Obiedat Hadeel, Alrabadi Nasr, Sultan Eyad, Al Shatti Marwa, Zihlif Malek
Department of Pharmacology, Faculty of Medicine, The University of Jordan, Amman, 11942, Jordan.
Department of Pharmacology, Faculty of medicine, Jordan University of Science and Technology (JUST), Irbid, 22110, Jordan.
BMC Med Genet. 2018 Jul 6;19(1):112. doi: 10.1186/s12881-018-0627-4.
Cisplatin is one of the major drugs that used in the treatment of osteosarcoma. Cisplatin exerts its function by making cisplatin-DNA adducts culminating in cellular death. These adducts found to be repaired by nucleotide excision repair (NER) pathway. This study aimed to evaluate if polymorphisms in two main genes in the NER pathway, excision repair cross-complementing group 1 and 2 (ERCC1 and ERCC2) could affect the histological response to cisplatin based chemotherapy or clinical outcomes, particularly, event free survival (EFS) and overall survival (OS) rates.
ERCC1 (C118T (rs11615) and C8092A (rs3212986)) and ERCC2 (A751C (rs171140) and G312A (rs1799793)) polymorphisms were analysed in 44 patients with osteosarcoma, who were treated with cisplatin based neoadjuvant chemotherapy. DNA was extracted from patient's formalin-fixed paraffin-embedded (FFPE) samples, patient's genotypes were determined by using polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP assay. The distribution of the patients' genotype and the allele frequencies were reported. The association between each of these genotypes and many clinical and patho-histological parameters (e.g. EFS, OS and patho-histological response to treatment) was examined. The associations between gender, tumor location, presence of metastasis at diagnosis, histological subtypes, and type of neoadjuvant chemotherapy and between the histological response, EFS and OS rates were also examined.
This study revealed that there was a positive and significant association between ERCC1 C8092 A genotypes and median EFS rate in years; patients who were carriers of C allele (CC & CA) were found to have longer EFS rates than patients with AA genotype (P value = 0.006) and the median EFS rates were respectively as following: 2.04, 0.24 years. As well, both the presence of metastasis and the histological subtype at the time of diagnosis, were able to affect the EFS rate but not the OS. However, there was a positive correlation between OS rate and the patients' primary response to treatment.
Our results suggested that ERCC1 8092 C allele may play a role as a candidate prognostic marker in patients with osteosarcoma.
顺铂是用于治疗骨肉瘤的主要药物之一。顺铂通过形成顺铂 - DNA加合物发挥作用，最终导致细胞死亡。这些加合物可通过核苷酸切除修复（NER）途径进行修复。本研究旨在评估NER途径中两个主要基因，即切除修复交叉互补基因1和2（ERCC1和ERCC2）的多态性是否会影响基于顺铂的化疗的组织学反应或临床结局，特别是无事件生存期（EFS）和总生存期（OS）率。
对44例接受基于顺铂的新辅助化疗的骨肉瘤患者进行ERCC1（C118T（rs11615）和C8092A（rs3212986））和ERCC2（A751C（rs171140）和G312A（rs1799793））多态性分析。从患者的福尔马林固定石蜡包埋（FFPE）样本中提取DNA，使用聚合酶链反应 - 限制性片段长度多态性PCR - RFLP分析法确定患者的基因型。报告患者基因型的分布和等位基因频率。检查这些基因型中的每一种与许多临床和病理组织学参数（例如EFS、OS和治疗的病理组织学反应）之间的关联。还检查了性别、肿瘤位置、诊断时转移的存在、组织学亚型和新辅助化疗类型之间以及组织学反应、EFS和OS率之间的关联。
本研究表明，ERCC1 C8092 A基因型与以年为单位的中位EFS率之间存在正相关且具有显著性；发现携带C等位基因（CC和CA）的患者的EFS率比AA基因型的患者更长（P值 = 0.006），中位EFS率分别如下：2.04年、0.24年。同样，转移的存在和诊断时的组织学亚型均能够影响EFS率，但不影响OS。然而，OS率与患者对治疗的初始反应之间存在正相关。
我们的结果表明，ERCC1 8092 C等位基因可能在骨肉瘤患者中作为候选预后标志物发挥作用。
