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Project Title
Diabetes and Cancer Initiative in the Cohort Consortium
Project Group
(N/A)
Project Status
Active
Primary Contact Information
Marc J. Gunter
Investigator
m.gunter@imperial.ac.uk
Imperial College London
European Prospective Investigation into Cancer and Nutrition (EPIC)
Alternate Contact Information
Elio Riboli
Professor
e.riboli@imperial.ac.uk
Imperial College London
European Prospective Investigation into Cancer and Nutrition (EPIC)
Project Details
Other
Multiple sites
Combined Intra- and extra-mural funding through NCI; possibly also NIDDK, NHLBI.
There is emerging evidence for a link between T2DM and cancer-as outlined in the consensus report of the American Diabetes Association and the American Cancer Society of 2010 (Giovannucci et al; Diabetes Care; 33(7)1674-1685). Rationale for further research in this subject area is strong given that the prevalence of T2DM is high in many regions (~10% in the U.S) and rising and therefore may represent an important and growing source of cancer cases. A major meta-analysis (Vigneri et al; Endocr Relat Cancer; 16(1) 1103-1123) and recent study on T2DM and cancer incidence in the NIH-AARP Diet and Health Study (Lai et al; J Clin Endocrinol Metab; 98(3): E497-E502) generally concluded:
Convincing evidence for a positive association between T2DM and cancers of the liver (~RR=2), pancreas (~RR=1.5-2), endometrium (~RR=1.5), colorectum (~RR=1.2-1.3), breast (~RR=1.2), kidney (~RR=1.2) and bladder (~RR=1.2-1.4).
Inverse association between T2DM and prostate cancer risk (~RR=0.7-0.8).
Limited data on less common cancers but suggestive positive associations for lymphoma, thyroid cancer and possibly others.
There are a number of major unanswered questions that could be addressed in the proposed initiative:
1. Is the association of T2DM with cancer independent of body habitus? Can we detect significant associations among leaner diabetics? Data from the NIH-AARP study indicated significant associations between T2DM and risk of colorectum, kidney, pancreas, prostate and liver cancer among leaner (BMI<25Kg/M2) individuals, suggesting an independent effect.
2. Is there an association between T2DM and less common malignancies? Most of the existing cohorts, if considered in isolation, are completely underpowered to address this question.
3. Is T2DM related to cancer prognosis and survival, once body habitus is taken into account? Currently, data is very limited.
4. What is the biological mechanism? Several hypotheses deserve careful consideration, namely:_
Direct effect of hyperinsulinemia on cancers
Indirect effects of hyperinsulinemia through elevated IGF-I and steroid hormones-also linked to these malignancies
Inflammation
Insulin down-regulation of steroidogenesis and testosterone synthesis in Leydig cells, which may be potentially pertinent for prostate cancer?
5. Are there site-specific differences? Tumour sub-types?_
6. Is the T2DM-cancer relationship modified by other risk factors (e.g. sex, ethnicity, body size, physical activity etc.?)
7. Diabetes Treatments-do they influence cancer incidence and survival? Treatment data may not have been collected in some cohorts which is a limitation._
8. Among diabetics, what are the molecular parameters/pathways that are associated with cancer development? Genetic factors? Can we address this question using newly-emerging techniques such as metabolomics etc.?
To further understanding on the relation of diabetes with cancer both in terms of epidemiology and underlying molecular mechanisms
1. To investigate the association of type II diabetes mellitus (T2DM) with cancer incidence and survival for all major cancer sites and to explore whether these relationships are modified by risk factors such as (i) sex (ii)ethnicity (iii) body habitus (iv) physical activity (v) smoking (vi) diet (vii) alcohol.
2. To explore the association of diabetes treatments with cancer incidence and survival.
3. To identify genetic and metabolic predictors of cancer risk among diabetics.
Stratified cohort design to investigate association of T2DM and diabetes treatments with cancer outcomes and survival (Cox proportional hazards modeling)
To investigate the association of T2DM with a range of cancer outcomes (including rarer cancer types); very large numbers of cases are required. Further, an important aspect will be stratification by body size, ethnicity etc, thus it will be necessary to include a high number of subjects with a range of body sizes and ethnic groups to address these questions with sufficient precision.
To be determined
Incidence of all cancer types
Survival and mortality data among cancer patients
Type II diabetes
Diabetes treatments (e.g. metformin)
Age, Sex, Ethnicity, Body mass index, Waist circumference, Waist: Hip Ratio, Physical Activity, smoking, alcohol, dietary variables (e.g. meat, fiber, fruit/Vegetables, glycemic load/index, fat etc), cancer treatment data (if available),NSAID use, Hormone therapies,
Yes
Yes
N/A
No
Yes
<200ul
No
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Coffee drinking and Mortality
- Participating Cohorts: N/A
- Has funding been awarded?: Complete
- Have contracts been signed?: Not Yet Started
- Has data been transferred?: Not Yet Started
- Summarized successes:
- In 2024, we successfully transitioned the "Coffee and Mortality" project to the DCPP. Dr. Smith-Warner and I agreed on an analytic plan to address the main aims of the proposal, and I was approved for funding for the contract. The contract was awarded in late 2024, and analyses are underway. The plan was summarized during an oral presentation at the 2024 NCI Cohort Consortium Meeting.
- Summarized challenges:
- The coffee and mortality project was always intended to be a subproject within an existing project with harmonized data on coffee and major risk factors for mortality. Given the overlap in variables of interest with the Diabetes in Cancer Epidemiology (DICE) cohort consortium project, the plan was to complete the analysis within DICE. Dr. Marc Gunter and I tried to make this work, but there were challenges in terms of funding, data access and analyst bandwidth. Consequently, I approached Dr. Stephanie Smith-Warner in 2023 about making this a DCPP subproject. We are working through the contracts process so that one of her analysts can run the analyses under her and my supervision. Once, a contract is in place to pay for the analysis (funding is secured), she will work with her group to contact each of the participating DCPP cohorts to ascertain whether each will participate in the coffee-mortality study.