Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
Nature. 2020 Aug;584(7819):130-135. doi: 10.1038/s41586-020-2426-2. Epub 2020 Jun 24.
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. 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.
肿瘤发生和衰老的生物学在多大程度上受到区分人群的因素的影响尚不清楚。随着年龄的增长，获得性突变的造血克隆变得常见，并可能导致血液癌。在这里，我们根据我们在日本生物银行队列的 179417 名参与者中检测到的 33250 个常染色体镶嵌染色体改变，描述了造血细胞中共享和人群特异性的基因组突变和克隆选择模式，并将其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，超过 35.0%（s.e.m.，1.4%）的 90 岁以上个体中检测到镶嵌染色体改变，这表明随着年龄的增长，此类克隆有必然趋势。日本和欧洲个体在其各自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（在欧洲个体中更为常见）和 T 细胞白血病（在日本个体中更为常见）的相对发生率。慢性淋巴细胞白血病的三个不同突变前体（包括 12 号三体、13q 和 13q 缺失以及杂合性丢失的拷贝中性）在日本个体中分别少 2 到 6 倍，这表明在临床上明显的慢性淋巴细胞白血病发展之前，日本和欧洲人群在克隆的选择压力上存在差异。日本和英国人群也表现出来自 B 和 T 细胞谱系的克隆的非常不同的发生率，这预测了这些人群中 B 和 T 细胞癌的相对发生率。我们确定了六个以前未描述的位点，其中遗传变异易导致重复或消除遗传风险等位基因的镶嵌染色体改变，包括 NBN、MRE11 和 CTU2 中的大效应罕见变异（比值比，28-91）。我们认为，克隆选择的选择压力受特定于人群的因素调节。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特征分析。
