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.

Bingjie Chen;Xianrui Wu;Yongsen Ruan;Yulin Zhang;Qichun Cai;Luis Zapata;Chung-I Wu;Ping Lan;Haijun Wen

State Key Laboratory of Biocontrol,School of Life Sciences,Sun Yat-sen University,Guangzhou 510275,China;GMU-GIBH Joint School of Life Sciences,Guangzhou Medical University,Guangzhou 511436,China;Evolutionary Genomics and Modelling Lab,Centre for Evolution and Cancer,The Institute of Cancer Research,London SW7 3RP,UK;Department of Colorectal Surgery,The Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou 510655,China;Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases,The Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou 510655,China;Cancer Center, Clifford Hospital, Jinan University, Guangzhou 511495, China

国家科学评论（英文版）

[1]Bingjie Chen;Xianrui Wu;Yongsen Ruan;Yulin Zhang;Qichun Cai;Luis Zapata;Chung-I Wu;Ping Lan;Haijun Wen-.Very large hidden genetic diversity in one single tumor:evidence for tumors-in-tumor)[J].国家科学评论（英文版）,2022(12):118-128

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