期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32986-7
关键词
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资金
- intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute
- National Institutes of Health
- Federal funds from the National Cancer Institute, National Institutes of Health, under NCI [75N910D00024]
- Public Health Service from the National Cancer Institute (NCI) [U24CA076518]
- National Heart, Lung and Blood Institute (NHLBI) [U24CA076518]
- National Institute of Allergy and Infectious Diseases (NIAID) [U24CA076518]
- Health Resources and Services Administration (HRSA) [HHSH250201700006C]
- Office of Naval Research [N00014-20-1-2705, N00014-20-1-2832]
- Be the Match Foundation, the Medical College of Wisconsin, the National Marrow Donor Program
- Welsh Assembly Government
- British Heart Foundation
- Diabetes UK
The study identified 6 germline susceptibility loci and high frequencies of mosaic chromosomal alterations (mCAs) in myelofibrosis cases. The mCAs involving JAK2 were found to be strong promoters of clonal expansion in mutated clones of myelofibrosis cases.
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(V617F) mutations, demonstrating with long-read sequencing that this relationship occurs in cis. We also describe recurrent 9p24.1 large mCAs that selectively retained JAK2(V617F) 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. Myelofibrosis is a risk factor for the development of Acute Myeloid Leukaemia. Here, the authors carry out an integrated genomic investigation of 933 myelofibrosis patients, and identified interactions between germline and somatic variation in patients who required haematopoietic cell transplantation.
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