Department of Dermatology,University Hospital Essen, West German Cancer Center, University Duisburg-Essen, Essen and the German Cancer Consortium (KGG, BS, EL, TS, IM, MS, AS, UH, LZ, DS), Germany; Department of Pathology and Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY (RM); CIBER Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain (JAPB, MP, CC, CB, JM, SP); Department of Dermatology, Hospital Clinic Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain (CC, JM, SP); Biochemistry and Molecular Genetics Department, Hospital Clinic Barcelona, IDIBAPS, Barcelona, Spain (CB); Integriertes Forschungs- und Behandlungszentrum (IFB) Sepsis und Sepsisfolgen Center for Sepsis Control and Care (CSCC) University Hospital Jena, Jena, Germany (AS).
J Natl Cancer Inst. 2014 Sep 13;106(9). doi: 10.1093/jnci/dju246. Print 2014 Sep.
Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics.
410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed.
TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006).
UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis.
最近，在皮肤黑色素瘤肿瘤样本和细胞系中发现 TERT 启动子突变高频出现。这些突变具有 UV 特征，并且导致 TERT 基因表达增加。我们分析了一大群黑色素瘤患者，以确定 TERT 启动子突变的存在和分布及其与临床病理特征的关联。
通过 Sanger 测序分析 410 个黑色素瘤肿瘤样本，以确定 TERT 启动子突变的存在。分析突变状态与各种临床和病理变量之间的关联。
在 362 个成功测序的黑色素瘤中，有 154 个（43%）发现了 TERT 启动子突变。突变频率因黑色素瘤亚型而异，非肢端皮肤黑色素瘤（48%）和隐匿性原发性黑色素瘤（50%）的突变频率最高，黏膜（23%）和肢端（19%）黑色素瘤的突变频率较低。突变具有 UV 特征（C>T 或 CC>TT）。TERT 启动子突变与 BRAF 或 NRAS 突变（P <.001）、组织学类型（P =.002）和 Breslow 厚度（P <.001）等因素有关。在非肢端皮肤黑色素瘤患者中，TERT 启动子突变与总生存较差独立相关（中位生存 80 个月与野生型相比为 291 个月；校正其他协变量的风险比为 2.47；95%置信区间[CI]为 1.29 至 4.74；P =.006）。
UV 诱导的 TERT 启动子突变是黑色素瘤中最常见的遗传改变之一，其频率因黑色素瘤亚型而异。在非肢端皮肤黑色素瘤中，TERT 启动子突变的存在与不良预后独立相关。
