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Abstract

Colorectal cancer is currently the third most common and the second most deadly of all cancers. Despite the success of global colorectal cancer screening programs in reduction of both incidence and mortality, in recent decades the incidence in young individuals, particularly before the age of 50, has risen in several countries. Resultantly, there is a call for colorectal cancer screening programs to alter screening recommendation and identify risk factors that make young people susceptible. Diabetes is a disease that has also been rising in young people in recent decades. Additionally, diabetes shares several risk factors with colorectal cancer and has been associated with colorectal cancer in some studies. Hence, it becomes increasingly important to determine if diabetic patients are at increased risk and if they should be directed for an earlier screening than the general population. This study aimed to investigate the associations between diabetes and early-onset and late-onset colorectal cancer and determine what effect age of diabetes diagnosis, family history of colorectal cancer, and sex have on these associations. In addition, if diabetic patients are at increased risk of colorectal cancer, it aimed to provide evidence-based risk-adapted screening ages in diabetic patients with and without a family history of colorectal cancer, given that diabetes has yet to be mentioned in global screening guidelines. The analysis was conducted using the Swedish family-cancer datasets, the world’s largest of their kinds with record linkage to the Swedish Inpatient and Outpatient Registers. The study population consisted of 12,614,256 individuals with valid genealogical information (at least one first-degree relatives) and up to 52 years of follow-up spanning from 1964 to 2015. Among the

12.6 million individuals, 559,375 cases of diabetes and 162,226 cases of colorectal cancer were identified. Standardized incidence ratios, lifetime cumulative risk (age 0 to 79), and 10-year cumulative risk of colorectal cancer in diabetic patients with and without a family history of colorectal cancer were calculated. Both family and personal disease histories were ascertained using a dynamic (time-dependent) method, in which individuals were treated as cases only from their age at diagnosis onwards. It was observed that diabetic patients are at an increased risk of colorectal cancer, particularly early-onset colorectal cancer and that the magnitude of this association was similar to that of having a first-degree relative with colorectal cancer. This risk was further elevated in diabetic patients with an additional family history of colorectal cancer with nearly 7 times the risk of colorectal cancer compared to those in the general population with no diabetes and no family history of colorectal cancer. Building on these findings, the study provided risk-adapted ages of initial colorectal cancer screening for diabetic patients with and without a family history of colorectal cancer. It was found that diabetic patients reached the population level of risk several years earlier irrespective of the benchmark age of screening in the population (age 45, 50, 55 or 60). The results regarding risk of colorectal cancer in diabetic patients provide clinically-relevant and evidence-based data designed for real-time counselling of diabetic patients who are at an increased risk for early-onset colorectal cancer. The findings could help physicians provide personalized screening recommendation for diabetic patients and at the very least make patients wary of their increased risk so they can make lifestyle changes accordingly. Overall, irrespective of the specific application, the findings carry strong potential in impacting the management of diabetes, especially in young patients who are not targeted by colorectal cancer screening.