Department of Computer Science, University of Crete, 700 13, Heraklion, Crete, Greece.
Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, 7030, Trondheim, Norway.
J Cancer Res Clin Oncol. 2024 Jul 20;150(7):355. doi: 10.1007/s00432-024-05882-4.
Blood biomarkers for early detection of lung cancer (LC) are in demand. There are few studies of the full microRNome in serum of asymptomatic subjects that later develop LC. Here we searched for novel microRNA biomarkers in blood from non-cancer, ever-smokers populations up to eight years before diagnosis.
Serum samples from 98,737 subjects from two prospective population studies, HUNT2 and HUNT3, were considered initially. Inclusion criteria for cases were: ever-smokers; no known cancer at study entrance; 0-8 years from blood sampling to LC diagnosis. Each future LC case had one control matched to sex, age at study entrance, pack-years, smoking cessation time, and similar HUNT Lung Cancer Model risk score. A total of 240 and 72 serum samples were included in the discovery (HUNT2) and validation (HUNT3) datasets, respectively, and analysed by next-generation sequencing. The validated serum microRNAs were also tested in two pre-diagnostic plasma datasets from the prospective population studies NOWAC (n = 266) and NSHDS (n = 258). A new model adding clinical variables was also developed and validated.
Fifteen unique microRNAs were discovered and validated in the pre-diagnostic serum datasets when all cases were contrasted against all controls, all with AUC > 0.60. In combination as a 15-microRNAs signature, the AUC reached 0.708 (discovery) and 0.703 (validation). A non-small cell lung cancer signature of six microRNAs showed AUC 0.777 (discovery) and 0.806 (validation). Combined with clinical variables of the HUNT Lung Cancer Model (age, gender, pack-years, daily cough parts of the year, hours of indoor smoke exposure, quit time in years, number of cigarettes daily, body mass index (BMI)) the AUC reached 0.790 (discovery) and 0.833 (validation). These results could not be validated in the plasma samples.
There were a few significantly differential expressed microRNAs in serum up to eight years before diagnosis. These promising microRNAs alone, in concert, or combined with clinical variables have the potential to serve as early diagnostic LC biomarkers. Plasma is not suitable for this analysis. Further validation in larger prospective serum datasets is needed.
人们对用于早期检测肺癌（LC）的血液生物标志物有很大的需求。目前只有少数研究对无症状但后来患有 LC 的个体的血清全 microRNome 进行了研究。在这里，我们在非癌症、持续吸烟人群中，在诊断前 8 年内搜索血液中的新型 microRNA 生物标志物。
首先考虑了来自两个前瞻性人群研究 HUNT2 和 HUNT3 的 98737 名受试者的血清样本。病例的纳入标准为：持续吸烟者；研究开始时无已知癌症；从采血到 LC 诊断的时间为 0-8 年。每个未来的 LC 病例都有一个与性别、研究开始时的年龄、吸烟包年数、戒烟时间和类似的 HUNT 肺癌模型风险评分相匹配的对照。总共纳入了 240 例和 72 例来自发现（HUNT2）和验证（HUNT3）数据集的血清样本，分别通过下一代测序进行分析。在来自前瞻性人群研究 NOWAC（n=266）和 NSHDS（n=258）的两个预诊断血浆数据集中也对验证的血清 microRNAs 进行了测试。还开发和验证了一个添加临床变量的新模型。
当所有病例与所有对照相比时，在预诊断血清数据集中发现并验证了 15 个独特的 microRNAs，所有 microRNAs 的 AUC 均大于 0.60。作为 15 个 microRNAs 特征的组合，AUC 达到 0.708（发现）和 0.703（验证）。一个非小细胞肺癌的 6 个 microRNAs 特征的 AUC 为 0.777（发现）和 0.806（验证）。与 HUNT 肺癌模型的临床变量（年龄、性别、吸烟包年数、每年咳嗽的部分、室内烟雾暴露小时数、戒烟时间（年）、每日吸烟量、体重指数（BMI））相结合，AUC 达到 0.790（发现）和 0.833（验证）。这些结果在血浆样本中无法验证。
在诊断前 8 年内，血清中存在一些差异表达的 microRNAs。这些有前途的 microRNAs 单独、协同或与临床变量相结合，有可能作为早期诊断 LC 的生物标志物。血浆不适合这种分析。需要在更大的前瞻性血清数据集中进一步验证。
