Relationship between SEL1L gene polymorphism and overall survival and temozolomide sensitivity in glioma

doi:10.19854/j.cnki.1008-2425.2024.04.0003

Abstract

Abstract: Objective To investigate the relationship between Lin-12-like (C.elegans) (SEL1L) suppressant gene polymorphism and overall survival or temozolomide (TMZ) sensitivity in patients with glioma. Methods A total of 66 patients with pathologically confirmed glioma,including 32 cases of glioblastoma (GBM) and 34 cases of low-grade glioma (LGG),were enrolled between January 2019 and January 2023.All patients received TMZ adjuvant chemotherapy and/or radiotherapy after surgery.Tumor tissue O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was measured by bisulfite transformation and pyrosequencing,and the frequency of rs12435998 single nucleotide genetic variation in SEL1L intron 3 in tumor tissue and peripheral blood mononuclear cells (control samples) was determined by SNaPShot^TM assays.Overall survival (OST) was followed up. Results The allele frequency of rs12435998 minor allele G was 19.70% (26/132) in tumor samples,but only 9.85% (13/132) in control samples.The proportion of AG/GG genotypes in GBM patients was significantly higher (P=0.047).In addition,the rs12435998 genotype in tumor tissue matched the rs12435998 genotype trend in control sample.Tumor rs12435998 genotype was not associated with OST in patients with GBM (P=0.520) or MGMT hypermethylation (P=0.299).However,LGG patients with rs12435998AG/GG genotype had a shorter median OST (17.10 months vs.53.20 months) (HR:6.844;95%CI:1.991~23.530;P=0.002).Similarly,for MGMT hypomethylation patients,the median OST in patients with tumor rs12435998AG/GG genotype was shorter than that in patients with AA genotype (7.10 months vs.44.80 months) (HR:2.937;95%CI:1.155~7.464;P=0.024). Conclusion SEL1L rs12435998 gene polymorphism may be a new molecular stratification of LGG,and its G suballele is associated with poor TMZ sensitivity and survival prognosis.

Key words: Brain glioma, Lin-12-like (C.elegans) suppressor gene, Temozolomide, Low grade brain glioma, Overall survival

摘要： 目的本研究旨在分析脑胶质瘤患者Lin-12样(秀丽隐杆线虫)(Caenorhabditis elegans,SEL1L)抑制基因多态性与总生存率和替莫唑胺(temozolomide,TMZ)敏感性的关系。方法 2019年1月至2023年1月间共招募了66名经病理证实的神经胶质瘤患者,包括32例胶质母细胞瘤(glioblastoma,GBM)和34例低级别脑胶质瘤(low grade glioma,LGG)。所有患者术后均接受TMZ辅助化疗和/或放疗。肿瘤组织O-6-甲基鸟嘌呤-DNA甲基转移酶(O-6-methylguanine-DNA methyltransferase,MGMT)启动子甲基化通过亚硫酸氢盐转化和焦磷酸测序来测量,通过SNaPShot^TM测定法确定了肿瘤组织和外周血单核细胞(对照样本)SEL1L内含子3中rs12435998单核苷酸遗传变异的频率。随访患者总生存期(OST)。结果 rs12435998次要等位基因G在肿瘤样本中的等位基因频率为19.70%(26/132),在对照样本中仅为9.85%(13/132)。GBM患者AG/GG基因型比例明显更高(P=0.047),另外,肿瘤组织rs12435998基因型与对照样本rs12435998基因型趋势相匹配。肿瘤rs12435998基因型与GBM患者(P=0.520)或MGMT超甲基化患者(P=0.299)的OST无关。但是rs12435998AG/GG基因型的LGG患者中位OST更短(17.10个月 vs.53.20个月)(HR:6.844;95%CI:1.991~23.530;P=0.002)。同样,对于MGMT低甲基化患者,肿瘤rs12435998AG/GG基因型患者中位OST短于AA基因型患者(7.10个月 vs.44.80个月)(HR:2.937;95%CI:1.155~7.464;P=0.024)。结论 SEL1L rs12435998基因多态性可能是LGG的一种新的分子分层,其G次等位基因与较差的TMZ敏感性和生存预后有关。

关键词: 脑胶质瘤, Lin-12样(秀丽隐杆线虫)抑制基因, 替莫唑胺, 低级别脑胶质瘤, 总生存期

CLC Number:

R739.4

Peng Chao, Chen Yucheng, Zhang Zhijuan, Liao Liqing. Relationship between SEL1L gene polymorphism and overall survival and temozolomide sensitivity in glioma[J]. Chinese Journal of Stereotactic and Functional Neurosurgery, 2024, 37(4): 205-209.

