Abstract
The World Health Organization predicts that the proportion of the world's population over 60 will almost double from 12% to 22% between 2015 and 2050. Ageing is the biggest risk factor for cancer, which is a leading cause of deaths worldwide. Unfortunately, research describing how genetic variants affect cancer progression commonly neglects to account for the ageing process. Herein is the first systematic analysis that combines a large longitudinal data set with a targeted candidate gene approach to examine the effect of genetic variation on survival as a function of age in cancer patients. Survival was significantly decreased in individuals with heterozygote or rare homozygote (i.e. variant) genotypes compared to those with a common homozygote genotype (i.e. wild type) for two single nucleotide polymorphisms (rs11574358 and rs4147918), one gene (SIRT3) and one pathway (FoxO signalling) in an age-dependent manner. All identified genes and pathways have previously been associated with ageing and cancer. These observations demonstrate that there are ageing-related genetic elements that differentially affect mortality in cancer patients in an age-dependent manner. Understanding the genetic determinants affecting prognosis differently with age will be invaluable to develop age-specific prognostic biomarkers and personalized therapies that may improve clinical outcomes for older individuals.
Highlights
Cancer is a leading cause of death worldwide; approximately 14.1 million new cancer cases and 8.2 million cancer-related deaths were recorded globally in 2012 [1]
The investigation described is the first systematic study to address how the ageing process impacts the effect that single nucleotide polymorphisms have on cancer survival; a field that could greatly affect the possibility of individualising cancer prognoses and treatments in the post-genomic era
WRN is responsible for the progeroid Werner Syndrome, characterised by the accelerated appearance of features associated with ageing [100,101,102]
Summary
Cancer is a leading cause of death worldwide; approximately 14.1 million new cancer cases and 8.2 million cancer-related deaths were recorded globally in 2012 [1]. The evolving age demography affects cancer incidence and mortality rates, which has serious consequences for a country’s healthcare system and economy [4,5]. Novel insights into the age-related genetic predisposition of cancer survival would be a major breakthrough in expanding healthy life span in humans. Case-control studies that compare population SNP www.aging‐us.com frequency to disease characteristics often list a set of SNPs statistically significantly associated with a particular condition, not accounting for the ageing process. This is an oversight, as molecular systems affected by such genetic variants are evolving entities whose interactions change with age [23,24]. The ageing process affects multiple inter-linked molecular systems including the immune [3,25,26], metabolic [27,28] and cardiovascular [29] systems
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