Genetic progression and the waiting time to cancer.
Genetic progression and the waiting time to cancer.
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DOI：
10.1371/journal.pcbi.0030225
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发表时间：
2007-11
影响因子：
4.3
通讯作者：
Nowak, Martin A.
中科院分区：
文献类型：
--
作者：
Beerenwinkel, Niko;Antal, Tibor;Dingli, David;Traulsen, Arne;Kinzler, Kenneth W.;Velculescu, Victor E.;Vogelstein, Bert;Nowak, Martin A.
癌症是由扰乱细胞正常合作行为的基因改变引起的。最近对癌细胞的高通量基因组研究表明，癌症的突变景观是复杂的，个体癌症可能通过多达20种不同的癌症相关基因的突变而进化。我们利用Sjöblom等人（2006年）发表的数据，为结直肠癌的体细胞进化建立了一个新的数学模型。我们采用Wright-Fisher过程来探索这一进化过程的基本参数，并推导出癌症表型预期等待时间的分析近似。我们的结果强调了选择在风险细胞群大小和突变率上的相对重要性。该模型预测，如果每个突变的平均选择优势在1%左右，则在正常突变率下可以产生观察到的癌症基因组遗传多样性。由于遗传不稳定而增加的突变率将在肿瘤发生过程中允许更小的选择优势。癌症进展的复杂性可以理解为多个连续突变的结果，每一个突变对净细胞生长都有相对较小但积极的影响。癌症是一种多细胞生物的疾病，其特征是单个细胞之间的合作破裂。癌症的进展是通过一系列克隆扩增，从单个基因改变的细胞发展到数十亿个侵袭性细胞。在肿瘤发生过程中，癌细胞经历复制和突变，从而增加肿瘤的大小和侵袭性。最近的癌细胞测序项目表明，多达20种不同基因的突变可能是驱动单个肿瘤发展的原因。这种见解与大多数癌症进展的数学模型形成对比，这些模型假设癌症表型仅由少数基因突变驱动。我们提出了一个新的数学模型，其中肿瘤的发生是由许多基因的突变驱动的，其中大多数只赋予一个小的选择优势。具体地说，结肠良性肿瘤（腺瘤）向恶性肿瘤（癌）的进展可以用Wright-Fisher过程来描述，并且随着人群规模的增长。我们探索了与观测数据一致的模型的基本参数。我们也推导出了从良性肿瘤到恶性肿瘤进展的预期等待时间的分析公式，该公式考虑了群体大小、突变率、选择优势和易感基因的数量。
Cancer results from genetic alterations that disturb the normal cooperative behavior of cells. Recent high-throughput genomic studies of cancer cells have shown that the mutational landscape of cancer is complex and that individual cancers may evolve through mutations in as many as 20 different cancer-associated genes. We use data published by Sjöblom et al. (2006) to develop a new mathematical model for the somatic evolution of colorectal cancers. We employ the Wright-Fisher process for exploring the basic parameters of this evolutionary process and derive an analytical approximation for the expected waiting time to the cancer phenotype. Our results highlight the relative importance of selection over both the size of the cell population at risk and the mutation rate. The model predicts that the observed genetic diversity of cancer genomes can arise under a normal mutation rate if the average selective advantage per mutation is on the order of 1%. Increased mutation rates due to genetic instability would allow even smaller selective advantages during tumorigenesis. The complexity of cancer progression can be understood as the result of multiple sequential mutations, each of which has a relatively small but positive effect on net cell growth. Cancer is a disease of multicellular organisms that is characterized by a breakdown of cooperation between individual cells. The progression of cancer proceeds from a single genetically altered cell to billions of invasive cells through a series of clonal expansions. During tumorigenesis the cancer cells undergo replication and mutation, thereby increasing the size and invasiveness of the tumor. Recent sequencing projects of cancer cells suggest that mutations in up to 20 different genes might be responsible for driving an individual tumor's development. This insight contrasts with most mathematical models of cancer progression, which assume that the cancer phenotype is driven by mutations in only a few genes. We present a new mathematical model in which tumorigenesis is driven by mutations in many genes, most of which confer only a small selective advantage. Specifically, the progression of a benign tumor of the colon (adenoma) to a malignant tumor (carcinoma) is described by a Wright-Fisher process with growing population size. We explore the basic parameters of the model that are consistent with observed data. We also derive an analytical formula for the expected waiting time for the progression from benign to maligant tumor in terms of the population size, the mutation rate, the selective advantage, and the number of susceptible genes.
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关于癌症诱导机制的新理论。
影响因子：
8.8
作者：
NORDLING, C O
通讯作者：
NORDLING, C O
DOI：
10.1073/pnas.222118199
发表时间：
2002-11-12
影响因子：
11.1
作者：
Luebeck, EG;Moolgavkar, SH
通讯作者：
Moolgavkar, SH
DOI：
10.1073/pnas.0607057103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Bielas, Jason H.;Loeb, Keith R.;Loeb, Lawrence A.
通讯作者：
Loeb, Lawrence A.
影响因子：
4.7
作者：
Little, Mark P.;Li, Guangquan
通讯作者：
Li, Guangquan
影响因子：
64.8
作者：
O'Brien, Catherine A.;Pollett, Aaron;Dick, John E.
通讯作者：
Dick, John E.