umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Ghasimi, Soma
Publications (10 of 12) Show all publications
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
Show others...
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
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
Show others...
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
Mörén, L., Bergenheim, A. T., Ghasimi, S., Brännström, T., Johansson, M. & Antti, H. (2015). Metabolomic screening of tumor tissue and serum in glioma patients reveals diagnostic and prognostic information. Metabolites, 5(3), 502-520
Open this publication in new window or tab >>Metabolomic screening of tumor tissue and serum in glioma patients reveals diagnostic and prognostic information
Show others...
2015 (English)In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 5, no 3, p. 502-520Article in journal (Refereed) Published
Abstract [en]

Glioma grading and classification, today based on histological features, is not always easy to interpret and diagnosis partly relies on the personal experience of the neuropathologists. The most important feature of the classification is the aimed correlation between tumor grade and prognosis. However, in the clinical reality, large variations exist in the survival of patients concerning both glioblastomas and low-grade gliomas. Thus, there is a need for biomarkers for a more reliable classification of glioma tumors as well as for prognosis. We analyzed relative metabolite concentrations in serum samples from 96 fasting glioma patients and 81 corresponding tumor samples with different diagnosis (glioblastoma, oligodendroglioma) and grade (World Health Organization (WHO) grade II, III and IV) using gas chromatography-time of flight mass spectrometry (GC-TOFMS). The acquired data was analyzed and evaluated by pattern recognition based on chemometric bioinformatics tools. We detected feature patterns in the metabolomics data in both tumor and serum that distinguished glioblastomas from oligodendrogliomas (p(tumor) = 2.46 × 10(-8), p(serum) = 1.3 × 10(-5)) and oligodendroglioma grade II from oligodendroglioma grade III (p(tumor) = 0.01, p(serum) = 0.0008). Interestingly, we also found patterns in both tumor and serum with individual metabolite features that were both elevated and decreased in patients that lived long after being diagnosed with glioblastoma compared to those who died shortly after diagnosis (p(tum)(o)(r) = 0.006, p(serum) = 0.004; AUROCC(tumor) = 0.846 (0.647-1.000), AUROCC(serum) = 0.958 (0.870-1.000)). Metabolic patterns could also distinguish long and short survival in patients diagnosed with oligodendroglioma (p(tumor) = 0.01, p(serum) = 0.001; AUROCC(tumor) = 1 (1.000-1.000), AUROCC(serum) = 1 (1.000-1.000)). In summary, we found different metabolic feature patterns in tumor tissue and serum for glioma diagnosis, grade and survival, which indicates that, following further verification, metabolomic profiling of glioma tissue as well as serum may be a valuable tool in the search for latent biomarkers for future characterization of malignant glioma.

Place, publisher, year, edition, pages
MDPI, 2015
Keywords
glioma, diagnosis, prognosis, blood, tumor, metabolomics, chemometrics, latent biomarkers
National Category
Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:umu:diva-111307 (URN)10.3390/metabo5030502 (DOI)000363208200007 ()26389964 (PubMedID)
Available from: 2015-11-13 Created: 2015-11-13 Last updated: 2018-06-07Bibliographically approved
Ghasimi, S. (2013). Genotype-phenotype studies in brain tumors. (Doctoral dissertation). Umeå: Umeå Universitet
Open this publication in new window or tab >>Genotype-phenotype studies in brain tumors
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Meningioma and glioma are the most common primary brain tumors, but their etiologies are largely unknown. Although meningioma is usually benign, their intracranial location can lead to lethal consequences, and despite progress in surgery, radiotherapy, and chemotherapy the prognosis for patients with glioma remains poor. The only well-established environmental risk factor for meningioma and glioma is ionizing radiation. Evidence for inherited predisposition to meningioma and glioma is provided by a number of rare inherited syndromes where collectively these diseases account for only a small proportion of the twofold increased risk of brain tumors seen in first-degree relatives for meningioma and glioma patients. It is very possible that much of the excess familial risk is a consequence of co-inheritance of multiple low-risk genetic variations. With this in mind, the aims of the studies in this thesis were to discover genetic risk variants influencing the probability of acquiring the disease and to identify the association between risk variants on the tumor phenotype.

