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XB-ART-58949
Cancer Res 2022 Apr 15;828:1482-1491. doi: 10.1158/0008-5472.CAN-21-3458.
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Single-Hit Inactivation Drove Tumor Suppressor Genes Out of the X Chromosome during Evolution.

Wang X , Hu W , Li X , Huang D , Li Q , Chan H , Zeng J , Xie C , Chen H , Liu X , Gin T , Wang MH , Cheng ASL , Kang W , To KF , Plewczynski D , Zhang Q , Chen X , Chan DCW , Ko H , Wong SH , Yu J , Chan MTV , Zhang L , Wu WKK .


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Cancer-related genes are under intense evolutionary pressure. In this study, we conjecture that X-linked tumor suppressor genes (TSG) are not protected by the Knudson's two-hit mechanism and are therefore subject to negative selection. Accordingly, nearly all mammalian species exhibited lower TSG-to-noncancer gene ratios on their X chromosomes compared with nonmammalian species. Synteny analysis revealed that mammalian X-linked TSGs were depleted shortly after the emergence of the XY sex-determination system. A phylogeny-based model unveiled a higher X chromosome-to-autosome relocation flux for human TSGs. This was verified in other mammals by assessing the concordance/discordance of chromosomal locations of mammalian TSGs and their orthologs in Xenopus tropicalis. In humans, X-linked TSGs are younger or larger in size. Consistently, pan-cancer analysis revealed more frequent nonsynonymous somatic mutations of X-linked TSGs. These findings suggest that relocation of TSGs out of the X chromosome could confer a survival advantage by facilitating evasion of single-hit inactivation. SIGNIFICANCE: This work unveils extensive trafficking of TSGs from the X chromosome to autosomes during evolution, thus identifying X-linked TSGs as a genetic Achilles' heel in tumor suppression.

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Species referenced: Xenopus tropicalis
Genes referenced: twsg1