Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma.
Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma.
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DOI：
10.1186/s13148-017-0357-z
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发表时间：
2017
影响因子：
5.7
通讯作者：
Fratta E
中科院分区：
文献类型：
--
作者：
Furlan C;Polesel J;Barzan L;Franchin G;Sulfaro S;Romeo S;Colizzi F;Rizzo A;Baggio V;Giacomarra V;Dei Tos AP;Boscolo-Rizzo P;Vaccher E;Dolcetti R;Sigalotti L;Fratta E
迫切需要纳入新的生物标志物来改善口咽鳞状细胞癌（OPSCC）的个性化治疗方法。长散布核苷酸元件 1 (LINE-1) 重复元件是一种被广泛接受的整体基因组 DNA 甲基化含量的替代元件，其低甲基化被发现与多种癌症的不良预后相关。目前尚无研究探讨LINE-1甲基化水平对OPSCC复发的影响。本研究的主要目标是评估 LINE-1 甲基化状态在预测局部晚期 OPSCC 早期肿瘤复发中的预后价值。我们回顾性审查了 77 名 III-IVB 期 OPSCC 患者的队列。通过实时定量甲基化特异性 PCR 在福尔马林固定石蜡包埋的组织中评估 LINE-1 重复序列的甲基化。通过比较治疗结束后 2 年内复发的患者（病例）和未复发的患者（对照）来评估 LINE-1 甲基化的预后相关性。结果在 33 名 OPSCC 患者的独立队列中得到验证。对于早期 OPSCC 复发，复发病例中的平均 LINE-1 甲基化水平显着低于对照组（p<0.01）。有趣的是，在 HPV16 阴性和 HPV16 阳性 OPSCC 患者中，复发病例中的 LINE-1 甲基化水平均低于对照组，即使仅前一组患者达到了统计学显着性 (p = 0.01)。与 OPSCC 当前吸烟者的对照相比，复发病例中的 LINE-1 甲基化水平也显着降低 (p = 0.02)。一致地，在 HPV16 阴性的当前吸烟者中，OPSCC 复发与 LINE-1 甲基化水平降低显着相关 (p = 0.02)。使用逻辑回归模型，我们发现 LINE-1 低甲基化患者的早期复发风险比高甲基化患者高 3.5 倍（OR = 3.51；95% CI 1.03–12.00）。对潜在混杂因素的调整并没有显着改变风险程度。验证队列的结果证实，与无复发患者相比，早期复发患者的 LINE-1 甲基化较低。 LINE-1 低甲基化与 III-IVB 期 OPSCC 早期复发的较高风险相关。其在日常临床实践中的应用需要进一步的前瞻性研究验证。
Inclusion of new biomarkers to improve a personalized treatment approach for oropharyngeal squamous cell carcinoma (OPSCC) is urgently needed. Hypomethylation of the Long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was found to be associated with a poor prognosis in several cancers. At present, no studies have investigated the influence of LINE-1 methylation levels on OPSCC relapse. The main goal of this study was the evaluation of the prognostic value of LINE-1 methylation status in predicting early tumor relapse in locally advanced OPSCC. We retrospectively reviewed a cohort of 77 patients with stage III–IVB OPSCC. Methylation of LINE-1 repetitive sequences was evaluated by real-time quantitative methylation-specific PCR in formalin-fixed paraffin-embedded tissues. The prognostic relevance of LINE-1 methylation was assessed by comparing patients who relapsed within 2 years from the end of treatment (cases) with those who did not (controls). Results were validated in an independent cohort of 33 patients with OPSCC. With respect to early OPSCC relapse, the mean LINE-1 methylation level was significantly lower in relapsed cases than in control group (p < 0.01). Interestingly, LINE-1 methylation was lower in relapsed cases than in controls in both HPV16-negative and HPV16-positive OPSCC patients, even if statistical significance was reached only for the former group (p = 0.01). LINE-1 methylation levels were also significantly reduced in relapsed cases with respect to the controls in OPSCC current smokers (p = 0.02). Consistently, in HPV16-negative current smokers, OPSCC relapse was significantly associated with decreased levels of LINE-1 methylation (p = 0.02). Using logistic regression model, we found that patients with hypomethylated LINE-1 were associated with a 3.5 higher risk of early relapse than hypermethylated ones (OR = 3.51; 95% CI 1.03–12.00). Adjustment for potential confounders did not substantially change the risk magnitude. Results from the validation cohort confirmed the lower LINE-1 methylation in patients who early relapsed compared to relapse-free patients. LINE-1 hypomethylation is associated with higher risk of early relapse in stage III–IVB OPSCC. Further validation in a prospective study is needed for its application in daily clinical practice.