3.32 (95% CI 2.69–4.10, p<.001), and non-SSRI treatment a HR of 3.54 (95% CI 2.52–4.99, p<.001), compared to glioma patients without antidepressants. In grade 2-3 glioma, the HR for SSRI treatment was 3.26 (95% CI 2.19–4.85, p<.001), and for non-SSRI treatment 7.71 (95% CI 4.22-14.12, p<.001).

Conclusions: Our results demonstrate a negative association between antidepressant medication and survival in glioma. Further research will be needed to clarify causation.

Place, publisher, year, edition, pages
Oxford University Press, 2023
National Category
Neurosciences
Research subject
Neurosurgery
Identifiers
urn:nbn:se:umu:diva-213864 (URN)10.1093/nop/npad057 (DOI)
Funder
Cancerforskningsfonden i NorrlandSwedish Research CouncilSwedish Cancer SocietyRegion Västerbotten
Available from: 2023-08-30 Created: 2023-08-30 Last updated: 2023-08-31
Wu, W.-Y. Y., Haider, Z., Feng, X., Heath, A. K., Tjønneland, A., Agudo, A., . . . Johansson, M. (2023). Assessment of the EarlyCDT-Lung test as an early biomarker of lung cancer in ever-smokers: A retrospective nested case-control study in two prospective cohorts. International Journal of Cancer, 152(9), 2002-2010
Open this publication in new window or tab >>Assessment of the EarlyCDT-Lung test as an early biomarker of lung cancer in ever-smokers: A retrospective nested case-control study in two prospective cohorts
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2023 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 152, no 9, p. 2002-2010Article in journal (Refereed) Published
Abstract [en]

The EarlyCDT-Lung test is a blood-based autoantibody assay intended to identify high-risk individuals for low-dose computed tomography lung cancer screening. However, there is a paucity of evidence on the performance of the EarlyCDT-Lung test in ever-smokers. We conducted a nested case-control study within two prospective cohorts to evaluate the risk-discriminatory performance of the EarlyCDT-Lung test using prediagnostic blood samples from 154 future lung cancer cases and 154 matched controls. Cases were selected from those who had ever smoked and had a prediagnostic blood sample <3 years prior to diagnosis. Conditional logistic regression was used to estimate the association between EarlyCDT-Lung test results and lung cancer risk. Sensitivity and specificity of the EarlyCDT-Lung test were calculated in all subjects and subgroups based on age, smoking history, lung cancer stage, sample collection time before diagnosis and year of sample collection. The overall lung cancer odds ratios were 0.89 (95% CI: 0.34-2.30) for a moderate risk EarlyCDT-Lung test result and 1.09 (95% CI: 0.48-2.47) for a high-risk test result compared to no significant test result. The overall sensitivity was 8.4% (95% CI: 4.6-14) and overall specificity was 92% (95% CI: 87-96) when considering a high-risk result as positive. Stratified analysis indicated higher sensitivity (17%, 95% CI: 7.2-32.1) in subjects with blood drawn up to 1 year prior to diagnosis. In conclusion, our study does not support a role of the EarlyCDT-Lung test in identifying the high-risk subjects in ever-smokers for lung cancer screening in the EPIC and NSHDS cohorts.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
biomarkers, EarlyCDT-Lung test, lung cancer, prediagnostic samples
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-201192 (URN)10.1002/ijc.34340 (DOI)000879090900001 ()36305647 (PubMedID)2-s2.0-85141537278 (Scopus ID)
Funder
Cancerforskningsfonden i Norrland, AMP19-962Swedish Cancer SocietySwedish Research Council, 2017-00650
Available from: 2023-01-05 Created: 2023-01-05 Last updated: 2023-06-19Bibliographically approved
Namba, S., Saito, Y., Kogure, Y., Masuda, T., Bondy, M. L., Gharahkhani, P., . . . Kataoka, K. (2023). Common germline risk variants impact somatic alterations and clinical features across cancers. Cancer Research, 83(1), 20-27
Open this publication in new window or tab >>Common germline risk variants impact somatic alterations and clinical features across cancers
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2023 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 83, no 1, p. 20-27Article in journal (Refereed) Published
Abstract [en]

Aggregation of genome-wide common risk variants, such as polygenic risk score (PRS), can measure genetic susceptibility to cancer. A better understanding of how common germline variants associate with somatic alterations and clinical features could facilitate personalized cancer prevention and early detection. We constructed PRSs from 14 genome-wide association studies (median n = 64,905) for 12 cancer types by multiple methods and calibrated them using the UK Biobank resources (n = 335,048). Meta-analyses across cancer types in The Cancer Genome Atlas (n = 7,965) revealed that higher PRS values were associated with earlier cancer onset and lower burden of somatic alterations, including total mutations, chromosome/arm somatic copy-number alterations (SCNA), and focal SCNAs. This contrasts with rare germline pathogenic variants (e.g., BRCA1/2 variants), showing heterogeneous associations with somatic alterations. Our results suggest that common germline cancer risk variants allow early tumor development before the accumulation of many somatic alterations characteristic of later stages of carcinogenesis.

