Exploring Mechanisms Linking Glucose Levels And Cancer-Related Phenotypes In Healthy People: A Recall By Genotype Study

Vanessa TAN, University of Bristol, United Kingdom
CORBIN L. 1 , PERKS C. 2 , HOLLY J. 2 , TIMPSON N. 1

1 MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
2 IGFs and Metabolic Endocrinology (IMEG), School of Clinical Sciences, University of Bristol, Bristol, United Kingdom

Purpose 
Extensive epidemiological studies have suggested a link between western lifestyle factors that worsen glycemic control and cancer [1-5]. Despite growing evidence that hyperglycemia contributes to cancer progression and compromises the effectiveness of treatment, the mechanisms by which raised glucose contributes to increased cancer progression is not fully established. Previous in vitro studies found that IGFBP-2 expression was increased in hyperglycemic conditions through the acetylation of histones associated with IGFBP-2 promoter [6, 7].  Furthermore, it was found that up-regulation of IGFBP-2 and down-regulation of PTEN levels mediated hyperglycemia-induced chemoresistance [6, 7]. The aim of this RBG study implemented in a population cohort is to evaluate the impact of genetic variants associated with fasting glucose levels on circulating IGFBP-2 protein levels in healthy individuals. 

Methods
We will recall 100 healthy participants from the Avon Longitudinal Study of Parents and Children study (ALSPAC) from each tail of the genotypic risk score for glucose for the measurement of IGFBP-2 expression by enzyme-linked immunosorbent assay (ELISA) and acetylation of histones associated with the IGFBP-2 promoter by Chromatin immunoprecipitation assay (ChIP). 

Results
Samples of 50 participants from each tail of the genotypic risk score for glucose in ALSPAC yields groups capable of delivering reliable contrasts in glucose levels based on iteratively simulating a random draw of differing proportions of the 5% tails (a=0.01. power>80%).

Conclusions
This study has the potential to improve our understanding of the causal relationship between hyperglycemia and IGFBP-2 levels and to elucidate the biological pathways regulated by hyperglycemia that is pertinent to cancer risk and progression. The study will also educate comparison studies in cancer specific samples. This novel recall-by-genotype design is efficient, maximising statistical power, and enables the collection of extremely precise phenotypic data that is impractical to collect in a larger sample.

Funding Source
Cancer research UK