Criticality in tumor evolution and clinical outcome.
Criticality in tumor evolution and clinical outcome.
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DOI：
10.1073/pnas.1807256115
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发表时间：
2018-11-20
影响因子：
11.1
通讯作者：
Ruppin E
中科院分区：
文献类型：
--
作者：
Persi E;Wolf YI;Leiserson MDM;Koonin EV;Ruppin E
突变和选择如何共同决定癌症进化的进程仍然是一个悬而未决的基本问题。我们构建了突变-选择相图，使用肿瘤突变负荷(ML)和选择强度(dN/ds)作为关键变量，并评估它们与临床结果的相关性。结果揭示了一个两阶段的进化制度，在这个制度下，除了一个关键的ML，肿瘤的适合性随着突变的数量而下降，尽管蛋白质组进化到接近中性--也就是说，没有强烈的选择。极端ML时偏离中性的情况显示了正选择(低ML时)和净化选择(高ML时)如何维持肿瘤的适合性。这些结果证实了理论预测的癌症发展中存在临界状态，并具有基本的和可能的临床意义。突变和选择如何决定肿瘤的适合性，从而决定临床结果，是癌症生物学中一个开放的基本问题，对于评估治疗策略和治疗耐药性至关重要。在这里，我们通过量化每个肿瘤整个蛋白质组中的总体体细胞点突变负荷(ML)和选择(dN/ds)来探索代表23种癌症类型的6,721个肿瘤的突变选择相图。我们表明ML与患者生存密切相关，揭示了临界点周围的两个对立的制度。在低ML癌症中，大量突变表明预后较差，而高ML癌症表现出相反的趋势，可能是由于突变的融化。虽然大多数癌症的进展接近中性，但在极端的最大似然率下观察到偏差。黑色素瘤具有最高的ML，在净化选择下进化，而在低ML癌症中，观察到正选择的迹象，说明选择如何影响肿瘤的适合性。此外，不同的癌症在ML-dN/ds平面上占据特定的位置，揭示了不同的进化轨迹。这些结果支持和拓展了肿瘤进化及其对生存的非线性影响的理论。
How mutation and selection co-determine the course of cancer evolution remains an open, fundamental question. We construct a mutation-selection phase diagram, using tumor mutation load (ML) and selection strength (dN/dS) as key variables, and assess their association with clinical outcome. The results reveal a biphasic evolutionary regime whereby beyond a critical ML, tumor fitness decreases with the number of mutations, although the proteome evolves near neutrality—that is, without strong selection. Deviations from neutrality at extreme ML show how positive selection (at low ML) and purifying selection (at high ML) may act to maintain tumor fitness. These results corroborate the existence of a critical state in cancer evolution predicted by theory and have fundamental and likely clinical implications. How mutation and selection determine the fitness landscape of tumors and hence clinical outcome is an open fundamental question in cancer biology, crucial for the assessment of therapeutic strategies and resistance to treatment. Here we explore the mutation-selection phase diagram of 6,721 tumors representing 23 cancer types by quantifying the overall somatic point mutation load (ML) and selection (dN/dS) in the entire proteome of each tumor. We show that ML strongly correlates with patient survival, revealing two opposing regimes around a critical point. In low-ML cancers, a high number of mutations indicates poor prognosis, whereas high-ML cancers show the opposite trend, presumably due to mutational meltdown. Although the majority of cancers evolve near neutrality, deviations are observed at extreme MLs. Melanoma, with the highest ML, evolves under purifying selection, whereas in low-ML cancers, signatures of positive selection are observed, demonstrating how selection affects tumor fitness. Moreover, different cancers occupy specific positions on the ML–dN/dS plane, revealing a diversity of evolutionary trajectories. These results support and expand the theory of tumor evolution and its nonlinear effects on survival.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.2
作者：
Birkbak NJ;Eklund AC;Li Q;McClelland SE;Endesfelder D;Tan P;Tan IB;Richardson AL;Szallasi Z;Swanton C
通讯作者：
Swanton C
鉴定癌症类型的显着突变区域的鉴定突出了功能分子改变的丰富景观。
影响因子：
30.8
作者：
Araya CL;Cenik C;Reuter JA;Kiss G;Pande VS;Snyder MP;Greenleaf WJ
通讯作者：
Greenleaf WJ
影响因子：
82.9
作者：
Andor N;Graham TA;Jansen M;Xia LC;Aktipis CA;Petritsch C;Ji HP;Maley CC
通讯作者：
Maley CC