Evolutionary Theory Group, Max Planck Institute for Evolutionary Biology, Plön, Germany.
J R Soc Interface. 2013 Jun 5;10(85):20130349. doi: 10.1098/rsif.2013.0349. Print 2013 Aug 6.
Cancers are rarely caused by single mutations, but often develop as a result of the combined effects of multiple mutations. For most cells, the number of possible cell divisions is limited because of various biological constraints, such as progressive telomere shortening, cell senescence cascades or a hierarchically organized tissue structure. Thus, the risk of accumulating cells carrying multiple mutations is low. Nonetheless, many diseases are based on the accumulation of such multiple mutations. We model a general, hierarchically organized tissue by a multi-compartment approach, allowing any number of mutations within a cell. We derive closed solutions for the deterministic clonal dynamics and the reproductive capacity of single clones. Our results hold for the average dynamics in a hierarchical tissue characterized by an arbitrary combination of proliferation parameters. We show that hierarchically organized tissues strongly suppress cells carrying multiple mutations and derive closed solutions for the expected size and diversity of clonal populations founded by a single mutant within the hierarchy. We discuss the example of childhood acute lymphoblastic leukaemia in detail and find good agreement between our predicted results and recently observed clonal diversities in patients. This result can contribute to the explanation of very diverse mutation profiles observed by whole genome sequencing of many different cancers.
癌症很少由单个突变引起，但通常是多个突变共同作用的结果。对于大多数细胞来说，由于各种生物学限制，如端粒逐渐缩短、细胞衰老级联或分层组织结构，其可能的细胞分裂次数是有限的。因此，积累携带多个突变的细胞的风险很低。尽管如此，许多疾病还是基于这种多个突变的积累。我们通过多腔室方法对一般的分层组织进行建模，允许一个细胞内存在任意数量的突变。我们推导出了确定性克隆动力学和单克隆繁殖能力的封闭解。我们的结果适用于具有任意增殖参数组合的分层组织的平均动力学。我们表明，分层组织强烈抑制携带多个突变的细胞，并推导出由单个突变在层次结构中建立的克隆群体的预期大小和多样性的封闭解。我们详细讨论了儿童急性淋巴细胞白血病的例子，并发现我们的预测结果与最近在患者中观察到的克隆多样性之间存在很好的一致性。这一结果有助于解释对许多不同癌症进行全基因组测序时观察到的非常多样的突变谱。
