Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7429-33. doi: 10.1073/pnas.1221099110. Epub 2013 Apr 8.
Acute lymphoblastic leukemia (ALL) is the major pediatric cancer. At diagnosis, the developmental timing of mutations contributing critically to clonal diversification and selection can be buried in the leukemia's covert natural history. Concordance of ALL in monozygotic, monochorionic twins is a consequence of intraplacental spread of an initiated preleukemic clone. Studying monozygotic twins with ALL provides a unique means of uncovering the timeline of mutations contributing to clonal evolution, pre- and postnatally. We sequenced the whole genomes of leukemic cells from two twin pairs with ALL to comprehensively characterize acquired somatic mutations in ALL, elucidating the developmental timing of all genetic lesions. Shared, prenatal, coding-region single-nucleotide variants were limited to the putative initiating lesions. All other nonsynonymous single-nucleotide variants were distinct between tumors and, therefore, secondary and postnatal. These changes occurred in a background of noncoding mutational changes that were almost entirely discordant in twin pairs and likely passenger mutations acquired during leukemic cell proliferation.
急性淋巴细胞白血病（ALL）是主要的儿科癌症。在诊断时，对克隆多样化和选择有重要贡献的突变的发育时间可能隐藏在白血病的隐蔽自然史中。同卵双胞胎的 ALL 一致性是受胎盘内起始前白血病克隆传播的结果。研究 ALL 的同卵双胞胎提供了一种独特的方法，可以揭示导致克隆进化的突变的时间线，包括产前和产后。我们对两对 ALL 双胞胎的白血病细胞进行了全基因组测序，全面描述了 ALL 中获得的体细胞突变，阐明了所有遗传病变的发育时间。共享的、产前的、编码区单核苷酸变异仅限于假定的起始病变。所有其他非同义单核苷酸变异在肿瘤之间是不同的，因此是继发的和产后的。这些变化发生在非编码突变变化的背景下，在双胞胎中几乎完全不一致，并且可能是在白血病细胞增殖过程中获得的乘客突变。
