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Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression
Umeå University, Faculty of Medicine, Department of Radiation Sciences.
Department of Pathology, Center of Laboratory Medicine, Tampere University .
Department of Pathology, Center of Laboratory Medicine, Tampere University .
Department of Neurosurgery, Turku University Hospital, Turku, Finland.
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2012 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 108, no 3, 435-441 p.Article 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.

Place, publisher, year, edition, pages
2012. Vol. 108, no 3, 435-441 p.
Keyword [en]
Meningiomas, LRIG1, LRIG2, Estrogen receptor
National Category
Cancer and Oncology
Research subject
URN: urn:nbn:se:umu:diva-79953DOI: 10.1007/s11060-012-0856-xOAI: diva2:645966
Available from: 2013-09-06 Created: 2013-09-04 Last updated: 2013-11-21Bibliographically approved
In thesis
1. Genotype-phenotype studies in brain tumors
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. 64 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1657
Glioma, Meningioma, SNP, IHC, FISH, LRIG2, EGF, EGFR, ERBB2, ER, CDKN2A/B, IDH1
National Category
Cancer and Oncology
Research subject
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)

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: 2014-05-12Bibliographically approved

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