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SEL1L SNP rs12435998, a predictor of glioblastoma survival and response to radio-chemotherapy.

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.

SUBMITTER: Mellai M

PROVIDER: S-EPMC4494950 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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SEL1L SNP rs12435998, a predictor of glioblastoma survival and response to radio-chemotherapy.

Mellai Marta M Cattaneo Monica M Storaci Alessandra Maria AM Annovazzi Laura L Cassoni Paola P Melcarne Antonio A De Blasio Pasquale P Schiffer Davide D Biunno Ida I

Oncotarget 20150501 14

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 st ...[more]

PMID: 25948789

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Project description:Abstract Background: Glioblastoma (GBM) accounts for approximately 50% of all glioma and among these tumors, are the most malignant. The current standard of care for patients with newly diagnosed GBM includes temozolomide and radiotherapy. Melanocortins are peptides with well-recognized anti-inflammatory and neuroprotective activity. No data are currently available on MC4R gene polymorphisms and gliomas or their relationship with radiotherapy or chemotherapy. Given the association of MC4R with antiinflammatory activity, neuroprotection, induction of neural stem/progenitor cell proliferation in brain hypoxia, and prevention of astrocyte apoptosis, the aim of this study was to retrospectively evaluate the possible prognostic/predictive role of the MC4R SNPs on GBM therapy. Methods: Sixty-one patients with a proven diagnosis of GBM, ECOG PS 0–2, age greater than18 years, and treated with radiotherapy and temozolomide were enrolled. Blood samples (3 ml) were collected in EDTA tubes and stored at -80°C. Genomic DNA was extracted using QIAamp DNA Blood Mini Kit. MC4R gene SNPs (rs17782313, rs489693, rs8087522, rs17700633) were analyzed; the allelic discrimination was performed using an ABI PRISM 7900 SDS and with validated TaqMan® SNP genotyping assays. PCR reactions were carried out according to the manufacturer’s protocol. Kaplan Meier curves were performed for statistical association with genotypes. A P value less than 0.0125 (Bonferroni’s correction) was considered significant. Results: Fifty-six patients were clinically evaluated. The median  progression-free survival (PFS) and median overall survival (OS) were 10.8 months and 23 months, respectively. The distribution of genotypes in the 56 patients did not deviate from Hardy-Weinberg equilibrium. A relevant finding of our study was the identification of a MC4R genotype that was significantly associated with PFS. Indeed, with regard to PFS, patients harbouring the rs489693 AA genotype had a median PFS of 3 months whereas patients with AC/CC genotypes had a median PFS of 13.7 months (P=0.0088). Interestingly, the rs489693 AA patients also had a lower median OS, even though the difference was not sta[[Unsupported Character - Codename ]]tistically significant as compared with the median OS of the AC/CC genotypes (15.6 vs. 24.6 months, respectively, P=0.274). No significant differences in PFS and OS for the other genotypes of the investigated MC4R polymorphisms were found. Conclusion: The rs489693 AA genotype is significantly associated with a shorter PFS in GBM patients treated with radiotherapy and temozolomide schedule. The present pharmacogenetic, retrospective, pilot study may represent the stimulus to prospectively investigate the role of rs489693 MC4R polymorphism as a predictive pharmacogenetic marker of GBM radio-chemotherapy.

Project description:CONTEXT:Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies. OBJECTIVE:To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer. DESIGN, SETTING, AND PATIENTS:Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens (then endocrine therapy if estrogen receptor [ER]-positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response. MAIN OUTCOME MEASURES:Distant relapse-free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years). RESULTS:Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy. CONCLUSION:A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.

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SEL1L SNP rs12435998, a predictor of glioblastoma survival and response to radio-chemotherapy.

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SEL1L SNP rs12435998, a predictor of glioblastoma survival and response to radio-chemotherapy.

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