Cancer is caused by genetic alterations that affect cellular fitness, and multicellular organisms have evolved mechanisms to suppress cancer such as cell cycle checkpoints and apoptosis. These pathways may be enhanced by the addition of tumor suppressor gene paralogs or deletion of oncogenes. To provide insights to the evolution of cancer suppression across the mammalian radiation, we estimated copy numbers for 548 human tumor suppressor gene and oncogene homologs in 63 mammalian genome assemblies. The naked mole rat contained the most cancer gene copies, consistent with the extremely low rates of cancer found in this species. We found a positive correlation between a species’ cancer gene copy number and its longevity, but not body size, contrary to predictions from Peto’s Paradox. Extremely long-lived mammals also contained more copies of caretaker genes in their genomes, suggesting that the maintenance of genome integrity is an essential form of cancer prevention in long-lived species. We found the strongest association between longevity and copy numbers of genes that are both germline and somatic tumor suppressor genes, suggesting that selection has acted to suppress both hereditary and sporadic cancers. We also found a strong relationship between the number of tumor suppressor genes and the number of oncogenes in mammalian genomes, suggesting that complex regulatory networks mediate the balance between cell proliferation and checks on tumor progression. This study is the first to investigate cancer gene expansions across the mammalian radiation and provides a springboard for potential human therapies based on evolutionary medicine.

中文翻译：

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跨哺乳动物人类癌症基因复制的演变。

癌症是由影响细胞适应性的遗传改变引起的，多细胞生物已经进化出抑制癌症的机制，例如细胞周期检查点和细胞凋亡。这些途径可以通过添加肿瘤抑制基因旁系同源物或癌基因缺失来增强。为了提供跨哺乳动物辐射的癌症抑制进化的见解，我们估算了63个哺乳动物基因组装配体中548个人类肿瘤抑制基因和癌基因同源物的拷贝数。裸mole鼠含有最多的癌症基因拷贝，这与该物种中极低的癌症发生率一致。与Peto's Paradox的预测相反，我们发现一个物种的癌症基因拷贝数与其寿命（而不是体型）之间呈正相关。寿命极长的哺乳动物在其基因组中还包含看守基因的更多拷贝，这表明维持基因组完整性是长寿物种预防癌症的重要形式。我们发现寿命与种系和体细胞肿瘤抑制基因的基因的拷贝数之间存在最强的关联，这表明选择已起到抑制遗传性和散发性癌症的作用。我们还发现哺乳动物基因组中的抑癌基因数量与致癌基因数量之间存在很强的关系，这表明复杂的调控网络介导了细胞增殖与肿瘤进展检查之间的平衡。