Dysregulated expression of suppressor loop of circadian rhythm genes in colorectal cancer pathogenesis.

BACKGROUND: Colorectal cancer (CRC) is a heterogeneous disease and activation of WNT and TGFß mediated oncogenic pathways is frequently observed in this pathology. However, to date, limited reports have been published addressing the association of circadian clock with CRC pathogenesis and stratification. The current study aims at assessing the expression of important circadian markers, PER2, PER3 and NR1D1, in independent CRC cohorts and their associations with CRC-related pathways. METHODS: Gene expression analysis was performed using available GEO (GSE39582) and TCGA datasets. Quantitative real time polymerase chain reaction was used to quantify the expression levels of PER2, PER3 and NRID1 in FFPE (formalin fixed paraffin embedded) CRC tissue samples. Furthermore, enrichment of circadian markers in WNT and TGFß pathways-activated tumors was assessed. RESULTS: Statistically significant downregulation of PER3 was found in tumor versus control samples in GEO (P<0.0001) and TCGA colon and rectal adenocarcinoma datasets (P<0.05). Analysis of GEO dataset revealed a statistically significant upregulation of PER2 (P<0.01), and NR1D1 in colon adenocarcinoma, which was confirmed by qRT-PCR in CRC tumor samples versus controls in FFPE validation cohort. Higher expression of NR1D1 was associated with poor prognosis in colon adenocarcinoma. Contrastingly, PER3 was significantly downregulated in tumors (P<0.001) compared to controls and was associated with high-grade CRC tumors versus low-grade tumors. Tumors with WNT pathway activation had significantly low PER3 and slightly upregulated PER2 (<0.0001) expression. Interestingly, differential expression of PER3 and NR1D1 was significantly correlated with TGFß1-expressing tumors (P<0.0001). Moreover, MYC- amplified tumors exhibited decreased PER3 levels. CONCLUSIONS: Thus, low PER3 expression in CRC and poor survival of patients with NR1D1-high tumors reveal that genes in the suppressor loop of circadian rhythm are dysregulated in CRC, hence pointing out to the importance of dissecting the circadian pathway in cancer.

Mesenteric lipoma leading to small gut strangulation and short gut syndrome.

A rare case of mesenteric lipoma was presented to us as acute abdomen. His abdominal x-ray showed dilated small gut. Ultrasonography of abdomen revealed dilated small gut loops and minimal amount of free fluid in the peritoneal cavity. On exploration, most of the small gut was gangrenous and tightly twisted twice around its mesentery that contained a lump which was confirmed as lipoma on histopathology.