Table_1_Gene Promoter-Methylation Signature as Biomarker to Predict Cisplatin-Radiotherapy Sensitivity in Locally Advanced Cervical Cancer.xlsx

Despite efforts to promote health policies focused on screening and early detection, cervical cancer continues to be one of the leading causes of mortality in women; in 2020, estimated 30,000 deaths in Latin America were reported for this type of tumor. While the therapies used to treat cervical cancer have excellent results in tumors identified in early stages, those women who are diagnosed in locally advanced and advanced stages show survival rates at 5 years of <50%. Molecular patterns associated with clinical response have been studied in patients who present resistance to treatment; none of them have reached clinical practice. It is therefore necessary to continue analyzing molecular patterns that allow us to identify patients at risk of developing resistance to conventional therapy. In this study, we analyzed the global methylation profile of 22 patients diagnosed with locally advanced cervical cancer and validated the genomic results in an independent cohort of 70 patients. We showed that BRD9 promoter region methylation and CTU1 demethylation were associated with a higher overall survival (p = 0.06) and progression-free survival (p = 0.0001), whereas DOCK8 demethylation was associated with therapy-resistant patients and a lower overall survival and progression-free survival (p = 0.025 and p = 0.0001, respectively). Our results suggest that methylation of promoter regions in specific genes may provide molecular markers associated with response to treatment in cancer; further investigation is needed.

尽管学界已大力推广以筛查与早诊为核心的健康政策，宫颈癌（cervical cancer）仍是导致女性死亡的主要病因之一；2020年，拉丁美洲地区据报因该肿瘤致死的病例约达3万例。尽管针对宫颈癌的治疗方案在早期确诊患者中可获得优异疗效，但局部晚期及晚期确诊的女性患者，其五年生存率不足50%。此前已有研究针对治疗耐药患者的临床应答相关分子特征展开探索，但相关成果尚未能落地临床应用。因此，亟需进一步挖掘可识别传统治疗耐药风险患者的分子特征。本研究对22名局部晚期宫颈癌患者的全基因组甲基化谱（global methylation profile）进行了分析，并在包含70名患者的独立队列（independent cohort）中对基因组学结果进行了验证。研究发现，BRD9启动子区域甲基化与CTU1基因去甲基化，分别与更高的总生存期（overall survival，p=0.06）及无进展生存期（progression-free survival，p=0.0001）相关；而DOCK8基因去甲基化则与治疗耐药患者群体、更低的总生存期及无进展生存期显著相关（分别对应p=0.025与p=0.0001）。本研究结果表明，特定基因启动子区域的甲基化状态，或可作为肿瘤治疗应答相关的分子标志物；后续仍需开展更深入的研究。