Cancer Prevalence across Vertebrates

Abstract

Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto's paradox) and somatic mutation rate but decreases with gestation time. The relationship between adult mass and malignancy prevalence was only apparent when we controlled for gestation time. Evolution of cancer susceptibility appears to have undergone sudden shifts followed by stabilizing selection. Outliers for neoplasia prevalence include the common porpoise (<1.3%), the Rodrigues fruit bat (<1.6%), the black-footed penguin (<0.4%), ferrets (63%), and opossums (35%). Discovering why some species have particularly high or low levels of cancer may lead to a better understanding of cancer syndromes and novel strategies for the management and prevention of cancer. Significance: Evolution has discovered mechanisms for suppressing cancer in a wide variety of species. By analyzing veterinary necropsy records, we can identify species with exceptionally high or low cancer prevalence. Discovering the mechanisms of cancer susceptibility and resistance may help improve cancer prevention and explain cancer syndromes. See related commentary by Metzger, p. 14.

Figure 1.

A, Vertebrate species represented in our database overlaid upon the entire vertebrate phylogeny. Neoplasia and malignancy prevalence across (B) mammals, (C) sauropsids (Aves, Squamata, Testudines, and Crocodylia), and (D) amphibians. Silhouetted species indicate that zero neoplasms were reported in our data.

Figure 2.

Distributions of (A) neoplasia (Kruskal–Wallis test: P = 2.906 × 10⁻¹²) and (B) malignancy (Kruskal–Wallis test: P = 6.519 × 10⁻¹¹) prevalences are different across four clades, Amphibia, Mammalia, Aves, and Squamata. Dots show the estimated species neoplasia prevalence and bars show the median for the clade. Neoplasia and malignancy prevalence for species were calculated by the proportion of the reported lesions among the total number of necropsies for that species. N indicates the number of necropsies in each clade.

Figure 3.

Significant life history factors associated with neoplasia and malignancy prevalence. A, Larger organisms have a higher neoplasia prevalence than smaller organisms (2.1% neoplasia per Log₁₀g adult body mass, P = 0.007, R² = 0.26, λ = 0.46). B, Larger organisms may have a higher malignancy prevalence than smaller organisms but it is not statistically significant when we do not control for gestation time (0.65% malignancies per Log₁₀g adult body mass, P = 0.29, R² = 0.28, λ = 0.61). C, Longer lived organisms have more neoplasia (0.01% neoplasia per Log₁₀ month lifespan, P = 0.02, R² = 0.19, λ = 0.34). D, Longer lived organisms also have more malignancies (3.3% malignancies per Log₁₀ month lifespan, P = 0.17, R² = 0.21, λ = 0.47). E, Organisms with longer gestation times have a lower neoplasia prevalence (−5.30% neoplasia per Log₁₀ months, P = 0.10, R² = 0.11, λ = 0.34). F, Organisms with longer gestation times have a lower malignancy prevalence (−5.65% malignancies per Log₁₀ months, P = 0.02, R² = 0.16, λ = 0.41). When controlling for adult body mass, organisms with longer gestation times also have fewer neoplasms at death (−15.8% neoplasia per Log₁₀ months gestation, P = 0.0002).

Figure 4.

A, Cell cycle arrest as measured by % cell growth over time (AUC) relative to untreated at 10 Gy of radiation (plotted and analyzed on a Log₁₀ scale) as a predictor of neoplasia prevalence in species’ fibroblast cell lines. (0.31% neoplasia per % cell growth over time, P = 0.19, R² = 0.32, λ = 0.86). B, Log₁₀ mean mutation rate as a predictor of neoplasia prevalence (47.26% per single base substitution per genome per year, P = 0.0059, R² = 0.63, λ = 1.00).

Figure 5.

The density distribution of ages at death in animals with neoplasia vs. non-neoplasia, adjusted for each species’ lifespan as specified in PanTHERIA. While the distributions of ages at death are different between necropsies showing neoplasia vs. those that do not (two-sample Kolmogorov–Smirnov test: (A and B) Mammals: D = 0.11, P = 1.81 × 10⁻⁶; (C and D) Sauropsids: D = 0.18; P = 4.48 × 10⁻⁸; (E and F) Amphibians: D = 0.5, P = 0.011); we found few neoplasms that could be explained by an organism living an extraordinarily long time in captivity, except in amphibians. We only had seven amphibians with a malignancy at death, one of which lived past its normal lifespan, so the shape of the distribution in F is noisy.

Figure 6.

Cladogram depiction of cancer prevalence within (A) Mammals, (B) Sauropsids, and (C) Amphibians. Cladograms with the species labels at each tip can be found in Supplementary Fig. S72. Heat map coloration indicates relative prevalence of cancer within each branch, illustrating the diversity of neoplastic disease among closely related species. The scale is the same for each panel so that the differences between the clades are apparent.