biostudies-literatureVazquez JMNIH HHSDivision of Intramural Research, National Institute of Allergy and Infectious DiseasesNational Science Foundatione82558https://www.ebi.ac.uk/biostudies/studies/S-EPMC9810328biostudies-literatureUnknown11The risk of developing cancer is correlated with body size and lifespan within species, but there is no correlation between cancer and either body size or lifespan between species indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Previously we showed that several large bodied <i>Afrotherian</i> lineages evolved reduced intrinsic cancer risk, particularly elephants and their extinct relatives (<i>Proboscideans</i>), coincident with pervasive duplication of tumor suppressor genes (Vazquez and Lynch, 2021). Unexpectedly, we also found that <i>Xenarthrans</i> (sloths, armadillos, and anteaters) evolved very low intrinsic cancer risk. Here, we show that: (1) several <i>Xenarthran</i> lineages independently evolved large bodies, long lifespans, and reduced intrinsic cancer risk; (2) the reduced cancer risk in the stem lineages of <i>Xenarthra</i> and <i>Pilosa</i> coincided with bursts of tumor suppressor gene duplications; (3) cells from sloths proliferate extremely slowly while <i>Xenarthran</i> cells induce apoptosis at very low doses of DNA damaging agents; and (4) the prevalence of cancer is extremely low <i>Xenarthrans</i>, and cancer is nearly absent from armadillos. These data implicate the duplication of tumor suppressor genes in the evolution of remarkably large body sizes and decreased cancer risk in <i>Xenarthrans</i> and suggest they are a remarkably cancer-resistant group of mammals.eLifeParallel evolution of reduced cancer risk and tumor suppressor duplications in <i>Xenarthra</i>.PMC9810328R56AG071860AAI150062028459Muhammad BAdams LBKraft MPena MTVazquez JMLynch VJfalseParallel evolution of reduced cancer risk and tumor suppressor duplications in <i>Xenarthra</i>.The risk of developing cancer is correlated with body size and lifespan within species, but there is no correlation between cancer and either body size or lifespan between species indicating that large, long-lived species have evolved enhanced cancer protection mechanisms. Previously we showed that several large bodied <i>Afrotherian</i> lineages evolved reduced intrinsic cancer risk, particularly elephants and their extinct relatives (<i>Proboscideans</i>), coincident with pervasive duplication of tumor suppressor genes (Vazquez and Lynch, 2021). Unexpectedly, we also found that <i>Xenarthrans</i> (sloths, armadillos, and anteaters) evolved very low intrinsic cancer risk. Here, we show that: (1) several <i>Xenarthran</i> lineages independently evolved large bodies, long lifespans, and reduced intrinsic cancer risk; (2) the reduced cancer risk in the stem lineages of <i>Xenarthra</i> and <i>Pilosa</i> coincided with bursts of tumor suppressor gene duplications; (3) cells from sloths proliferate extremely slowly while <i>Xenarthran</i> cells induce apoptosis at very low doses of DNA damaging agents; and (4) the prevalence of cancer is extremely low <i>Xenarthrans</i>, and cancer is nearly absent from armadillos. These data implicate the duplication of tumor suppressor genes in the evolution of remarkably large body sizes and decreased cancer risk in <i>Xenarthrans</i> and suggest they are a remarkably cancer-resistant group of mammals.2022-01-01T00:00:00Z2022 Dec2025-04-19T04:47:47.676Z2025-04-19T04:47:47.676ZS-EPMC98103283648026610.7554/eLife.82558