Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.
Nat Commun. 2022 Sep 8;13(1):5284. doi: 10.1038/s41467-022-32986-7.
Myelofibrosis is a rare myeloproliferative neoplasm (MPN) with high risk for progression to acute myeloid leukemia. Our integrated genomic analysis of up to 933 myelofibrosis cases identifies 6 germline susceptibility loci, 4 of which overlap with previously identified MPN loci. Virtual karyotyping identifies high frequencies of mosaic chromosomal alterations (mCAs), with enrichment at myelofibrosis GWAS susceptibility loci and recurrently somatically mutated MPN genes (e.g., JAK2). We replicate prior MPN associations showing germline variation at the 9p24.1 risk haplotype confers elevated risk of acquiring JAK2 mutations, demonstrating with long-read sequencing that this relationship occurs in cis. We also describe recurrent 9p24.1 large mCAs that selectively retained JAK2 mutations. Germline variation associated with longer telomeres is associated with increased myelofibrosis risk. Myelofibrosis cases with high-frequency JAK2 mCAs have marked reductions in measured telomere length - suggesting a relationship between telomere biology and myelofibrosis clonal expansion. Our results advance understanding of the germline-somatic interaction at JAK2 and implicate mCAs involving JAK2 as strong promoters of clonal expansion of those mutated clones.
骨髓纤维化是一种罕见的骨髓增生性肿瘤（MPN），有向急性髓系白血病进展的高风险。我们对多达 933 例骨髓纤维化病例的综合基因组分析确定了 6 个种系易感性位点，其中 4 个与先前确定的 MPN 位点重叠。虚拟核型分析确定了镶嵌染色体改变（mCAs）的高频率，在骨髓纤维化 GWAS 易感性位点和反复体细胞突变的 MPN 基因（例如 JAK2）处富集。我们复制了先前的 MPN 关联，表明 9p24.1 风险单倍型的种系变异赋予了获得 JAK2 突变的风险升高，通过长读测序证明这种关系发生在顺式。我们还描述了复发性 9p24.1 大型 mCAs，选择性保留了 JAK2 突变。与较长端粒相关的种系变异与骨髓纤维化风险增加相关。具有高频 JAK2 mCAs 的骨髓纤维化病例的端粒长度明显缩短-表明端粒生物学与骨髓纤维化克隆扩张之间存在关系。我们的研究结果加深了对 JAK2 种系-体细胞相互作用的理解，并暗示涉及 JAK2 的 mCAs 是那些突变克隆克隆扩张的强有力促进剂。