SIGNIFICANCE: Meta-analyses across cancers show that common germline risk variants affect not only cancer predisposition but the age of cancer onset and burden of somatic alterations, including total mutations and copy-number alterations.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2023
National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-203795 (URN)10.1158/0008-5472.CAN-22-1492 (DOI)000907944500001 ()36286845 (PubMedID)2-s2.0-85145492173 (Scopus ID)
Available from: 2023-01-20 Created: 2023-01-20 Last updated: 2023-09-05Bibliographically approved
Öfverholm, A., Törngren, T., Rosén, A., Arver, B., Einbeigi, Z., Haraldsson, K., . . . Ehrencrona, H. (2023). Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer. BMC Cancer, 23(1), Article ID 738.
Open this publication in new window or tab >>Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer
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2023 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 23, no 1, article id 738Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Genetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting.

METHODS: Women with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records.

RESULTS: In 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding.

CONCLUSIONS: This study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
BRCA1, BRCA2, Breast cancer, Cancer, Genetic testing, Hereditary breast cancer, Hereditary cancer, Hereditary ovarian cancer, Ovarian cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-213067 (URN)10.1186/s12885-023-11229-y (DOI)37563628 (PubMedID)2-s2.0-85167704638 (Scopus ID)
Funder
Swedish Cancer Society, 2011/323Swedish Cancer Society, 2012/509Mrs. Berta Kamprad's Cancer FoundationRegion SkåneRegion Stockholm, FoUI-961732Region Stockholm, SLL 500306
Available from: 2023-08-24 Created: 2023-08-24 Last updated: 2023-08-24Bibliographically approved
Lindström, S., Wang, L., Feng, H., Majumdar, A., Huo, S., Macdonald, J., . . . Kraft, P. (2023). Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions. Journal of the National Cancer Institute, 115(6), 712-732
Open this publication in new window or tab >>Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions
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2023 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 115, no 6, p. 712-732Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.

METHODS: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.

RESULTS: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.

CONCLUSIONS: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

Place, publisher, year, edition, pages
Oxford University Press, 2023
National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-211988 (URN)10.1093/jnci/djad043 (DOI)000975864100001 ()36929942 (PubMedID)2-s2.0-85163236294 (Scopus ID)
Available from: 2023-07-12 Created: 2023-07-12 Last updated: 2024-02-08Bibliographically approved
Rosenbaum, A., Dahlin, A. M., Andersson, U., Björkblom, B., Wu, W.-Y. Y., Hedman, H., . . . Melin, B. S. (2023). Low-grade glioma risk SNP rs11706832 is associated with type I interferon response pathway genes in cell lines. Scientific Reports, 13, Article ID 6777.
Open this publication in new window or tab >>Low-grade glioma risk SNP rs11706832 is associated with type I interferon response pathway genes in cell lines
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2023 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, article id 6777Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies (GWAS) have contributed to our understanding of glioma susceptibility. To date, 25 risk loci for development of any of the glioma subtypes are known. However, GWAS studies reveal little about the molecular processes that lead to increased risk, especially for non-coding single nucleotide polymorphisms (SNP). A particular SNP in intron 2 of LRIG1, rs11706832, has been shown to increase the susceptibility for IDH1 mutated low-grade gliomas (LGG). Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is important in cancer development as it negatively regulates the epidermal growth factor receptor (EGFR); however, the mechanism responsible for this particular risk SNP and its potential effect on LRIG1 are not known. Using CRISPR-CAS9, we edited rs11706832 in HEK293T cells. Four HEK293T clones with the risk allele were compared to four clones with the non-risk allele for LRIG1 and SLC25A26 gene expression using RT-qPCR, for global gene expression using RNA-seq, and for metabolites using gas chromatography-mass spectrometry (GC–MS). The experiment did not reveal any significant effect of the SNP on the expression levels or splicing patterns of LRIG1 or SLC25A26. The global gene expression analysis revealed that the risk allele C was associated with upregulation of several mitochondrial genes. Gene enrichment analysis of 74 differentially expressed genes in the genome revealed a significant enrichment of type I interferon response genes, where many genes were downregulated for the risk allele C. Gene expression data of IDH1 mutated LGGs from the cancer genome atlas (TCGA) revealed a similar under expression of type I interferon genes associated with the risk allele. This study found the expression levels and splicing patterns of LRIG1 and SLC25A26 were not affected by the SNP in HEK293T cells. However, the risk allele was associated with a downregulation of genes involved in the innate immune response both in the HEK293T cells and in the LGG data from TCGA.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-208211 (URN)10.1038/s41598-023-33923-4 (DOI)000984494600021 ()37185361 (PubMedID)2-s2.0-85154566176 (Scopus ID)
Available from: 2023-05-16 Created: 2023-05-16 Last updated: 2023-09-05Bibliographically approved
Feng, X., Wu, W.-Y. Y., Onwuka, J. U., Haider, Z., Alcala, K., Smith-Byrne, K., . . . Johansson, M. (2023). Lung cancer risk discrimination of prediagnostic proteomics measurements compared with existing prediction tools. Journal of the National Cancer Institute, 115(9), 1050-1059
Open this publication in new window or tab >>Lung cancer risk discrimination of prediagnostic proteomics measurements compared with existing prediction tools
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2023 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 115, no 9, p. 1050-1059Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: We sought to develop a proteomics-based risk model for lung cancer and evaluate its risk-discriminatory performance in comparison with a smoking-based risk model (PLCOm2012) and a commercially available autoantibody biomarker test.

