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Colorectal cancer is the third most common cancer worldwide, and the proportion of individuals diagnosed under the age of 50 years, referred to as early-onset colorectal cancer (EOCRC), is increasing. The aim of this study was to evaluate how the demographic and clinical features of EOCR in northern Sweden and Finland have changed over time. All patient data were extracted from local hospital surgical department databases between 1995 and 2022. Two CRC cohorts, Study Cohort I (1995-2005) 1237 patients and Study Cohort II (2006-2022) 4526 patients, were compared for age, sex, disease stage, tumour grade, tumour location, and mismatch repair status. EOCRC patients comprised 7% of all CRCs in Study Cohort I and 4% in Study Cohort II. The mean ages were 42 and 43 years respectively, and 55% of patients were female. The vast part of EOCRC tumours were left-sided stage III-IV cancers. Most tumours (n = 204, 73%) were low grade, and 10% showed mismatch repair deficiency. No significant differences in demographic or tumour characteristics were seen over time. EOCRC in northern Sweden and Finland is characterised by advanced-stage, low tumour grade, a slight female predominance, and stable clinical and pathological features. These findings partly contrast with reports on EOCRC from other high-income countries, highlighting the need for further research on advanced molecular characteristics and potential gender differences in incidence and survival of this population.

Objectives: FDG PET/MRI is a promising imaging modality for nodal staging in rectal cancer; however, its role remains to be defined. We aimed to assess its performance in detecting mesorectal malignant lymph node involvement based on both metabolic and morphological criteria at PET/MRI versus at MRI alone.

Materials & methods: Sixty-five patients (median age 70 years, IQR 61–74; 39 men) were examined with FDG PET/MRI followed by individual anatomical matching of mesorectal nodal structures between histopathology and MRI. PET N-stage assessment was evaluated using FDG uptake over background levels, MRI N-stage by the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus criteria and PET/MRI was evaluated using both in combination. Histopathological assessment served as gold standard, and the accuracy of identifying malignancy at both nodal and patient level was calculated. Furthermore, FDG PET/MRI and MRI using ESGAR criteria for nodal restaging after neoadjuvant treatment were also evaluated.

Results: In total, 835 nodal structures were matched, of which 104 were malignant (12%); among these, 59/104 (57%) were histopathologically proven lymph node metastases. MRI alone yielded a sensitivity of 54% and specificity of 85% for nodal malignancy, while the corresponding estimates for FDG-avidity gave a 75% sensitivity and 79% specificity. The different combined FDG PET/MRI criteria for malignancy were evaluated: FDG-positivity or malignancy according to ESGAR criteria resulted in a sensitivity of 76%; while the combination of FDG-positivity and malignancy according to ESGAR criteria achieved a specificity of 90%.

Conclusion: Compared to MRI alone, FDG PET/MRI offers potential added value by reducing the risk of nodal understaging.

Recent studies have revealed that the long-recognized link between the historically defined Fusobacterium nucleatum group and colorectal cancer is largely driven by Fusobacterium animalis. This species, along with two others (Fusobacterium polymorphum and Fusobacterium vincentii), was recently reclassified as distinct from F. nucleatum, highlighting functional divergence within this group. Due to their close genetic relatedness, traditional partial 16S rRNA gene sequencing lacks the resolution to reliably distinguish these species. Nevertheless, accurate species-level identification remains essential in cancer-associated microbiome research. Here, we demonstrate that full-length 16S rRNA sequencing using Oxford Nanopore Technology, combined with a novel custom demultiplexing software, enables robust species-level discrimination within the Fusobacterium genus. Our approach accurately classified clinically relevant Fusobacterium species and recovered their expected proportions from whole cells, DNA mixtures, and clinical CRC specimens. This method provides high-resolution profiling to elucidate species-specific roles of Fusobacterium in colorectal cancer.

Background/Aim: Deficient mismatch repair (dMMR) colorectal cancer (CRC) arises from either sporadic epigenetic changes or hereditary Lynch syndrome. This retrospective multicenter cohort study is the first to evaluate the differences in risk for dMMR non-colorectal malignancy between patients with sporadic CRC and those with Lynch syndrome-associated CRC.

