Correlation of alterations in the KEAP1/CUL3/NFE2L2 pathway with radiation failure in larynx squamous cell carcinoma.
Correlation of alterations in the KEAP1/CUL3/NFE2L2 pathway with radiation failure in larynx squamous cell carcinoma.
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DOI：
10.1002/lio2.588
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发表时间：
2021-08
影响因子：
1.9
通讯作者：
Hayes DN
中科院分区：
文献类型：
--
作者：
Sheth S;Farquhar DR;Schrank TP;Stepp W;Mazul A;Hayward M;Lenze N;Little P;Jo H;Major MB;Chera BS;Zevallos JP;Hayes DN
喉鳞状细胞癌（LSCC）患者接受放射治疗（RT）时，无论是单药治疗还是与其他治疗方式联合治疗，通常都失败。RT失败的机制知之甚少。我们假设RT失败的肿瘤会增加与辐射抗性相关的基因的体细胞突变率，特别是与NFE 2L 2氧化应激途径相关的基因。使用靶向外显子组测序预处理的喉鳞状细胞癌肿瘤，我们回顾性比较体细胞突变谱与临床数据和治疗反应。肿瘤被分类为辐射抗性（RR）或辐射敏感性（RS）。RR定义为接受全剂量RT后2年内疾病持续或复发。早期（ES）LSCC定义为无淋巴结受累的I或II期肿瘤。与辐射抗性相关的八个基因被优先用于分析。对5个NFE 2L 2途径基因进行RT-qPCR。纳入20例LSCC肿瘤，并将其分类为RR（n = 8）或RS（n = 12）。与辐射抗性相关的基因的体细胞突变的个体率没有差异。在RR与RS肿瘤中观察到更高的总突变负荷（TMB）率和与NFE 2L 2通路相关的增加的改变（P <0.05）。在仅对ES-LSCC患者（RR，n = 3和RS，n = 3）进行的分析中，RR肿瘤的NFE 2L 2体细胞通路突变增加（P = .014）和NQO 1 mRNA表达增加（P = .05）。TMB和NFE 2L 2通路的改变与喉鳞癌的放射抵抗有关。NQO 1 mRNA表达可作为ES-LSCC RT反应的生物标志物。证据等级：II 1。在喉鳞状细胞癌患者中，我们发现治疗前氧化应激途径的突变导致放射治疗失败率增加。更高的肿瘤突变负荷也与辐射抗性相关。
Patients with laryngeal squamous cell carcinoma (LSCC) often fail radiation therapy (RT), when received as monotherapy or in combination with other treatment modalities. Mechanisms for RT failure are poorly understood. We hypothesized that tumors failing RT would have increased rates of somatic mutations in genes associated with radiation resistance, particularly in genes associated with the NFE2L2 oxidative stress pathway. Using targeted exome sequencing on pretreated LSCC tumors, we retrospectively compared somatic mutation profile with clinical data and response to treatment. Tumors were classified as either radiation‐resistant (RR) or radiation‐sensitive (RS). RR was defined as persistent or recurrent disease within 2 years of receiving full‐dose RT. Early stage (ES) LSCC was defined as Stage I or II tumors without lymph node involvement. Eight genes associated with radiation resistance were prioritized for analysis. RT‐qPCR was performed on five NFE2L2 pathway genes. Twenty LSCC tumors were included and classified as either RR (n = 8) or RS (n = 12). No differences in individual rates of somatic mutations by genes associated with radiation resistance were identified. Higher rates of total mutational burden (TMB) and increased alterations associated with the NFE2L2 pathway was observed in RR vs RS tumors (P < .05). In an analysis of only ES‐LSCC patients (RR, n = 3 and RS, n = 3), RR tumors had increased NFE2L2 somatic pathway mutations (P = .014) and increased NQO1 mRNA expression (P = .05). Increased TMB and NFE2L2 pathway alterations were associated with radiation resistance in LSCC. NQO1 mRNA expression may serve as a biomarker for RT response in ES‐LSCC. Level of Evidence: II1. In patients with laryngeal squamous cell carcinoma, we found that mutations in the oxidative stress pathway prior to treatment resulted in increased rates of radiation therapy failures. Higher tumor mutation burden was also associated with radiation resistance.
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