Abstract
The suppressor of Lin-12-like (C. elegans) (SEL1L) is involved in the endoplasmic reticulum (ER)-associated degradation pathway, malignant transformation and stem cells. In 412 formalin-fixed and paraffin-embedded brain tumors and 39 Glioblastoma multiforme (GBM) cell lines, we determined the frequency of five SEL1L single nucleotide genetic variants with regulatory and coding functions by a SNaPShot™ assay. We tested their possible association with brain tumor risk, prognosis and therapy. We studied the in vitro cytotoxicity of valproic acid (VPA), temozolomide (TMZ), doxorubicin (DOX) and paclitaxel (PTX), alone or in combination, on 11 GBM cell lines, with respect to the SNP rs12435998 genotype. The SNP rs12435998 was prevalent in anaplastic and malignant gliomas, and in meningiomas of all histologic grades, but unrelated to brain tumor risks. In GBM patients, the SNP rs12435998 was associated with prolonged overall survival (OS) and better response to TMZ-based radio-chemotherapy. GBM stem cells with this SNP showed lower levels of SEL1L expression and enhanced sensitivity to VPA.
Highlights
Primary brain tumors consist of tumors with neuroepithelial and/or mesodermal origin
Five genetic variants were genotyped in 328 gliomas and 84 non-glial tumors from Caucasian patients with diagnosis of brain tumors
Our investigation started from the assumption that suppressor of Lin-12-like (SEL1L) is a putative tumor suppressor gene involved in the ERAD pathway and in the neoplastic progression [11, 12]
Summary
Primary brain tumors consist of tumors with neuroepithelial and/or mesodermal origin. The former are prevailingly gliomas and represent the greatest part, whereas meningiomas are the most frequent mesodermal tumors. Gliomas can be subdivided in astrocytic and oligodendroglial and, for clinical purpose, in low grade and high grade tumors, among which Glioblastoma multiforme (GBM) is the most frequent tumor type. Gliomas are classified in four histologic grades in agreement with the World Health Organization (WHO). The two main features of GBM are the phenotypic and genotypic heterogeneity, and the cell resistance to therapy. GBM has a median overall survival (OS) of six months after surgery, 12.1 months after radiotherapy (RT) and 14.6 months after adjuvant chemotherapy (CHT) by temozolomide (TMZ) [2]
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