Very large hidden genetic diversity in one single tumor: evidence for tumors-in-tumor.
Very large hidden genetic diversity in one single tumor: evidence for tumors-in-tumor.
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DOI：
10.1093/nsr/nwac250
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发表时间：
2022-12
影响因子：
20.6
通讯作者：
中科院分区：
文献类型：
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尽管肿瘤内的遗传多样性受到关注，但这种多样性实际上受到肿瘤中细胞之间的亲缘关系的限制。事实上，基因组学研究已经充分支持了诺厄尔教条，即同一肿瘤的细胞是从单个祖细胞下来的。同时，基因组数据还表明，如果肿瘤细胞具有多种来源，其多样性可能会扩大10倍。我们提出了一个进化论假设，即单个肿瘤可能经常含有多个来源独立的细胞克隆，但只有一个大到足以被检测到。为了验证这一假设，我们在一个较大的肿瘤(或肿瘤中的肿瘤)中搜索独立的肿瘤。对2例结肠肿瘤进行了极高密度采样。病例1确实有13个大小不同的独立克隆，其中许多具有沉重的突变负担，并具有潜在的高致瘤性。在案例2中，尽管进行了非常密集的搜索，但只能找到两个独立的小克隆。这两个病例显示显性克隆的运动和转移非常相似。细胞最初在不断膨胀的肿瘤中活动活跃，但在晚期变得几乎不活动。总而言之，肿瘤中的肿瘤是有可能的，但发现起来可能非常困难。尽管它们的体积很小，但它们可以在数量级上增强肿瘤内的多样性。这种增加可能会导致与抗癌治疗相关的基因多样性缺失。
Despite the concern of within-tumor genetic diversity, this diversity is in fact limited by the kinship among cells in the tumor. Indeed, genomic studies have amply supported the ‘Nowell dogma’ whereby cells of the same tumor descend from a single progenitor cell. In parallel, genomic data also suggest that the diversity could be >10-fold larger if tumor cells are of multiple origins. We develop an evolutionary hypothesis that a single tumor may often harbor multiple cell clones of independent origins, but only one would be large enough to be detected. To test the hypothesis, we search for independent tumors within a larger one (or tumors-in-tumor). Very high density sampling was done on two cases of colon tumors. Case 1 indeed has 13 independent clones of disparate sizes, many having heavy mutation burdens and potentially highly tumorigenic. In Case 2, despite a very intensive search, only two small independent clones could be found. The two cases show very similar movements and metastasis of the dominant clone. Cells initially move actively in the expanding tumor but become nearly immobile in late stages. In conclusion, tumors-in-tumor are plausible but could be very demanding to find. Despite their small sizes, they can enhance the within-tumor diversity by orders of magnitude. Such increases may contribute to the missing genetic diversity associated with the resistance to cancer therapy.
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DOI：
10.1126/science.aau3879
发表时间：
2018-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Martincorena I;Fowler JC;Wabik A;Lawson ARJ;Abascal F;Hall MWJ;Cagan A;Murai K;Mahbubani K;Stratton MR;Fitzgerald RC;Handford PA;Campbell PJ;Saeb-Parsy K;Jones PH
通讯作者：
Jones PH
影响因子：
64.5
作者：
Snippert, Hugo J.;van der Flier, Laurens G.;Clevers, Hans
通讯作者：
Clevers, Hans
影响因子：
64.8
作者：
Lee-Six, Henry;Olafsson, Sigurgeir;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
影响因子：
29.4
作者：
Galandiuk, Susan;Rodriguez-Justo, Manuel;Graham, Trevor A.
通讯作者：
Graham, Trevor A.
影响因子：
16.6
作者：
Keogh MJ;Wei W;Aryaman J;Walker L;van den Ameele J;Coxhead J;Wilson I;Bashton M;Beck J;West J;Chen R;Haudenschild C;Bartha G;Luo S;Morris CM;Jones NS;Attems J;Chinnery PF
通讯作者：
Chinnery PF