异常甲基化特征可预测晚期高级别浆液性卵巢癌的化疗耐药性和不良预后。
Abnormal methylation characteristics predict chemoresistance and poor prognosis in advanced high-grade serous ovarian cancer.
机构信息
Department of Gynecology and Oncology, Guangxi Medical University Cancer Hospital and Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, 71 Hedi Road, Nanning, 530021, Guangxi, People's Republic of China.
出版信息
Clin Epigenetics. 2021 Jul 21;13(1):141. doi: 10.1186/s13148-021-01133-2.
BACKGROUND
Primary or acquired chemoresistance is a key link in the high mortality rate of ovarian cancer. There is no reliable method to predict chemoresistance in ovarian cancer. We hypothesized that specific methylation characteristics could distinguish chemoresistant and chemosensitive ovarian cancer patients.
METHODS
In this study, we used 450 K Infinium Methylation BeadChip to detect the different methylation CpGs between ovarian cancer patients. The differential methylation genes were analyzed by GO and KEGG Pathway bioinformatics analysis. The candidate CpGs were confirmed by pyrosequencing. The expression of abnormal methylation gene was identified by QRT-PCR and IHC. ROC analysis confirmed the ability to predict chemotherapy outcomes. Prognosis was evaluated using Kaplan-Meier.
RESULTS
In advanced high-grade serous ovarian cancer, 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) remained hypermethylated in chemoresistant patients. The sensitivity, specificity and AUC of 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) methylation to predict chemotherapy sensitivity were 63.60-97.00%, 46.40-89.30% and 0.774-0.846. PFS of 6 candidate genes (ITGB6:cg21105318, cg07896068; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934) hypermethylation patients was significantly shorter. The expression of NCALD and LAMA3 in chemoresistant patients was lower than that of chemosensitive patients. Spearman analysis showed that NCALD and LAMA3 methylations were negatively correlated with their expression.
CONCLUSIONS
As a new biomarker of chemotherapy sensitivity, hypermethylation of NCALD and LAMA3 is associated with poor PFS in advanced high-grade serous ovarian cancer. In the future, further research on NCALD and LAMA3 will be needed to provide guidance for clinical stratification of demethylation therapy.
背景
原发性或获得性化疗耐药是卵巢癌高死亡率的关键环节。目前尚无可靠的方法来预测卵巢癌的化疗耐药性。我们假设特定的甲基化特征可以区分化疗耐药和化疗敏感的卵巢癌患者。
方法
本研究使用 450K Infinium 甲基化 BeadChip 检测卵巢癌患者之间不同的甲基化 CpG。通过 GO 和 KEGG 通路生物信息学分析对差异甲基化基因进行分析。通过焦磷酸测序验证候选 CpG。通过 QRT-PCR 和 IHC 鉴定异常甲基化基因的表达。ROC 分析证实了预测化疗结果的能力。采用 Kaplan-Meier 评估预后。
结果
在晚期高级别浆液性卵巢癌中，8 个 CpG（ITGB6：cg21105318、cg07896068、cg18437633；NCALD：cg27637873、cg26782361、cg16265707；LAMA3：cg20937934、cg13270625）在化疗耐药患者中仍呈高甲基化状态。8 个 CpG（ITGB6：cg21105318、cg07896068、cg18437633；NCALD：cg27637873、cg26782361、cg16265707；LAMA3：cg20937934、cg13270625）甲基化预测化疗敏感性的灵敏度、特异性和 AUC 分别为 63.60%-97.00%、46.40%-89.30%和 0.774-0.846。6 个候选基因（ITGB6：cg21105318、cg07896068；NCALD：cg27637873、cg26782361、cg16265707；LAMA3：cg20937934）高甲基化患者的无进展生存期明显缩短。NCALD 和 LAMA3 在化疗耐药患者中的表达低于化疗敏感患者。Spearman 分析表明，NCALD 和 LAMA3 的甲基化与它们的表达呈负相关。
结论
作为一种新的化疗敏感性生物标志物，NCALD 和 LAMA3 的高甲基化与晚期高级别浆液性卵巢癌患者的不良 PFS 相关。未来需要进一步研究 NCALD 和 LAMA3，为去甲基化治疗的临床分层提供指导。
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