Department for Stem Cell Transplantation, University of Hamburg, Hamburg, Germany.
Br J Haematol. 2012 Jan;156(1):67-75. doi: 10.1111/j.1365-2141.2011.08911.x. Epub 2011 Oct 24.
TET2 mutations have been identified in 10-25% of patients with myeloid malignancies, but TET2 gene copy number alterations remain to be evaluated. We performed interphase and metaphase fluorescence in situ hybridization (FISH), using newly designed probes that span TET2, in 893 patients with acute myeloid leukaemia (AML) and chronic myeloid malignancies and validated the new assay by single nucleotide polymorphism arrays. Next-generation sequencing for molecular TET2 mutations was performed in 37/50 del(TET2) patients. We identified TET2 deletions in 50/893 patients (26 males, 24 females; 44-87 years) resulting in a 5.6% frequency [22/425 AML (5.2%), 15/217 chronic myelomonocytic leukaemia (CMML; 6.9%), 9/188 myelodysplastic syndromes (4.8%), 4/63 myeloproliferative neoplasms (6.3%)]. Cytogenetic alterations (mostly complex) were detected in 35/50 (70.0%) of del(TET2) cases. TET2 deletions were cytogenetically cryptic in 25/50 (50.0%). Sequencing detected TET2mut in 19/37 (51.4%) del(TET2) cases investigated, predominantly CMML (10/14; 71.4%). In de novo AML with intermediate cytogenetics, presence of any TET2 alteration was related to worse median overall survival (347 d vs. not reached; P = 0.052) and event-free survival (164 vs. 457 d; P = 0.024). JAK2(V617F) was found in 6/18 (33.3%) del(TET2) cases analysed. Thus, TET2 haploinsufficiency recurrently occurs in myeloid malignancies, frequently combined with TET2 mutations on the remaining allele. The prognostic impact of del(TET2) in myeloid malignancies should be further evaluated.
TET2 基因突变在 10-25%的髓系恶性肿瘤患者中被发现，但 TET2 基因拷贝数改变仍有待评估。我们使用新设计的跨越 TET2 的探针进行了 893 例急性髓系白血病 (AML) 和慢性髓系恶性肿瘤患者的间期和中期荧光原位杂交 (FISH)，并通过单核苷酸多态性微阵列验证了新的检测方法。对 50/893 例患者 (26 名男性，24 名女性；年龄 44-87 岁) 进行了分子 TET2 突变的下一代测序。我们发现 50/893 例患者 (26 名男性，24 名女性；年龄 44-87 岁) 存在 TET2 缺失，频率为 5.6%[22/425 AML (5.2%)、15/217 慢性髓单核细胞白血病 (CMML；6.9%)、9/188 骨髓增生异常综合征 (4.8%)、4/63 骨髓增生性肿瘤 (6.3%)]。35/50 (70.0%) 的 del(TET2) 病例检测到细胞遗传学改变(主要是复杂的)。25/50 (50.0%) 的 del(TET2) 病例中的 TET2 缺失在细胞遗传学上是隐匿的。对 37 例 (51.4%) 经测序检测的 del(TET2) 病例进行了 TET2mut 检测，主要是 CMML(10/14；71.4%)。在伴有中等细胞遗传学的初发性 AML 中，任何 TET2 改变的存在与中位总生存期 (347 天 vs. 未达到；P = 0.052) 和无事件生存期 (164 天 vs. 457 天；P = 0.024) 较差相关。在分析的 18 例 del(TET2) 病例中，有 6 例 (33.3%) 存在 JAK2(V617F)。因此，TET2 单倍体不足在髓系恶性肿瘤中频繁发生，常伴有剩余等位基因上的 TET2 突变。del(TET2) 在髓系恶性肿瘤中的预后影响需要进一步评估。