To identify genetic variants influencing meningioma risk, a comprehensive tagging of the selected genes in a case-control study was performed. We identified nine risk variants in

EGF, ERBB2, and LRIG2 genes. However, these findings could not be confirmed in another larger independent dataset. In addition, the study identified a correlation between LRIG2 protein expression and ER status when analyzed with different parameters. In a separate study with a larger sample of meningioma patients, the same correlation between LRIG2 and ER status was observed.

To explore the potential association between reported germline risk variants and somatic genetic events, matched tumor and blood samples from glioma patients were analyzed by SNP array. The results identified correlations between

EGFR gene variants and somatic aberrations within the EGFR locus and CDKN2A/B locus. To further study the relationship between germline risk variants and tumor phenotype, the same patient material was used and analyzed by three different techniques: SNP array, IHC, and FISH. The results revealed EGFR risk variants effecting copy number variation of the EGFR gene and the expression of the IDH1 and p53. Further comparison between different techniques such as SNP array and FISH analysis revealed the difficulty in achieving consistent results with different techniques.

To summarize, the glioma studies show a link between genotype and phenotype where genetic risk variants in the

EGFR gene were found to be associated with specific somatic aberrations. These associations are biologically interesting because EGFR is involved in multiple cellular processes. Additional studies of the direct functional role of these observations need to be conducted to elucidate the molecular mechanisms underlying the identified association between germline gene variants and somatic aberrations. For the meningioma studies, no significant risk variants influencing the disease were found but a correlation between LRIG2 and ER status was observed. This result suggests a potential role for the LRIG protein in the pathogenesis of meningioma, but more studies are needed to confirm this hypothesizes.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2013. p. 64
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1657
Keywords
Glioma, Meningioma, SNP, IHC, FISH, LRIG2, EGF, EGFR, ERBB2, ER, CDKN2A/B, IDH1
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-83185 (URN)978-91-7459-754-7 (ISBN)
Public defence
2013-12-12, Betula, by 6M, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Note

Cancer research foundation in northern Sweden and Lions cancer research foundation at Umeå university

Available from: 2013-11-21 Created: 2013-11-20 Last updated: 2018-06-08Bibliographically approved
Sjöström, S., Ghasimi, S., Broholm, H., Brannstrom, T., Johansen, C., Collatz-Laier, H., . . . Melin, B. (2012). EGFR expression and glioblastoma outcome. Paper presented at 10th Congress of the European-Association-of-NeuroOncology, SEP 06-09, 2012, Marseille, FRANCE. Neuro-Oncology, 14(Suppl. 3), 19-19
Open this publication in new window or tab >>EGFR expression and glioblastoma outcome
Show others...
2012 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no Suppl. 3, p. 19-19Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Oxford: Oxford University Press, 2012
National Category
Cancer and Oncology Neurosciences
Identifiers
urn:nbn:se:umu:diva-60322 (URN)000308545600070 ()
Conference
10th Congress of the European-Association-of-NeuroOncology, SEP 06-09, 2012, Marseille, FRANCE
Available from: 2012-11-09 Created: 2012-10-09 Last updated: 2018-06-08Bibliographically approved
Wibom, C., Ghasimi, S., Van Loo, P., Brännström, T., Trygg, J., Lau, C., . . . Melin, B. (2012). EGFR gene variants are associated with specific somatic aberrations in glioma. PLoS ONE, 7(12), e47929
Open this publication in new window or tab >>EGFR gene variants are associated with specific somatic aberrations in glioma
Show others...
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e47929-Article in journal (Refereed) Published
Abstract [en]

A number of gene variants have been associated with an increased risk of developing glioma. We hypothesized that the reported risk variants may be associated with tumor genomic instability. To explore potential correlations between germline risk variants and somatic genetic events, we analyzed matched tumor and blood samples from 95 glioma patients by means of SNP genotyping. The generated genotype data was used to calculate genome-wide allele-specific copy number profiles of the tumor samples. We compared the copy number profiles across samples and found two EGFR gene variants (rs17172430 and rs11979158) that were associated with homozygous deletion at the CDKN2A/B locus. One of the EGFR variants (rs17172430) was also associated with loss of heterozygosity at the EGFR locus. Our findings were confirmed in a separate dataset consisting of matched blood and tumor samples from 300 glioblastoma patients, compiled from publically available TCGA data. These results imply there is a functional effect of germline EGFR variants on tumor progression.

