Harland Mark, Petljak Mia, Robles-Espinoza Carla Daniela, Ding Zhihao, Gruis Nelleke A, van Doorn Remco, Pooley Karen A, Dunning Alison M, Aoude Lauren G, Wadt Karin A W, Gerdes Anne-Marie, Brown Kevin M, Hayward Nicholas K, Newton-Bishop Julia A, Adams David J, Bishop D Timothy
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK.
Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
Fam Cancer. 2016 Jan;15(1):139-44. doi: 10.1007/s10689-015-9841-9.
Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP, POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.-57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.-57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.-57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.
种系CDKN2A突变出现在40%的有3例或更多病例的黑色素瘤家族中，而CDK4、BAP1以及参与端粒功能的基因（ACD、TERF2IP、POT1）的突变也与黑色素瘤的发生有关。在一个家族中报道了端粒酶逆转录酶（TERT）基因启动子的突变（c.-57 T>G变异）。我们在675个已知高外显率家族性黑色素瘤基因野生型的多病例家族、1863例英国人群来源的黑色素瘤病例和529例对照中检测了TERT启动子变异。对携带者的种系淋巴细胞端粒长度进行了估计。在一个有7例病例的家族中发现了c.-57 T>G TERT启动子变异，该家族有多个原发性肿瘤且发病年龄较早（最早为15岁），但在人群病例或对照中未发现。一名家族成员患有多发性原发性黑色素瘤、基底细胞癌和膀胱肿瘤。一名携带者的血液白细胞端粒长度与野生型病例相似。我们提供的证据证实，TERT的一种罕见启动子变异（c.-57 T>G）与高外显率、早发性黑色素瘤以及可能的其他癌症有关，且在英国黑色素瘤多病例家族中所占比例不到1%。POT1和TERT种系突变的鉴定突出了端粒完整性在黑色素瘤生物学中的重要性。
