| Title: | Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis |
| Journal: | Nature Communications |
| Published: | 8 Sep 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36075929/ |
| DOI: | https://doi.org/10.1038/s41467-022-32986-7 |
| URL: | https://www.nature.com/articles/s41467-022-32986-7.pdf |
Publication 10459
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Abstract
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 JAK2V617F mutations, demonstrating with long-read sequencing that this relationship occurs in cis. We also describe recurrent 9p24.1 large mCAs that selectively retained JAK2V617F 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.</p>
31 Authors
- Derek W. Brown
- Weiyin Zhou
- Youjin Wang
- Kristine Jones
- Wen Luo
- Casey Dagnall
- Kedest Teshome
- Alyssa Klein
- Tongwu Zhang
- Shu-Hong Lin
- Olivia W. Lee
- Sairah Khan
- Jacqueline B. Vo
- Amy Hutchinson
- Jia Liu
- Jiahui Wang
- Bin Zhu
- Belynda Hicks
- Andrew St. Martin
- Stephen R. Spellman
- Tao Wang
- H. Joachim Deeg
- Vikas Gupta
- Stephanie J. Lee
- Neal D. Freedman
- Meredith Yeager
- Stephen J. Chanock
- Sharon A. Savage
- Wael Saber
- Shahinaz M. Gadalla
- Mitchell J. Machiela
1 Application
| Application ID | Title |
|---|---|
| 21552 | Detection of large-scale copy-number and copy-neutral mosaic alterations in circulating leukocyte DNA of UK Biobank cancer cases and cancer-free controls |
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