Place, publisher, year, edition, pages
plosone.org, 2012
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-62754 (URN)10.1371/journal.pone.0047929 (DOI)23236348 (PubMedID)
Available from: 2012-12-20 Created: 2012-12-17 Last updated: 2018-06-08Bibliographically approved
Wibom, C., Ghasimi, S., Van Loo, P., Brännström, T., Trygg, J., Henriksson, R., . . . Melin, B. (2012). EGFR gene variants are associated with specific somatic aberrations in glioma. Paper presented at 10th Congress of the European-Association-of-NeuroOncology, SEP 06-09, 2012, Marseille, FRANCE. Neuro-Oncology, 14(Suppl. 3), 46-46
Open this publication in new window or tab >>EGFR gene variants are associated with specific somatic aberrations in glioma
Show others...
2012 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no Suppl. 3, p. 46-46Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-60323 (URN)000308545600171 ()
Conference
10th Congress of the European-Association-of-NeuroOncology, SEP 06-09, 2012, Marseille, FRANCE
Available from: 2012-11-09 Created: 2012-10-09 Last updated: 2018-06-08Bibliographically approved
Ghasimi, S., Haapasalo, H., Eray, M., Korhonen, K., Brännström, T., Hedman, H. & Andersson, U. (2012). Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression. Journal of Neuro-Oncology, 108(3), 435-441
Open this publication in new window or tab >>Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression
Show others...
2012 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 108, no 3, p. 435-441Article in journal (Refereed) Published
Abstract [en]

The leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family is comprised of three integral membrane proteins: LRIG1, LRIG2, and LRIG3. LRIG1 is a negative regulator of growth factor signaling. The expression and subcellular localization of LRIG proteins have prognostic implications in primary brain tumors, such as oligodendrogliomas and astrocytomas. The expression of LRIG proteins has not previously been studied in meningiomas. In this study, the expression of LRIG1, LRIG2, and LRIG3 was analyzed in 409 meningiomas by immunohistochemistry, and potential associations between LRIG protein expression and tumor grade, gender, progesterone receptor status, and estrogen receptor (ER) status were investigated. The LRIG proteins were most often expressed in the cytoplasm, though LRIG1 also showed prominent nuclear expression. Cytoplasmic expression of LRIG1 and LRIG2 correlated with histological subtypes of meningiomas (p = 0.038 and 0.013, respectively). Nuclear and cytoplasmic expression of LRIG1 was correlated with ER status (p = 0.003 and 0.004, respectively), as was cytoplasmic expression of LRIG2 (p = 0.006). This study is the first to examine the expression of LRIG proteins in meningiomas, and it shows a correlation between ER status and the expression of LRIG1 and LRIG2, which suggests a possible role for LRIG proteins in meningioma pathogenesis.

Keywords
Meningiomas, LRIG1, LRIG2, Estrogen receptor
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-79953 (URN)10.1007/s11060-012-0856-x (DOI)
Available from: 2013-09-06 Created: 2013-09-04 Last updated: 2018-06-08Bibliographically approved
Ghasimi, S., Haapasalo, H., Eray, M., Korhonen, K., Brannstrom, T., Hedman, H. & Andersson, U. (2012). Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression. Paper presented at 10th Congress of the European-Association-of-NeuroOncology, SEP 06-09, 2012, Marseille, FRANCE. Neuro-Oncology, 14(Suppl 3), 69-69
Open this publication in new window or tab >>Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression
Show others...
2012 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no Suppl 3, p. 69-69Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2012
National Category
Neurosciences Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-60324 (URN)000308545600258 ()
Conference
10th Congress of the European-Association-of-NeuroOncology, SEP 06-09, 2012, Marseille, FRANCE
Available from: 2013-01-03 Created: 2012-10-09 Last updated: 2018-06-08Bibliographically approved
Ghasimi, S., Wibom, C., Dahlin, A., Brännström, T., Golovleva, I., Andersson, U. & Melin, B.Genetic risk variants in the EGFR regions are associated with copy number variation in the EGFR gene as well as IDH1, and p53 protein expression.
Open this publication in new window or tab >>Genetic risk variants in the EGFR regions are associated with copy number variation in the EGFR gene as well as IDH1, and p53 protein expression
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-83255 (URN)
Available from: 2013-11-21 Created: 2013-11-21 Last updated: 2018-06-08Bibliographically approved
Organisations

Search in DiVA

Show all publications