Diabetes and Cancer: Using Genomics to Probe the Biological Mechanism

  • Topic: Combination of cancers
  • Institution: Imperial College London
  • Country: United Kingdom
  • Status: Ongoing

Co-applicant/s

Dr Marc Gunter, International Agency for Research on Cancer, France
Prof Elio Riboli, Imperial College London, United Kingdom
Prof Philippe Froguel, Imperial College London, United Kingdom

Scientific abstract

(View plain language abstract)

Background

Type 2 diabetes (T2D) and cancer are two of the most significant causes of morbidity and mortality globally. Approximately 400 million adults have a diabetes diagnosis, and around 15 million new cases of cancer are diagnosed worldwide each year.

Accumulating observational and experimental evidence suggests that these two diseases are linked, and epidemiological data support an association between T2D and elevated risk of cancer at several anatomical sites. However, major questions regarding the pathophysiology and mechanisms underlying these relationships remain unanswered.

Genome-wide association studies (GWAS) have identified hundreds of T2D and cancer loci, with many shared variants between these outcomes. Moreover, preliminary data from our group indicates that some cancer loci are associated with metabolic abnormalities that predispose to T2D, including hyperinsulinaemia and dyslipidaemia. This suggests that the biologic mechanisms underlying the association of various genetic variants with cancer may, at least in part, involve metabolic dysfunction.

Hypothesis and objectives

T2D and cancer share a number of heritable factors and may have common biological pathways in their aetiology. We aim to advance knowledge on shared genetic effects of T2D and cancer and, therefore, to elucidate potential biological mechanisms underlying the relationships between these diseases, through the following objectives:

  • To elucidate the extent of overlap between DNA variants contributing to T2D susceptibility and T2D-related traits including hyperinsulinaemia, hyperglycaemia and dyslipidaemia, and three common malignancies - colorectal, prostate and postmenopausal breast cancer.
  • To gain mechanistic insights into the pathophysiological processes and metabolic pathways underlying effects of cancer loci on T2D risk, quantitative metabolic traits and blood metabolite variability.
  • To determine whether T2D and related metabolic traits are causally related to colorectal, prostate and postmenopausal breast cancer using a Mendelian Randomization (MR) approach.

Settings and methods

We propose to conduct a comprehensive cross-disciplinary investigation of T2D and cancer that utilises the rich resources of large international genetic consortia and the European Prospective Investigation into Cancer and Nutrition (EPIC) study data. We will use publically available large-scale GWAS consortia summary statistics to identify DNA variants associated with the risk of T2D and colorectal, prostate and breast cancers, and affecting cardiometabolic trait variability. We will investigate the mechanistic relationships between these variant effects on range of cardiometabolic traits and cancers using hierarchical cluster analysis. Further, we will apply powerful whole-genome multi-phenotype analyses (MPA) to GWAS, related cardiometabolic trait, metabolomic and prospective epidemiologic data for up to 26,000 EPIC individuals with T2D and cancer to dissect the genetic relationships between these diseases, and will validate these findings in large genetic consortia with which our team has strong links. We will apply MR approaches implementing polygenic risk scores to dissect the causal T2D/hyperglycemia/hyperinsulinaemia-cancer relationships.

Impact

Pathophysiological insights into increased/decreased cancer risk in T2D patients and novel omics-based cancer-T2D biomarkers would have important consequences at (i) an individual level (specific recommendations concerning lifestyle habits, screening frequency); (ii) a public health level (implementation of preventive strategies, improved cost-effectiveness of the testing and treatment); and (iii) a clinical level (personalised medicine).

Plain language abstract

Background

Type 2 diabetes (T2D) and cancer are two of the most significant causes of morbidity and mortality globally. Approximately 400 million adults have a diabetes diagnosis, and around 15 million new cases of cancer are diagnosed worldwide each year.

Large ongoing studies within populations suggest that these two diseases are linked, and it is widely accepted that individuals with T2D have an elevated risk of several cancers, while males with T2D might be protected from prostate cancer. However, the biological processes relating these conditions remain unclear.

Studies of DNA variability within the human genome have related hundreds of such variants to influencing our susceptibility to T2D and cancer, and highlighted that many of them are shared between these diseases. Moreover, our preliminary data indicates that some cancer DNA variants are associated with metabolic conditions that increase risk of T2D, such as higher lipid and insulin levels. We propose that biological processes contributing to cancer risk are triggered by metabolic dysfunction.

Aims and objectives

T2D and cancer share a number of heritable factors which may contribute to their shared susceptibility. We aim to advance knowledge on shared genetic factors between T2D and cancer and, therefore, to uncover novel biology underlying the relationships between these diseases. We will define DNA variants contributing to in combination to T2D risk and T2D-related conditions including high insulin, high glucose and unbalanced lipid levels and to three common malignancies - colorectal, prostate and postmenopausal breast cancer. We will shed light on biological processes that cancer-related DNA variants have on T2D risk and individual's metabolic health. We will evaluate whether diabetes and metabolic dysfunction might have causal contribution to individual's colorectal, prostate and postmenopausal breast cancer risk.

How it will be done

We propose to conduct a comprehensive study that will span across several disciplines and will utilise large resources accumulated by international genetic consortia and the European Prospective Investigation into Cancer and Nutrition (EPIC) study. We will use publically available data about DNA variants affecting individual's diabetes and cancer risks as well as metabolic health. We will explore in which physiological ways these variants affect our metabolic health, diabetes and cancer risk reciprocally using public resources, and will investigate their role directly in the data we have accumulated thus far on 26,000 EPIC individuals. We will use novel statistical approaches that help combining multiple data points into one analysis to help make biological inferences about how our metabolic health is related to cancer risks.

Potential impact

Our research will help in better evaluation of cancer risk in T2D patients and will have important consequences at (i) an individual level (specific recommendations concerning lifestyle habits, screening frequency); (ii) a public health level (implementation of preventive strategies, improved cost-effectiveness of the testing and treatment); and (iii) a clinical level (personalised medicine).