Objective Accumulating evidence links the intestinal microbiota and colorectal carcinogenesis. Fusobacterium nucleatum may promote colorectal tumour growth and inhibit T-cell-mediated immune responses against colorectal tumours. Thus, we hypothesized that the amount of Fusobacterium nucleatum in colorectal carcinoma might be associated with worse clinical outcome. Design We utilised molecular pathological epidemiology database of 1,069 rectal and colon cancer cases in the Nurses’ Health Study and the Health Professionals Follow-up Study, and measured Fusobacterium nucleatum DNA in carcinoma tissue. Cox proportional hazards model was used to compute hazard ratio (HR), controlling for potential confounders, including microsatellite instability (MSI, mismatch repair deficiency), CpG island methylator phenotype (CIMP), KRAS, BRAF, and PIK3CA mutations, and LINE-1 hypomethylation (low-level methylation). Results Compared to Fusobacterium nucleatum-negative cases, multivariable HRs (95% confidence interval) for colorectal cancer-specific mortality in Fusobacterium nucleatum-low cases and Fusobacterium nucleatum-high cases were 1.25 (0.82 to 1.92) and 1.58 (1.04 to 2.39), respectively (p for trend = 0.020). The amount of Fusobacterium nucleatum was associated with MSI-high (multivariable odds ratio, 5.22; 95% CI, 2.86 to 9.55) independent of CIMP and BRAF mutation status, whereas CIMP and BRAF mutation were associated with Fusobacterium nucleatum only in univariate analyses (p < 0.001) but not in multivariate analysis that adjusted for MSI status. Conclusions The amount of Fusobacterium nucleatum DNA in colorectal cancer tissue is associated with shorter survival, and may potentially serve as a prognostic biomarker. Our data may have implications in developing cancer prevention and treatment strategies through targeting gastrointestinal microflora by diet, probiotics, and antibiotics.

We developed a computational method to infer the complementarity determining region 3 (CDR3) sequences of tumor infiltrating T-cells in 9,142 RNA-seq samples across 29 cancer types. We identified over 600 thousand CDR3 sequences, including 15% with full-length. CDR3 sequence length distribution and amino acid conservation, as well as variable gene usage of infiltrating T-cells in many tumors, except brain and kidney cancers, resembled those in the peripheral blood of healthy donors. We observed a strong association between T-cell diversity and tumor mutation load, and predicted SPAG5 and TSSK6 as putative immunogenic cancer/testis antigens in multiple cancers. Finally, we identified 3 potential immunogenic somatic mutations based on their co-occurrence with CDR3 sequences. One of them, PRAMEF4 F300V, was predicted to bind strongly to both MHC-I and MHC-II, with matched HLA types in its carriers. Our analyses have the potential to simultaneously identify immunogenic neoantigens and the tumor-reactive T-cell clonotypes.

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In many cells throughout the body, vitamin D is converted into its active form calcitriol, and binds to vitamin D receptor (VDR), which functions as a transcription factor to regulate various biological processes including cellular differentiation and immune response. Vitamin D metabolizing enzymes (including CYP24A1 and CYP27B1) and VDR play major roles in exerting and regulating effects of vitamin D. Preclinical and epidemiological studies provide evidence for anticancer effects of vitamin D (in particular, against colorectal cancer), though clinical trials have yet to prove its benefit. Additionally, molecular pathological epidemiology research can provide insights into the interaction of vitamin D with tumour molecular and immunity status. Other future research directions include genome-wide research on VDR transcriptional targets, gene-environment interaction analyses, and clinical trials on vitamin D efficacy in colorectal cancer patients. Here we review the literature on vitamin D and colorectal cancer from both mechanistic and population studies, and discuss the links and controversies within and between the two parts of evidence.