Table 6. Standing questions on the relationship between DM and colorectal cancer.

Standing question	Relevance	What is required to address it
Is there an association between T2DM and colorectal cancer across all countries and cultures?	Provides insights into etiologic and pathophysiologic factors, may prevent a colorectal cancer epidemic in the developing world	Head-to-head comparison between developed and developing country cohorts
Is there an association between development of cancer and development of other complications of DM?	Provides the epidemiological basis to search for common mediators of disease	Epidemiological studies, ideally prospective
What molecular mediators explain the association between DM and cancer? Are they shared by other complications of DM?	Identification of potential diagnostic signatures and therapeutic targets	Interventional preclinical models that address function of key molecules. These may have been identified by non-biased systems biology approaches and hypothesis-driven studies designed from the analysis of available literature
Has DM-associated colorectal cancer a specific molecular signature?	This may identify diagnostic signatures and therapeutic targets specific for DM-associated colorectal cancer	Systems biology comparison between DM and non-DM associated colorectal cancer with DM and non-DM healthy colon as control
Can DM patients at high risk for cancer development be identified by diagnostic tests?	Early diagnosis of risk or cancer	Prospective systems biology approach to relevant biological samples (feces, urine, blood or others)
Can DM patients at high risk or early colorectal cancer be treated by specific, DM-tailored approaches? Do these approaches also prevent/treat other diabetic complications?	New preventive/therapeutic approaches that address both cancer and non-cancer DM complications	Early identification of patients at high risk or with early disease Unraveling of common pathogenic pathways
Are there common microbiota signatures for colorectal cancer and other DM complications?	New preventive/therapeutic approaches that address both cancer and non-cancer DM complications	Metagenomic studies
What is the optimal therapeutic approach for colorectal cancer in diabetic individuals and the optimal therapeutic approaches for DM in colorectal cancer patients?	Therapy individualization and improved outcomes	Hypothesis-generating observational studies followed by randomized clinical trials