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Epigenetic age acceleration of cervical squamous cell carcinoma converged to human papillomavirus 16/18 expression, immunoactivation, and favourable prognosis.
Clinical Epigenetics ( IF 5.7 ) Pub Date : 2020-02-10 , DOI: 10.1186/s13148-020-0822-y
Xiaofan Lu 1, 2 , Yujie Zhou 3 , Jialin Meng 4, 5 , Liyun Jiang 1, 2 , Jun Gao 1, 2 , Xiaole Fan 6 , Yanfeng Chen 6 , Yu Cheng 1, 2 , Yang Wang 7 , Bing Zhang 7 , Hangyu Yan 1, 2 , Fangrong Yan 1, 2
Affiliation  

BACKGROUND Ageing-associated molecular changes have been assumed to trigger malignant transformations and the epigenetic clock, and the DNA methylation age has been shown to be highly correlated with chronological age. However, the associations between the epigenetic clock and cervical squamous cell carcinoma (CSCC) prognosis, other molecular characteristics, and clinicopathological features have not been systematically investigated. To this end, we computed the DNA methylation (DNAm) age of 252 CSCC patients and 200 normal samples from TCGA and three external cohorts by using the Horvath clock model. We characterized the differences in human papillomavirus (HPV) 16/18 expression, pathway activity, genomic alteration, and chemosensitivity between two DNAm age subgroups. We then used Cox proportional hazards regression and restricted cubic spline (RCS) analysis to assess the prognostic value of epigenetic acceleration. RESULTS DNAm age was significantly associated with chronological age, but it was differentiated between tumour and normal tissue (P < 0.001). Two DNAm age groups, i.e. DNAmAge-ACC and DNAmAge-DEC, were identified; the former had high expression of the E6/E7 oncoproteins of HPV16/18 (P < 0.05), an immunoactive phenotype (all FDRs < 0.05 in enrichment analysis), CpG island hypermethylation (P < 0.001), and lower mutation load (P = 0.011), including for TP53 (P = 0.002). When adjusted for chronological age and tumour stage, every 10-year increase in DNAm age was associated with a 12% decrease in fatality (HR 0.88, 95% CI 0.78-0.99, P = 0.03); DNAmAge-ACC had a 41% lower mortality risk and 47% lower progression rate than DNAmAge-DEC and was more likely to benefit from chemotherapy. RCS revealed a positive non-linear association between DNAm age and both mortality and progression risk (both, P < 0.05). CONCLUSIONS DNAm age is an independent predictor of CSCC prognosis. Better prognosis, overexpression of HPV E6/E7 oncoproteins, and higher enrichment of immune signatures were observed in DNAmAge-ACC tumours.

中文翻译:

宫颈鳞状细胞癌的表观遗传年龄加速与人乳头瘤病毒16/18表达、免疫激活和良好预后相关。

背景 衰老相关的分子变化被认为会引发恶性转化和表观遗传时钟,并且 DNA 甲基化年龄已被证明与实际年龄高度相关。然而,表观遗传时钟与宫颈鳞状细胞癌(CSCC)预后、其他分子特征和临床病理特征之间的关联尚未得到系统研究。为此,我们使用 Horvath 时钟模型计算了来自 TCGA 和三个外部队列的 252 名 CSCC 患者和 200 名正常样本的 DNA 甲基化 (DNAm) 年龄。我们描述了两个 DNAm 年龄亚组之间人乳头瘤病毒 (HPV) 16/18 表达、通路活性、基因组改变和化疗敏感性的差异。然后,我们使用 Cox 比例风险回归和限制三次样条 (RCS) 分析来评估表观遗传加速的预后价值。结果 DNAm 年龄与实际年龄显着相关,但在肿瘤组织和正常组织之间存在差异(P < 0.001)。确定了两个 DNAm 年龄组,即 DNAmAge-ACC 和 DNAmAge-DEC;前者具有 HPV16/18 的 E6/E7 癌蛋白高表达(P < 0.05)、免疫活性表型(富集分析中所有 FDR < 0.05)、CpG 岛高甲基化(P < 0.001)和较低的突变负荷(P = 0.011),包括 TP53(P = 0.002)。根据实际年龄和肿瘤分期进行调整后,DNAm 年龄每增加 10 年,死亡率就会降低 12%(HR 0.88,95% CI 0.78-0.99,P = 0.03);与 DNAmAge-DEC 相比,DNAmAge-ACC 的死亡风险降低了 41%,进展率降低了 47%,并且更有可能从化疗中受益。RCS 显示 DNAm 年龄与死亡率和进展风险之间存在正非线性关联(均 P < 0.05)。结论 DNAm 年龄是 CSCC 预后的独立预测因子。在 DNAmAge-ACC 肿瘤中观察到更好的预后、HPV E6/E7 癌蛋白的过度表达以及免疫特征的更高富集。
更新日期:2020-04-22
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