Patients and Methods: A cohort of 1,753 patients treated between 1996 and 2019 in Sweden, Finland, and the Czech Republic was evaluated for MMR status by immunohistochemistry and classified as either proficient (pMMR) or dMMR. The last one underwent BRAF V600E and MLH1 methylation testing to classify sporadic versus Lynch-associated cases. Non-CRC malignancies occurring within ±20 years of CRC diagnosis were identified via national cancer registries and medical records. Incidence rate ratios (IRRs) were estimated using Poisson regression adjusted for age, sex, tumor site, and stage.

Results: Among 277 dMMR cases (186 sporadic, 91 Lynch), 101 patients (36%) developed at least one non-CRC malignancy. Sporadic dMMR was associated with significantly lower risk compared to Lynch-associated dMMR [multivariable IRR=0.82; 95% confidence interval (CI)=0.51-0.91; p=0.014]. The reduced risk was consistent for malignancies occurring both before (IRR=0.48; p=0.047) and after CRC diagnosis (IRR=0.37; p=0.026). Age was an independent predictor of risk.

Conclusion: Sporadic dMMR CRC confers a substantially lower risk of non-colorectal malignancy than Lynch syndrome-associated CRC. These findings underscore the importance of incorporating MMR etiology into personalized surveillance strategies.

To deepen the understanding of tissue-resident microbiota in colorectal cancer (CRC), we analyzed whole-genome and transcriptome data from 937 patients. We identified 249 genera and 361 species commonly present in both tumors and adjacent normal tissues (NATs). Distinct microbial signatures were associated with anatomical location, tumor stages, hypermutation status, mutations in CRC driver and DNA damage repair genes, as well as consensus molecular subtypes (CMSs). Notably, the presence of the pks island and elevated abundance of Enterobacteriaceae were linked to poor prognosis specifically in CMS2 tumors. Finally, microbial risk scores derived from taxa present in tumor or NATs predicted patient prognosis independently of established clinico-molecular factors. Prognostic taxa were strongly associated with tumor transcriptomic pathways related to hypoxia, immune response, and metabolic status. These findings revealed the heterogeneity of tissue-resident microbiota and their critical role in CRC progression, highlighting potential avenues for targeted intervention.

Colorectal cancer (CRC) represents a major global disease burden with nearly 1 million cancer-related deaths annually. TNM staging has served as the foundation for predicting patient prognosis, despite variation across staging groups. The consensus molecular subtype (CMS) is a transcriptome-based system classifying CRC tumors into four subtypes with different characteristics: CMS1 (immune), CMS2 (canonical), CMS3 (metabolic), and CMS4 (mesenchymal). Transcriptomics is too complex and expensive for clinical implementation; therefore, an immunohistochemical method is needed. The prognostic impact of the immunohistochemistry-based four CMS-like subtypes remains unclear. Due to the complexity and costs associated with transcriptomics, we developed an immunohistochemistry (IHC)-based method supported by convolutional neural networks (CNNs) to define subgroups that resemble CMS biological characteristics. Building on previous IHC-classifiers and incorporating β-catenin to refine differentiation between CMS2- and CMS3-like profiles, we categorized CRC tumors in a cohort of 538 patients. Classification was successful in 89.4% and 15.9% of tumors were classified as CMS1-like, 35.1% as CMS2-like, 38.7% as CMS3-like, and 11.7% as CMS4-like. CMS2-like patients exhibited the best overall survival (p = 0.018), including when local and metastasized disease were analyzed separately. Our method offers an accessible and clinically feasible CMS-inspired classification, although it does not serve as a replacement for transcriptomic CMS classification.

