Abstract:Focal copy number gains or losses are important genomic hallmarks of cancer. The genomic distribution of oncogenes and tumor-suppressor genes (TSG) in relation to focal copy number aberrations is unclear. Our analysis revealed that the mean distance of TSGs from oncogenes was significantly shorter than that of noncancer genes, suggesting that oncogenes and TSGs tend to be in close physical proximity in the human genome. Such relationship was conserved in mouse and drosophila. Pan-cancer analysis using data fro… Show more
“…However, longer-lived species may have more complex regulatory networks that mediate the balance between cellular proliferative potential and necessary checks on tumor progression. In the human and mouse genomes, oncogenes without a tumor suppressor gene at a nearby genomic location were found more likely to become amplified ( Wu et al. 2017 ).…”
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 it’s 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 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 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.
“…However, longer-lived species may have more complex regulatory networks that mediate the balance between cellular proliferative potential and necessary checks on tumor progression. In the human and mouse genomes, oncogenes without a tumor suppressor gene at a nearby genomic location were found more likely to become amplified ( Wu et al. 2017 ).…”
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 it’s 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 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 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.
“…However, longer-lived species may have more complex regulatory networks that mediate the balance between cellular proliferative potential and necessary checks on tumor progression. In the human and mouse genomes, oncogenes without a tumor suppressor gene at a nearby genomic location were found more likely to become amplified (Wu et al 2017). Oncogenes and tumor suppressor genes were found to be among the evolutionarily oldest sets of genes in eukaryotes, associated with the timing of the origins of both multicellular and vertebrate life (Makashov et al 2019); this is consistent with our observation that oncogenes are highly conserved at the sequence level.…”
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 it's 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 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 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.
“…2b, c ). The gained proximity to the POGs from 3q arm in hystricomorphs and from 19p13.11 in sciuromorphs might have allowed nullification of tumorigenic effects though co-deletion (or co-silencing) or co-amplification (or co-activation) of co-positioned TSG and POG clusters, as proposed elsewhere 45 . Fig.…”
Section: Resultsmentioning
confidence: 75%
“…Examples include co-amplification of POGs at 8p11–12 36 , at 14q13.3 37 – 40 and co-deletion of TSGs at 8p22 41 and at 3p21.31 42 – 44 regions. On the contrary, many other POGs exhibit linear proximity to TSGs under an evolutionary constraint to nullify tumorigenic effect through co-amplification or co-deletion of oncogenes and tumour-suppressor genes 45 . We hypothesise that certain genomic rearrangements of POG and TSG clusters can endow cancer resistance to some mammals.…”
The rodents of hystricomorpha and sciuromorpha suborders exhibit remarkably lower incidence of cancer. The underlying genetic basis remains obscure. We report a convergent evolutionary split of human 3p21.31, a locus hosting a large number of tumour-suppressor genes (TSGs) and frequently deleted in several tumour types, in hystrico- and sciuromorphs. Analysis of 34 vertebrate genomes revealed that the synteny of 3p21.31 cluster is functionally and evolutionarily constrained in most placental mammals, but exhibit large genomic interruptions independently in hystricomorphs and sciuromorphs, owing to relaxation of underlying constraints. Hystrico- and sciuromorphs, therefore, escape from pro-tumorigenic co-deletion of several TSGs in cis. The split 3p21.31 sub-clusters gained proximity to proto-oncogene clusters from elsewhere, which might further nullify pro-tumorigenic impact of copy number variations due to co-deletion or co-amplification of genes with opposing effects. The split of 3p21.31 locus coincided with the accelerated rate of its gene expression and the body mass evolution of ancestral hystrico- and sciuromorphs. The genes near breakpoints were associated with the traits specific to hystrico- and sciuromorphs, implying adaptive significance. We conclude that the convergently evolved chromosomal interruptions of evolutionarily constrained 3p21.31 cluster might have impacted evolution of cancer resistance, body mass variation and ecological adaptations in hystrico- and sciuromorphs.
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