1] Department of Paediatric Haematology and Oncology, Addenbrooke's Hospital, Cambridge, UK [2] Department of Pathology, University of Cambridge, Cambridge, UK.
Department of Paediatric Haematology and Oncology, Addenbrooke's Hospital, Cambridge, UK.
Oncogenesis. 2014 Feb 10;3(2):e87. doi: 10.1038/oncsis.2014.1.
DICER1 is a critical gene in the biogenesis of mature microRNAs, short non-coding RNAs that derive from either -3p or -5p precursor microRNA strands. Germline mutations of DICER1 are associated with a range of human malignancies, including pleuropulmonary blastoma (PPB). Additional somatic 'hotspot' mutations in the microRNA processing ribonuclease IIIb (RNase IIIb) domain of DICER1 are reported in cancer, and which affect microRNA biogenesis, resulting in a -3p mature microRNA strand bias. Here, in a germline (exon11 c.1806_1810insATTGA) DICER1-mutated PPB, we first confirmed the presence of an additional somatic RNase IIIb hotspot mutation (exon25 c.5425G>A [p.G1809R]) by conventional sequencing. Second, we investigated serum levels of mature microRNAs at the time of PPB diagnosis, and compared the findings with serum results from a comprehensive range of pediatric cancer patients and controls (n=52). We identified a panel of 45 microRNAs that were present at elevated levels in the serum at the time of PPB diagnosis, with a significant majority noted be derived from the -3p strand (P=0.013). In addition, we identified a subset of 10 serum microRNAs (namely miR-125a-3p, miR-125b-2-3p, miR-380-5p, miR-125b-1-3p, let-7f-2-3p, let-7a-3p, let-7b-3p, miR-708-3p, miR-138-1-3p and miR-532-3p) that were most abundant in the PPB case. Serum levels of two representative microRNAs, miR-125a-3p and miR-125b-2-3p, were not elevated in DICER1 germline-mutated relatives. In the PPB case, serum levels of miR-125a-3p and miR-125b-2-3p increased before chemotherapy, and then showed an early reduction following treatment. These microRNAs may offer future utility as serum biomarkers for screening patients with known germline DICER1 mutations for early detection of PPB, and for potential disease-monitoring in cases with confirmed PPB.
DICER1 是成熟 microRNA 生物发生的关键基因，microRNA 是源自 -3p 或 -5p 前体 microRNA 链的短非编码 RNA。DICER1 的种系突变与一系列人类恶性肿瘤有关，包括肺胸膜胚细胞瘤（PPB）。在癌症中还报道了 DICER1 中 microRNA 加工核糖核酸酶 IIIb（RNase IIIb）结构域的其他体细胞“热点”突变，这些突变影响 microRNA 的生物发生，导致 -3p 成熟 microRNA 链偏向。在这里，在一个种系（exon11 c.1806_1810insATTGA）DICER1 突变的 PPB 中，我们首先通过常规测序证实存在另一个体细胞 RNase IIIb 热点突变（exon25 c.5425G>A [p.G1809R]）。其次，我们在 PPB 诊断时调查了成熟 microRNA 的血清水平，并将结果与来自广泛儿科癌症患者和对照者（n=52）的血清结果进行了比较。我们确定了一组在 PPB 诊断时血清中升高的 45 种 microRNAs，其中绝大多数来自 -3p 链（P=0.013）。此外，我们还确定了一组 10 种血清 microRNAs（即 miR-125a-3p、miR-125b-2-3p、miR-380-5p、miR-125b-1-3p、let-7f-2-3p、let-7a-3p、let-7b-3p、miR-708-3p、miR-138-1-3p 和 miR-532-3p）在 PPB 病例中最为丰富。DICER1 种系突变亲属的血清中两种代表性 microRNAs，miR-125a-3p 和 miR-125b-2-3p 的水平没有升高。在 PPB 病例中，miR-125a-3p 和 miR-125b-2-3p 的血清水平在化疗前升高，然后在治疗后早期降低。这些 microRNAs 可能作为血清生物标志物，用于筛选已知 DICER1 种系突变的患者，以早期发现 PPB，并在确诊为 PPB 的病例中进行潜在的疾病监测。
