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科学家从系统发育学中推断出骨髓增生性肿瘤的发展史
2022-01-23 23:36

英国威康桑格研究所Jyoti Nangalia课题组从系统发育学中推断出骨髓增生性肿瘤的发展史。相关论文于2022年1月20日在线发表在《自然》杂志上。

研究人员利用12名骨髓增生性肿瘤患者的1,013个克隆造血细胞群的全基因组测序,确定了580,133个体细胞突变,用于重建造血系统发育并确定克隆历史。据估计,驱动性突变发生在生命的早期,包括子宫内的时期。JAK2V617F被估计为在5名患者中从妊娠33周到10.8岁时获得,其中JAK2V617F是第一个事件。在4名患者中,DNMT3A突变是在怀孕8周至7.6岁时获得的,而PPM1D突变是在5.8岁时获得的。其他的基因组事件发生在获得JAK2V617F之前或之后,并作为独立的克隆扩展。
 
连续驱动基因突变的获得在整个生命过程中被隔开了几十年,往往是与祖先的克隆相竞争。JAK2V617F的获得和诊断之间的平均潜伏期是30年(范围是11-54年)。估计的历史上的克隆扩展率有很大的不同(每年3%到190%),随着额外的驱动基因突变而增加,并预测了诊断的潜伏期。这项研究表明,早期驱动基因突变的获得和终生的生长和演变是成人骨髓增生性肿瘤的基础,这为早期干预和癌症发展的新模式提供了机会。
 
据了解,癌症相关基因的突变驱动着肿瘤的生长,但人们对驱动突变的时间和随后克隆动态的了解是有限的。
 
附:英文原文
 
Title: Life histories of myeloproliferative neoplasms inferred from phylogenies

Author: Williams, Nicholas, Lee, Joe, Mitchell, Emily, Moore, Luiza, Baxter, E. Joanna, Hewinson, James, Dawson, Kevin J., Menzies, Andrew, Godfrey, Anna L., Green, Anthony R., Campbell, Peter J., Nangalia, Jyoti

Issue&Volume: 2022-01-20

Abstract: Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1,2,3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F acquisition and diagnosis was 30 years (range 11–54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.

DOI: 10.1038/s41586-021-04312-6

Source: https://www.nature.com/articles/s41586-021-04312-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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