Concomitant and noncanonical JAK2 and MPL mutations in JAK2V617F-and MPLW515 L-positive myelofibrosis
Concomitant and noncanonical JAK2 and MPL mutations in JAK2V617F-and MPLW515 L-positive myelofibrosis
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DOI：
10.1002/gcc.22781
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发表时间：
2019-11-01
影响因子：
3.7
通讯作者：
Al-Ali, Haifa Kathrin
中科院分区：
文献类型：
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作者：
Schulze, Susann;Stengel, Rayk;Al-Ali, Haifa Kathrin
建议在骨髓增生性肿瘤患者中对JAK 2（外显子14）、CALR（外显子9）和MPL（外显子10）中的表型驱动突变进行顺序基因分型。然而，在一些三阴性患者中描述了非典型JAK 2和MPLS突变。无论表型驱动突变是否存在，骨髓纤维化（MF）中是否存在非典型和/或伴随的JAK 2和MPLS突变尚未阐明。为此，使用来自128名MF患者（原发性MF，n = 93;后ET-MF，n = 18;后PV-MF，n = 17）的血液基因组DNA进行下一代测序（NGS）。虽然在24例CALR阳性样本中未观察到非典型JAK 2或MPLS突变，但在21例三阴性患者中的2例（9.5%）中检测到两种JAK 2突变[c.3323A > G，p.N1108S; c.3188G > A，p.R1063H]。82例JAK 2 V617 F阳性病例中有12例（14.6%）存在共存的生殖系JAK 2突变[JAK 2 R1063 H，n = 6; JAK 2 R893 T，n = 1; JAK 2 T525 A，n = 1]或至少一种体细胞MPLS突变[MPLY 591 D，n = 3; MPLW 515 L，n = 2; MPLE 335 K，n = 1]。总体而言，MPLS突变总是与JAK 2 V617 F和/或其他MPLS突变共存。JAK 2 V617 F加第二个JAK 2突变均不携带TET 2突变，但所有JAK 2 V617 F加MPLS突变的患者均携带体细胞TET 2突变。在JAK 2 V617 F阳性组群中可以鉴定出四个基因组簇。与第四簇（5%）（TET 2（mut）+ MPLmut）相比，第一簇（10%）（非典型JAK 2（突变（mut））+TET 2（野生型（wt）更年轻，增殖性疾病更少。总之，在15.7%的JAK 2 V617 F和MPLW 515阳性MF患者中，NGS可检测到复发性伴随经典和/或非经典JAK 2和MPLW突变，且基因型-表型相关。许多生殖系和/或体细胞突变可能作为“显著突变基因”，导致发病机制和表型异质性。一个具有成本效益的基于NGS的方法可能是实现患者定制医疗的重要一步。
Sequential genotyping for phenotype-driver mutations in JAK2 (exon 14), CALR (exon 9), and MPL (exon 10) is recommended in patients with myeloproliferative neoplasms. Yet, atypical JAK2- and MPL-mutations were described in some triple-negative patients. Whether noncanonical and/or concomitant JAK2- and MPL-mutations exist in myelofibrosis (MF) regardless of phenotype-driver mutations is not yet elucidated. For this, next-generation sequencing (NGS) was performed using blood genomic DNA from 128 MF patients (primary MF, n = 93; post-ET-MF, n = 18; post-PV-MF, n = 17). While no atypical JAK2- or MPL-mutations were seen in 24 CALR-positive samples, two JAK2-mutations [c.3323A > G, p.N1108S; c.3188G > A, p.R1063H] were detected in two of the 21 (9.5%) triple-negative patients. Twelve of the 82 (14.6%) JAK2V617F-positive cases had coexisting germline JAK2-mutations [JAK2R1063H, n = 6; JAK2R893T, n = 1; JAK2T525A, n = 1] or at least one somatic MPL-mutation [MPLY591D, n = 3; MPLW515 L, n = 2; MPLE335K, n = 1]. Overall, MPL-mutations always coexisted with JAK2V617F and/or other MPL-mutations. None of the JAK2V617F plus a second JAK2-mutation carried a TET2-mutation but all patients with JAK2V617F plus an MPL-mutation harbored a somatic TET2-mutation. Four genomic clusters could be identified in the JAK2V617F-positive cohort. Cluster-I (10%) (noncanonical JAK2(mutated (mut)) + TET2(wildtype (wt))) were younger and had less proliferative disease compared with cluster-IV (5%) (TET2(mut) + MPLmut). In conclusion, recurrent concomitant classical and/or noncanonical JAK2- and MPL-mutations could be detected by NGS in 15.7% of JAK2V617F- and MPLW515-positive MF patients with genotype-phenotype associations. Many of the germline and/or somatic mutations might act as "Significantly Mutated Genes" contributing to the pathogenesis and phenotypic heterogeneity. A cost-effective NGS-based approach might be an important step towards patient-tailored medicine.