Incidence of early-onset (<50 years) colorectal cancer (EOCRC) is increasing in developed countries. The aim was to investigate autoimmune and metabolic conditions as risk factors for EOCRC. In a nationwide nested case–control study, we included all EOCRC cases in Sweden diagnosed during 2007–2016, together with controls, matched for birth year, sex, and county. Information on exposure of autoimmune or metabolic disease was collected from the National Patient Register and Prescribed Drugs Registry. Hazard ratios (HR) as measures of the association between EOCRC and the exposures were estimated using conditional logistic regression. In total, 2626 EOCRC patients and 15,756 controls were included. A history of metabolic disease nearly doubled the incidence hazard of EOCRC (HR 1.82, 95% CI 1.66–1.99). A sixfold increased incidence hazard of EOCRC (HR 5.98, 95% CI 4.78–7.48) was seen in those with inflammatory bowel disease (IBD), but the risk increment decreased in presence of concomitant metabolic disease (HR 3.65, 95% CI 2.57–5.19). Non-IBD autoimmune disease was not statistically significantly associated with EOCRC. IBD and metabolic disease are risk factors for EOCRC and should be considered in screening guidelines.

Wnt signaling orchestrates gene expression in a plethora of processes during development and adult cell homeostasis via the action of nuclear β-catenin. Yet, little is known about how β-catenin generates context-specific transcriptional outcomes. Understanding this will reveal how aberrant Wnt/β-catenin signaling causes neoplasia specifically of the colorectal epithelium. We have previously identified the transcription factor TBX3 as a tissue-specific component of the Wnt/β-catenin nuclear complex during mouse forelimb development. In this study, we show that TBX3 is functionally active in human colorectal cancer (CRC). Here, genome-wide binding and transcriptomics analyses reveal that TBX3 regulates cancer metastasis genes in cooperation with Wnt/β-catenin. Proteomics proximity labeling performed across Wnt pathway activation shows that TBX3 engages with several transcription factors and chromatin remodeling complexes found at Wnt responsive elements (WRE). Protein sequence and structure analysis of TBX3 revealed short motifs, including an exposed Asn-Pro-Phe (NPF), that mediate these interactions. Deletion of these motifs abrogates TBX3’s proximity to its protein partners and its ability to enhance the Wnt-dependent transcription. TBX3 emerges as a key modulator of the oncogenic activity of Wnt/β-catenin in CRC, and its mechanism of action exposes protein-interaction surfaces as putative druggable targets.

Early-onset colorectal cancer should raise suspicions of a hereditary colorectal cancer (CRC) syndrome, including Lynch syndrome (LS) and Familial Adenomatous Polyposis (FAP). Collection of family history and genetic counselling (GC) is mandatory but previous studies have revealed low awareness of hereditary CRC among clinicians why there has been an incentive to implement universal LS screening. In this population-based cohort study, we aimed to observe the uptake of GC in the Swedish South-Eastern medical care region for young CRC patients and to investigate the frequency of patients diagnosed with LS. Patients below 50 years of age diagnosed with CRC between 2008 and 2017 were identified from the national Swedish Colorectal Cancer Registry. Medical records were reviewed regarding family history, co-morbidity and referral for GC, with a follow-up time of at least three years. The analysis included 278 patients with 287 tumours, 108 (38%) located in rectum and 179 (62%) in colon. One hundred sixteen (42%) individuals were referred to the Regional Clinical Genetics service, whereof 74 (27%) underwent complete investigation. Thirteen (18%) patients were identified with a mutation, eleven (15%) had LS and two (3%) FAP. The remaining 61 (82%), without proven mutation, were considered as familial CRC. Younger age correlated with a higher chance of referral for GC. The study found that only a minority of young CRC patients underwent genetic counselling, contrary to clinical guidelines. Hereditary CRC is therefore probably underdiagnosed even among young individuals.

Aims: To estimate the impact of inflammatory bowel disease on survival in a national cohort of patients following surgical resection for colon cancer, and to describe the surgical treatment of colon cancer in patients with inflammatory bowel disease. Methods: Using the Colorectal Cancer Database, we included all patients ≥ 15 years of age with a diagnosis of stages I–III colon cancer treated with curative intent 2007–2021. We used Cox proportional hazards models to compare overall survival, recurrence‐free survival and cancer‐specific survival between patients with and without inflammatory bowel disease. Multivariable analyses were adjusted for sex, age, date of colon cancer surgery, Charlson Comorbidity Index and primary sclerosing cholangitis. Results: Among 35,640 patients with colon cancer, 675 (1.9%) had inflammatory bowel disease. Median age at colon cancer diagnosis was 68 years in patients with inflammatory bowel disease and 75 in those without; proportions of male sex were 55% and 49%, respectively. In patients with inflammatory bowel disease, surgical therapy was proctocolectomy in 10%, subtotal colectomy in 29% and segmental resection in 61%. From adjusted analyses, patients with inflammatory bowel disease had worse overall survival (HR = 1.38; 95% CI: 1.21–1.57), recurrence‐free survival (HR = 1.33; 95% CI: 1.18–1.50) and cancer‐specific survival (HR = 1.46; 95% CI: 1.23–1.73) than patients without. Conclusion: Inflammatory bowel disease negatively influences the prognosis of colon cancer. Proctocolectomy was performed only in a minority of those with inflammatory bowel disease. Outcomes need to be improved in patients with inflammatory bowel disease developing colon cancer.

Background: Patients with inflammatory bowel disease have an increased risk of colorectal cancer. There is a scarcity of large studies with a focus on rectal cancer in patients with inflammatory bowel disease. This study aimed to compare survival in resected patients with rectal cancer with and without inflammatory bowel disease. Methods: This national population-based study used the Colorectal Cancer Data Base. All Swedish patients ≥18 years of age with a diagnosis of stage I–III rectal cancer between 1997 and 2021, surgically treated with curative intent, were included and followed up until 2022. The outcome of interest was recurrence-free survival. Flexible parametric survival models adjusted for time since surgery, year of diagnosis, sex, age at diagnosis, and Charlson Co-morbidity Index were used to estimate proportional and time-dependent hazard ratios of recurrence-free survival with 95% confidence intervals. Results: Overall, 22 082 patients with rectal cancer were included, among whom 323 (1.5%) had inflammatory bowel disease. Neoadjuvant radiotherapy/chemoradiotherapy was given to 55% and 63% of patients with and without inflammatory bowel disease respectively. The median follow-up time was 5.2 years (interquartile range (i.q.r.) 2.3–10) in patients with inflammatory bowel disease and 5.9 years (i.q.r. 2.9–10) in patients without inflammatory bowel disease. Based on the adjusted proportional hazards model, no overall difference in recurrence-free survival was found (HR 1.05, 95% c.i. 0.87 to 1.26). In the time-dependent adjusted model, patients with rectal cancer with inflammatory bowel disease experienced a lower recurrence-free survival during the first year after surgery (1 year HR 1.36, 95% c.i. 1.06 to 1.73), after which there was no difference in comparison with patients without inflammatory bowel disease (5 years HR 0.77, 95% c.i. 0.56 to 1.06). Conclusion: Despite lower recurrence-free survival during the first year among those with inflammatory bowel disease, there were no long-term differences between patients with or without inflammatory bowel disease.