The recent introduction of immune checkpoint inhibitor therapy has significantly improved outcomes for patients with colorectal cancer (CRC). The most pronounced clinical benefits were observed in patients with immunogenic microsatellite instable (MSI)/deficient MMR (dMMR) tumors. However, emerging evidence indicates that a subset of patients with microsatellite stable tumors may also respond to therapy. Finding predictive markers to identify these patients is critical. In this study, we analyzed the immunohistochemical expression of immune checkpoints CTLA-4, PD-1, and PD-L1 using multispectral imaging in 151 CRC patients with defined molecular characteristics. Consistent with prior reports, MSI tumors had higher levels of all immune checkpoints analyzed than microsatellite stable tumors. Notably, distinct patterns of immune checkpoint expression were associated with KRAS and BRAF mutation status. KRAS-mutated tumors showed lower, and BRAF-mutated tumors higher, expression of immune checkpoints compared to wild-type/wild-type tumors. The strongest association with KRAS and BRAF mutations was observed for PD-L1 expression. The relationship between PD-L1 and KRAS/BRAF-mutational status was validated in a second cohort of 527 CRC patients, finding the association for PD-L1 expression in both stroma and in tumor cells. Furthermore, the role of BRAF mutation on immunity in CRC was found to be partly independent of MSI status. The strongest prognostic role was found for PD-L1 in stroma, underscoring the clinical significance of this marker. In conclusion, our findings suggest that KRAS and BRAF mutations, alongside MSI, may serve as valuable biomarkers for identifying CRC patient subgroups likely to benefit from immune checkpoint blockade in CRC.

Purpose: To evaluate current MRI-based criteria for malignancy in mesorectal nodal structures in rectal cancer.

Method: Mesorectal nodal structures identified on baseline MRI as lymph nodes were anatomically compared to their corresponding structures histopathologically, reported as lymph nodes, tumour deposits or extramural venous invasion. All anatomically matched nodal structures from patients with primary surgery and all malignant nodal structures from patients with neoadjuvant treatment were included. Mixed-effects logistic regression models were used to evaluate the morphological criteria irregular margin, round shape, heterogeneous signal and nodal size, as well as the combined 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus criteria, with histopathological nodal status as the gold standard.

Results: In total, 458 matched nodal structures were included from 46 patients (mean age, 67.7 years ± 1.5 [SD], 27 men), of which 19 received neoadjuvant treatment. The strongest associations in the univariable model were found for short-axis diameter ≥ 5 mm (OR 21.43; 95% CI: 4.13–111.29, p < 0.001) and heterogeneous signal (OR 9.02; 95% CI: 1.33–61.08, p = 0.024). Only size remained significant in multivariable analysis (OR 12.32; 95% CI: 2.03–74.57, p = 0.006). When applying the ESGAR consensus criteria to create a binary classification of nodal status, the OR of malignant outcome for nodes with positive ESGAR was 8.23 (95% CI: 2.15–31.50, p = 0.002), with corresponding sensitivity and specificity of 54% and 85%, respectively.

Conclusion: The results confirm the role of morphological and size criteria in predicting lymph node metastases. However, the current criteria might not be accurate enough for nodal staging.

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N = 1374; colon = 871, rectum = 503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases = 1001; Ncontrols = 667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted <= 0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted <= 0.04) and at the gene level (Punadjusted <= 0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at an SNP and gene level (both Punadjusted <= 0.01), but not colon cancer. Genes and SNPs were selected a priori; therefore, we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia, and CRC development.

Microsatellite-instable (MSI) tumours constitute one-fifth of colorectal cancers (CRCs). However, the MSI CRCs display substantial tumour microenvironment (TME) heterogeneity and variable responses to immunotherapy, necessitating a refined classification to guide personalized therapy. In this study, we analysed whole-genome and transcriptome sequences from 223 MSI CRC patients from a large prospective longitudinal cancer study in Sweden (Nunes L, Li F, Wu M, et al. Prognostic genome and transcriptome signatures in colorectal cancers. Nature. 2024;633(8028):137-146) and identified three molecular subclasses with distinct TME and genetic features: class 1a (immune-excluded), characterized by prominent stromal activation, transforming growth factor-β signalling, and low tumour neoantigen burdens (TNB); class 1b (immune-infiltrated), marked by intact neoantigen presentation and strong antitumour immunity; and class 2 (immune-cold), exhibiting epithelial features, high tumour mutation burden (TMB) and TNB, chromosomal instability, active metabolism, and a lack of immune activation. We further uncovered a correlation between mutL homolog 1 (MLH1) hypermethylation and the immune-cold phenotype in class 2, where anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) combination immunotherapy demonstrated significantly improved efficacy compared with anti-PD-1 monotherapy. Finally, the molecular features of these subclasses were validated in external MSI CRC cohorts and in MSI tumours from other cancers. Our findings offer a comprehensive understanding of the molecular landscape of MSI CRC, unveiling potential molecular mechanisms underlying different tumour-immune phenotypes and laying the foundation for future development of tailored treatment strategies.