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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