Brief report: The uricase mutation in humans increases our risk for cancer growth

Background Recent studies suggest that fructose, as well as its metabolite, uric acid, have been associated with increased risk for both cancer incidence and growth. Both substances are known to cause oxidative stress to mitochondria and to reduce adenosine triphosphate (ATP) production by blocking aconitase in the Krebs cycle. The uricase mutation that occurred in the Miocene has been reported to increase serum uric acid and to amplify the effects of fructose to stimulate fat accumulation. Here we tested whether the uricase mutation can also stimulate tumor growth. Methods Experiments were performed in mice in which uricase was inactivated by either knocking out the gene or by inhibiting uricase with oxonic acid. We also studied mice transgenic for uricase. These mice were injected with breast cancer cells and followed for 4 weeks. Results The inhibition or knockout of uricase was associated with a remarkable increase in tumor growth and metastases. In contrast, transgenic uricase mice showed reduced tumor growth. Conclusion A loss of uricase increases the risk for tumor growth. Prior studies have shown that the loss of the mutation facilitated the ability of fructose to increase fat which provided a survival advantage for our ancestors that came close to extinction from starvation in the mid Miocene. Today, however, excessive fructose intake is rampant and increasing our risk not only for obesity and metabolic syndrome, but also cancer. Obesity-associated cancer may be due, in part, to a mutation 15 million years ago that acted as a thrifty gene.

Brief Report: An Evolutionary Basis to Cancer Growth

Background. Recently we have reviewed the evidence that excessive intake of fructose, present in added sugars, may be a unique nutrient that stimulates tumor growth while also causing obesity and metabolic syndrome, thereby providing one of the reasons why obesity is associated with increased risk for various cancers. Prior studies have suggested that one of the reasons fructose increases the risk for cancer may be due in part to its metabolite uric acid, and both a meta-analysis and Mendelian randomization study confirm uric acid is a risk factor. Here we suggest that a mutation in uric acid metabolism may have provided survival advantage to our ancestors but ironically increase our risk for cancer today.Methods. Ancestral humans lost the gene uricase during the mid-Miocene where it led to higher uric acid levels that facilitated the effects of fructose to stimulate fat accumulation. Here we tested whether a loss of uricase would also facilitate tumor growth. Experiments were performed in mice in which uricase was inactivated by either knocking out the gene or by inhibiting uricase with oxonic acid. We also studied mice transgenic for uricase. These mice were injected with breast cancer cells and followed for 4 weeks.Results. The inhibition or knockout of uricase was associated with a remarkable increase in tumor growth and metastases. In contrast, transgenic uricase mice showed reduced tumor growth.Conclusion. A loss of uricase increases the risk for tumor growth. Prior studies have shown that the loss of the mutation facilitated the ability of fructose to increase fat which provided a survival advantage for our ancestors that came close to extinction from starvation in the mid Miocene. Today, however, excessive fructose intake is rampant and increasing our risk not only for obesity and metabolic syndrome, but also cancer. Obesity-associated cancer may be due, in part, to a mutation 15 million years ago that acted as a thrifty gene.

Commentary: The Invention of Aboriginal Diabetes: The Role of the Thrifty Gene Hypothesis in Canadian Health Care Provision

<p class="Default"> </p><p class="Pa7"> The purpose of this study was to analyze the extent to which the ‘thrifty gene hypoth­esis’ remains embedded within regimes of Canadian health care. The thrifty gene hypothesis, formulated by the American geneticist and travelling scientist James V. Neel in 1962, proposed that Indigenous peoples were genetically predisposed to Type 2 diabetes due to the foodways of their ancestors. The hypothesis was func­tionally racist and based on what biologi­cal anthropologists now call ‘the myth of forager food insecurity.’ Importantly, Neel reconsidered his own hypothesis in 1982 before he ultimately rejected it in 1999; nonetheless, in the mid-1990s, a team of Canadian scientists led by the endocrinolo­gist Robert Hegele of Western University conducted a genetic study on the OjiCree community of Sandy Lake First Nation in northern Ontario. Thereafter, Hegele told the academic world and news media that he had discovered a thrifty gene in Sandy Lake. Like Neel, Hegele later came to reject his own study in 2011. Nonetheless, the ‘thrifty gene hypothesis’ and Hegele’s Sandy Lake study continue to be cited, referenced, and reproduced in the current Clinical Guidelines of the Canadian Diabetes Asso­ciation, as well as across state-related health literature more broadly. The purpose of this study, then, will be to apply the PHCRP to the thrifty gene hypothesis in a Canadian context.</p><p class="Pa7"><em>Ethn Dis.</em>2018;28(Suppl 1):247- 252; doi:10.18865/ed.28.S1.247.</p>