Center for Molecular Medicine, Austrian Academy of Sciences, Lazarettgasse 14, AKH BT25.3, 1090 Vienna, Austria.
Haematologica. 2011 Mar;96(3):367-74. doi: 10.3324/haematol.2010.034488. Epub 2010 Dec 20.
Myeloproliferative neoplasms constitute a group of diverse chronic myeloid malignancies that share pathogenic features such as acquired mutations in the JAK2, TET2, CBL and MPL genes. There are recent reports that a JAK2 gene haplotype (GGCC or 46/1) confers susceptibility to JAK2 mutation-positive myeloproliferative neoplasms. The aim of this study was to examine the role of the JAK2 GGCC haplotype and germline mutations of TET2, CBL and MPL in familial myeloproliferative neoplasms.
We investigated patients with familial (n=88) or sporadic (n=684) myeloproliferative neoplasms, and a control population (n=203) from the same demographic area in Italy. Association analysis was performed using tagged single nucleotide polymorphisms (rs10974944 and rs12343867) of the JAK2 haplotype. Sequence analysis of TET2, CBL and MPL was conducted in the 88 patients with familial myeloproliferative neoplasms.
Association analysis revealed no difference in haplotype frequency between familial and sporadic cases of myeloproliferative neoplasms (P=0.6529). No germline mutations in TET2, CBL or MPL that segregate with the disease phenotype were identified. As we observed variability in somatic mutations in the affected members of a pedigree with myeloproliferative neoplasms, we postulated that somatic mutagenesis is increased in familial myeloproliferative neoplasms. Accordingly, we compared the incidence of malignant disorders between sporadic and familial patients. Although the overall incidence of malignant disorders did not differ significantly between cases of familial and sporadic myeloproliferative neoplasms, malignancies were more frequent in patients with familial disease aged between 50 to 70 years (P=0.0198) than in patients in the same age range with sporadic myeloproliferative neoplasms.
We conclude that the JAK2 GGCC haplotype and germline mutations of TET2, CBL or MPL do not explain familial clustering of myeloproliferative neoplasms. As we observed an increased frequency of malignant disorders in patients with familial myeloproliferative neoplasms, we hypothesize that the germline genetic lesions that underlie familial clustering of myeloproliferative neoplasms predispose to somatic mutagenesis that is not restricted to myeloid hematopoietic cells but cause an increase in overall carcinogenesis.
骨髓增殖性肿瘤构成了一组不同的慢性骨髓恶性肿瘤，它们具有获得性 JAK2、TET2、CBL 和 MPL 基因突变等致病特征。最近有报道称，JAK2 基因单倍型（GGCC 或 46/1）易患 JAK2 突变阳性骨髓增殖性肿瘤。本研究旨在探讨 JAK2 GGCC 单倍型和 TET2、CBL 和 MPL 种系突变在家族性骨髓增殖性肿瘤中的作用。
我们研究了来自意大利同一地区的家族性（n=88）或散发性（n=684）骨髓增殖性肿瘤患者，以及对照组（n=203）。使用 JAK2 单倍型的标记单核苷酸多态性（rs10974944 和 rs12343867）进行关联分析。对 88 例家族性骨髓增殖性肿瘤患者进行 TET2、CBL 和 MPL 序列分析。
关联分析显示家族性和散发性骨髓增殖性肿瘤病例的单倍型频率无差异（P=0.6529）。未发现与疾病表型分离的 TET2、CBL 或 MPL 种系突变。由于我们观察到一个家族性骨髓增殖性肿瘤家系中受影响成员的体细胞突变存在变异性，我们假设家族性骨髓增殖性肿瘤中的体细胞突变增加。因此，我们比较了散发性和家族性患者恶性疾病的发病率。尽管家族性和散发性骨髓增殖性肿瘤病例的恶性疾病总发病率无显著差异，但 50 至 70 岁家族性疾病患者的恶性疾病更为常见（P=0.0198），而年龄相同的散发性骨髓增殖性肿瘤患者则不常见。
我们得出结论，JAK2 GGCC 单倍型和 TET2、CBL 或 MPL 的种系突变不能解释骨髓增殖性肿瘤的家族聚集。由于我们观察到家族性骨髓增殖性肿瘤患者恶性疾病的频率增加，我们假设导致骨髓增殖性肿瘤家族聚集的种系遗传病变易导致体细胞突变，这种突变不仅限于骨髓造血细胞，而且导致整体致癌作用增加。
