Importance of metabolic rate to the relationship between the number of genes in a functional category and body size in Peto's paradox for cancer.

Kazuhiro Takemoto,Satoshi S Nishizuka,Masato Ii

doi:10.1098/rsos.160267

Kazuhiro Takemoto, Satoshi S Nishizuka + Show 1 more

Open Access

https://doi.org/10.1098/rsos.160267

Copy DOI

Abstract

Elucidation of tumour suppression mechanisms is a major challenge in cancer biology. Therefore, Peto's paradox, or low cancer incidence in large animals, has attracted focus. According to the gene-abundance hypothesis, which considers the increase/decrease in cancer-related genes with body size, researchers evaluated the associations between gene abundance and body size. However, previous studies only focused on a few specific gene functions and have ignored the alternative hypothesis (metabolic rate hypothesis): in this hypothesis, the cellular metabolic rate and subsequent oxidative stress decreases with increasing body size. In this study, we have elected to explore the gene-abundance hypothesis taking into account the metabolic rate hypothesis. Thus, we comprehensively investigated the correlation between the number of genes in various functional categories and body size while at the same time correcting for the mass-specific metabolic rate (Bc). A number of gene functions that correlated with body size were initially identified, but they were found to be artefactual due to the decrease in Bc with increasing body size. By contrast, immune system-related genes were found to increase with increasing body size when the correlation included this correction for Bc. These findings support the gene-abundance hypothesis and emphasize the importance of also taking into account the metabolic rate when evaluating gene abundance–body size relationships. This finding may be useful for understanding cancer evolution and tumour suppression mechanisms as well as for determining cancer-related genes and functions.

Highlights

Cancer is a complex and robust disease that remains difficult-to-treat despite the development of numerous anti-cancer therapies [1,2]
We found that number of genes in a functional category (NOGF) was generally associated with body size
We comprehensively evaluated the gene-abundance hypothesis in the context of the metabolic rate hypothesis, and found that NOGF generally showed a negative correlation with body size

Summary

Introduction

Cancer is a complex and robust disease that remains difficult-to-treat despite the development of numerous anti-cancer therapies [1,2]. Peto’s paradox, first reported in 1975 [3], has attracted renewed attention to this topic [4] This paradox is often explained as follows: assuming that the probability of normal cells transitioning to cancer cells is equivalent among all cells, larger animals (i.e. organisms with more cells) are expected to show a higher incidence of cancer. Previous studies have reported no association between body size and cancer incidence (and the lifespan-adjusted equivalent) [7,8]. These results indicate the existence of body-size-dependent mechanisms of tumour suppression

Methods

Results

Conclusion