Monday, November 12, 2007

Cancer Risk, Age and Declining P53 Function

The older a person gets the greater the risk of dying from cancer. The chart on the left comes from the Cancer Research UK site and it clearly illustrates how one's age has a profound impact on one's risk of dying from cancer. 75% of cancer deaths occur in people aged 65 and over. Why is this the case?

This article in the PNAS helps shed some light on this question. The title is "Declining p53 function in the aging process" by Zhaohui Feng et. al. The p53 gene is a tumour suppressor gene and you can read more about it over here on the NCBI site. But here is a sample from the PNAS study:

Cancer is largely a disease of the elderly. Most tumors arise in the last quarter of life, with the frequency increasing exponentially with time. Mice (2- to 3-year mean life spans) frequently acquire tumors after 1.5–2 years, whereas dogs (12- to 16-year mean life spans) acquire most tumors after 10 years, and humans (75-year mean life spans) acquire tumors with an increased frequency after 50–55 years of age. This observation has been thought to be caused by the accumulation of DNA mutations in oncogenes or tumor suppressor genes in individual cells over a lifetime (the somatic tissues). This hypothesis is supported by ample evidence from both humans and animal models showing that many tumors contain mutations in crucial tumor suppressor genes and oncogenes. The tumor suppressor p53 gene is the most frequently mutated gene in human tumors, and >50% of tumors harbor mutations in the p53 gene or the p53 pathway. The p53 protein can be activated by a wide variety of stress signals and results in various cellular responses, including apoptosis, cell cycle arrest, or senescence through transcriptional regulation of its target genes. Disruption of normal p53 function is in some circumstances a prerequisite for the development or progression of tumors. By preventing these tumors early in life, p53 is also an important longevity assurance gene. For example, p53-null mice all succumb to tumors within several months, and heterozygous p53 mutant mice develop tumors over a period of a year or more. Li–Fraumeni syndrome patients with heterozygous p53 gene display a 50% cancer incidence by the age of 30.

Aging is a natural process with gradual decline of many normal biological functions of cells or organisms. It has been reported that the function of DNA repair, regulation of cell proliferation, and immune response decrease with age in both animals and humans. These findings together raised an interesting hypothesis: could the function of the p53 protein decline with age, which may then contribute to the enhanced mutation frequency and tumorigenesis in the aging process along with the accumulation of DNA mutations? To explore this hypothesis, in this work we investigated the activity of the p53 protein and the efficiency of p53 responses to various stresses in several inbred mouse strains as a function of their ages.

....The results in this work demonstrate that the efficiency of the p53 pathway declines with age, predicting the increased rates of mutation (caused by a decline in DNA repair) and fixation of mutations (caused by a decline in p53-mediated apoptosis) in older individuals, especially in response to stress. This decline of p53 function could, along with the accumulated mutations over a lifetime, explain why older individuals have a lower rate of fidelity of cell division, a higher error rate, and a higher frequency of tumors.