PDF(Pubmed)
Abstract：
Somatic frameshift mutations in exon 9 of calreticulin (CALR) gene are recognized as disease drivers in primary myelofibrosis (PMF), one of the three classical Philadelphia-negative myeloproliferative neoplasms (MPNs). Type 1/type 1-like CALR mutations particularly confer a favorable prognostic and survival advantage in PMF patients. We report an unusual case of PMF incidentally diagnosed in a 68-year-old woman known with hepatitis C virus (HCV) cirrhosis who developed a progressive painful splenomegaly, without anomalies in blood cell counts. While harboring a type 1 CALR mutation, the patient underwent a leukemic transformation in less than 1 year from diagnosis, with a lethal outcome. Analysis of paired DNA samples from chronic and leukemic phases by a targeted next-generation sequencing (NGS) panel and single-nucleotide polymorphism (SNP) microarray revealed that the leukemic clone developed from the CALR-mutated clone through the acquisition of genetic events in the RAS signaling pathway: an increased variant allele frequency of the germline NRAS Y64D mutation present in the chronic phase (via an acquired uniparental disomy of chromosome 1) and gaining NRAS G12D in the blast phase. SNP microarray analysis showed five clinically significant copy number losses at regions 7q22.1, 8q11.1-q11.21, 10p12.1-p11.22, 11p14.1-p11.2, and Xp11.4, revealing a complex karyotype already in the chronic phase. We discuss how additional mutations, detected by NGS, as well as HCV infection and antiviral therapy, might have negatively impacted this type 1 CALR-mutated PMF. We suggest that larger studies are required to determine if more careful monitoring would be needed in MPN patients also carrying HCV and receiving anti-HCV treatment.
摘要：
钙网蛋白（CALR）基因外显子9的体细胞移码突变被认为是原发性骨髓纤维化（PMF）的疾病驱动因素，三个经典的费城阴性骨髓增殖性肿瘤（MPN）之一。1型/1型样CALR突变特别赋予PMF患者良好的预后和生存优势。我们报告了一个不寻常的PMF病例，该病例是一名68岁的女性，患有丙型肝炎病毒（HCV）肝硬化，患有进行性疼痛性脾肿大，血细胞计数无异常.虽然有1型CALR突变，患者在诊断后不到1年内经历了白血病转化，有致命的结果。通过靶向下一代测序（NGS）小组和单核苷酸多态性（SNP）微阵列分析来自慢性期和白血病期的配对DNA样品，表明白血病克隆是通过获得遗传事件而从CALR突变的克隆中发展而来的。RAS信号通路：慢性期（通过1号染色体的获得性亲本单染色体）中存在的种系NRASY64D突变的变异等位基因频率增加，并在NRAS胚期获得。SNP微阵列分析显示在7q22.1、8q11.1-q11.21、10p12.1-p11.22、11p14.1-p11.2和Xp11.4区域有5个临床上显著的拷贝数损失,揭示了已经处于慢性期的复杂核型。我们讨论了额外的突变，由NGS检测，以及HCV感染和抗病毒治疗，可能对这种1型CALR突变的PMF产生了负面影响。我们建议需要进行更大规模的研究，以确定是否需要在同时携带HCV并接受抗HCV治疗的MPN患者中进行更仔细的监测。
