Chromosomal alterations among age-related haematopoietic clones in Japan
Chromosomal alterations among age-related haematopoietic clones in Japan
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DOI：
10.1038/s41586-020-2426-2
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发表时间：
2020-06-24
期刊：
影响因子：
64.8
通讯作者：
Kamatani, Yoichiro
中科院分区：
文献类型：
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作者：
Terao, Chikashi;Suzuki, Akari;Kamatani, Yoichiro
肿瘤发生和衰老的生物学在多大程度上受到区分人类群体的因素的影响尚不清楚。随着年龄的增长，具有获得性突变的造血克隆变得常见，并可能导致血液癌症（1-10）。在这里，我们描述了造血细胞中基因组突变和克隆选择的共享和群体特异性模式，基于我们在BioBank Japan队列中检测到的179，417名日本参与者中的33，250个常染色体嵌合体染色体变异，并与英国生物银行的类似数据进行了比较。在这个长寿的日本人群中，在超过35.0%的人群中检测到嵌合体染色体变异（s.e.m.，1.4%）的人年龄超过90岁，这表明这种克隆的趋势是不可避免的随着年龄的增长。日本人和欧洲人在各自的造血克隆中突变的基因组位置表现出关键差异;这些差异预测了这些人群中慢性淋巴细胞白血病（在欧洲人中更常见）和T细胞白血病（在日本人中更常见）的相对发病率。慢性淋巴细胞白血病的三种不同的突变前体（包括12三体，染色体13 q和13 q的丢失，以及拷贝中性杂合性丢失）在日本人中的发生率低2 - 6倍，这表明日本人和欧洲人早在临床上明显的慢性淋巴细胞白血病发展之前就对克隆的选择压力不同。日本和英国人群也表现出非常不同的来自B和T细胞谱系的克隆率，这预测了这些人群中B和T细胞癌症的相对发病率。我们确定了6个以前未描述的基因座，在这些基因座上遗传变异易发生嵌合染色体改变，这些改变复制或去除了遗传风险等位基因，包括NBN、MRE 11和CTU 2的大效应罕见变异（比值比，28-91）。我们认为，克隆的选择压力是由特定于人类群体的因素调制的。因此，有必要对来自世界各地的人群中的克隆选择和癌症进行进一步的基因组表征。日本和欧洲参与者的基因组突变和造血克隆选择的人群特异性模式预测了这些人群中慢性淋巴细胞白血病和T细胞白血病的不同发病率。
The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with advancing age and can lead to blood cancers(1-10). Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal mosaic chromosomal alterations that we detected in 179,417 Japanese participants in the BioBank Japan cohort and compared with analogous data from the UK Biobank. In this long-lived Japanese population, mosaic chromosomal alterations were detected in more than 35.0% (s.e.m., 1.4%) of individuals older than 90 years, which suggests that such clones trend towards inevitability with advancing age. Japanese and European individuals exhibited key differences in the genomic locations of mutations in their respective haematopoietic clones; these differences predicted the relative rates of chronic lymphocytic leukaemia (which is more common among European individuals) and T cell leukaemia (which is more common among Japanese individuals) in these populations. Three different mutational precursors of chronic lymphocytic leukaemia (including trisomy 12, loss of chromosomes 13q and 13q, and copy-neutral loss of heterozygosity) were between two and six times less common among Japanese individuals, which suggests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent chronic lymphocytic leukaemia. Japanese and British populations also exhibited very different rates of clones that arose from B and T cell lineages, which predicted the relative rates of B and T cell cancers in these populations. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN, MRE11 and CTU2 (odds ratio, 28-91). We suggest that selective pressures on clones are modulated by factors that are specific to human populations. Further genomic characterization of clonal selection and cancer in populations from around the world is therefore warranted. Population-specific patterns of genomic mutations and selection of haematopoietic clones in Japanese and European participants predict the divergent rates of chronic lymphocytic leukaemia and T cell leukaemia in these populations.