彭超, 陈宇澄, 张之娟, 廖黎庆. 脑胶质瘤患者SEL1L基因多态性与总生存率和替莫唑胺敏感性的关系[J]. 立体定向和功能性神经外科杂志, 2024, 37(4): 205-209.

References

[1] 冯哲斌,张宇,孔东生,等.Crispr-Cas12a在成人弥漫性胶质瘤异柠檬酸脱氢酶2基因突变检测中的应用[J].中国临床神经外科杂志,2023,28(8):517~521.
[2] Butler M,Pongor L,Su YT,et al.MGMT status as a clinical biomarker in glioblastoma[J].Trends Cancer,2020,6(5):380~391.
[3] Mansouri A,Hachem LD,Mansouri S,et al.MGMT promoter methylation status testing to guide therapy for glioblastoma:refining the approach based on emerging evidence and current challenges[J].Neuro Oncol,2019,21(2):167~178.
[4] Zhang T,Guzman MA,Batanian JR.Narrowing down the common cytogenetic deletion 14q to a 5.6-mb critical region in 1p/19q codeletion oligodendroglioma-relapsed patients points to two potential relapse-related genes:SEL1L and STON2[J].Cytogenet Genome Res,2020,160(6):316~320.
[5] Mellai M,Annovazzi L,Boldorini R,et al.SEL1L plays a major role in human malignant gliomas[J].J Pathol Clin Res,2020,6(1):17~29.
[6] Saito R,Mimori S,Okuma Y,et al.Sel1l may contributes to the determinants of neuronal lineage and neuronal maturation regardless of Hrd1 via Atf6-Sel1l signaling[J].Neurochem Res,2023,48(1):263~272.
[7] Mellai M,Cattaneo M,Storaci AM,et al.SEL1L SNP rs12435998,a predictor of glioblastoma survival and response to radio-chemotherapy[J].Oncotarget,2015,6(14):12452~12467.
[8] Molinaro AM,Taylor JW,Wiencke JK,et al.Genetic and molecular epidemiology of adult diffuse glioma[J].Nat Rev Neurol,2019,15(7):405~417.
[9] Bahadur S,Sahu AK,Baghel P,et al.Current promising treatment strategy for glioblastoma multiform:a review[J].Oncol Rev,2019,13(2):417~427.
[10] Mathur R,Zhang Y,Grimmer MR,et al.MGMT promoter methylation level in newly diagnosed low-grade glioma is a predictor of hypermutation at recurrence[J].Neuro Oncol,2020,22(11):1580~1590.
[11] Chai R,Fang S,Pang B,et al.Molecular pathology and clinical implications of diffuse glioma[J].Chin Med J,2022,135(24):2914~2925.
[12] 刘玉仑,王永强,杨洁,等.SEL1L分子及内质网相关降解途径在肿瘤进展中的作用[J].医学研究杂志,2024,53(1):184~187,192.
[13] Iglesias Gómez JC,Mosquera Orgueira A.An integrative analysis of meningioma tumors reveals the determinant genes and pathways of malignant transformation[J].Front Oncol,2014,4:147~158.
[14] Okano A,Miyawaki S,Hongo H,et al.Associations of pathological diagnosis and genetic abnormalities in meningiomas with the embryological origins of the meninges[J].Sci Rep,2021,11(1):6987~6999.
[15] Singh N,Miner A,Hennis L,et al.Mechanisms of temozolomide resistance in glioblastoma-a comprehensive review[J].Cancer Drug Resist,2021,4(1):17~43.
[16] Cho YA,Kim D,Lee B,et al.Incidence,clinicopathologic,and genetic characteristics of mismatch repair gene-mutated glioblastomas[J].J Neurooncol,2021,153(1):43~53.