METHODS: We designed a case-control study nested in 6 prospective cohorts, including 624 lung cancer participants who donated blood samples at most 3 years prior to lung cancer diagnosis and 624 smoking-matched cancer free participants who were assayed for 302 proteins. We used 470 case-control pairs from 4 cohorts to select proteins and train a protein-based risk model. We subsequently used 154 case-control pairs from 2 cohorts to compare the risk-discriminatory performance of the protein-based model with that of the Early Cancer Detection Test (EarlyCDT)-Lung and the PLCOm2012 model using receiver operating characteristics analysis and by estimating models' sensitivity. All tests were 2-sided.

RESULTS: The area under the curve for the protein-based risk model in the validation sample was 0.75 (95% confidence interval [CI] = 0.70 to 0.81) compared with 0.64 (95% CI = 0.57 to 0.70) for the PLCOm2012 model (Pdifference = .001). The EarlyCDT-Lung had a sensitivity of 14% (95% CI = 8.2% to 19%) and a specificity of 86% (95% CI = 81% to 92%) for incident lung cancer. At the same specificity of 86%, the sensitivity for the protein-based risk model was estimated at 49% (95% CI = 41% to 57%) and 30% (95% CI = 23% to 37%) for the PLCOm2012 model.

CONCLUSION: Circulating proteins showed promise in predicting incident lung cancer and outperformed a standard risk prediction model and the commercialized EarlyCDT-Lung.

Place, publisher, year, edition, pages
Oxford University Press, 2023
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-214407 (URN)10.1093/jnci/djad071 (DOI)001002081000001 ()37260165 (PubMedID)2-s2.0-85169998430 (Scopus ID)
Funder
Swedish Research Council, 2017-00650Swedish Cancer SocietySwedish Research CouncilRegion SkåneRegion Västerbotten
Available from: 2023-09-19 Created: 2023-09-19 Last updated: 2023-09-19Bibliographically approved
Foss-Skiftesvik, J., Li, S., Rosenbaum, A., Munch Hagen, C., Stoltze, U. K., Ljungqvist, S., . . . Wiemels, J. L. (2023). Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus. Neuro-Oncology, 25(9), 1709-1720
Open this publication in new window or tab >>Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus
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2023 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 25, no 9, p. 1709-1720Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Although recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date.

METHODS: Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18 628 genes.

RESULTS: Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, P-value of 6.974e-10, OR 1.273, 95% CI 1.179-1.374). The association was driven by low-grade astrocytoma (P-value of 3.815e-9) and exhibited unidirectional effects across all 6 genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, P-value of 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (P-value of 8.090e-8).

CONCLUSIONS: In this population-based genome-wide association study meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.

Place, publisher, year, edition, pages
Oxford University Press, 2023
Keywords
Childhood brain tumors, genetic susceptibility, glioma, GWAS, pediatric neuro-oncology
National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-214245 (URN)10.1093/neuonc/noad042 (DOI)000959346400001 ()36810956 (PubMedID)2-s2.0-85151731119 (Scopus ID)
Funder
Swedish Childhood Cancer FoundationCancerforskningsfonden i NorrlandSwedish Research CouncilSwedish Cancer Society
Available from: 2023-09-18 Created: 2023-09-18 Last updated: 2023-09-18Bibliographically approved
Choi, D.-J., Armstrong, G., Lozzi, B., Vijayaraghavan, P., Plon, S. E., Wong, T. C., . . . Bainbridge, M. N. (2023). The genomic landscape of familial glioma. Science Advances, 9(17), Article ID eade2675.
Open this publication in new window or tab >>The genomic landscape of familial glioma
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2023 (English)In: Science Advances, E-ISSN 2375-2548, Vol. 9, no 17, article id eade2675Article in journal (Refereed) Published
Abstract [en]

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

Place, publisher, year, edition, pages
American Association for the Advancement of Science (AAAS), 2023
National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:umu:diva-209881 (URN)10.1126/SCIADV.ADE2675 (DOI)000989268500003 ()37115922 (PubMedID)2-s2.0-85161074771 (Scopus ID)
Funder
NIH (National Institutes of Health), R01CA217105
Available from: 2023-06-16 Created: 2023-06-16 Last updated: 2023-06-16Bibliographically approved
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