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Circadian Genes in Pancreatic Ductal Adenocarcinoma: Alterations and Clinical Correlations
Daniel Relles*, Galina Chipitsyna, Terry Hyslop, Charles J. Yeo, Hwyda a. Arafat
Surgery, Thomas Jefferson University, Philadelphia, PA

Background: The circadian rhythm regulates various metabolic processes, physiologic homeostasis and behavior. Epidemiologic studies have demonstrated that disruption of the circadian rhythm is associated with cancer development and tumor progression. Several circadian clock genes with tightly connected transcriptional feedback loops have been implicated in loss of cell cycle control, impaired DNA damage repair, and subsequent tumor formation in multiple cancer models. However, the direct links between aberrant circadian clock gene expression and human pancreatic ductal adenocarcinoma (PDA) have not been elucidated. In this study, we investigated the expression profiles of several circadian clock genes in PDA.

Methods: We analyzed the expression of 10 circadian clock genes in matched invasive human PDA (n=62) and surrounding adjacent tissues and in benign lesions (n=10). Quantitative real-time polymerase chain reaction (qPCR) was used to examine the following core clock genes: (BMAL, Clock, Cry1, Cry2, CK1E, Per1, Per2, Per3, Timeless, Timeless-interacting protein). Gene expression levels were correlated with clinicopathological parameters. Receiver operator curve (ROC) analysis was completed using logistic regression based on individual circadian genes measured in tumor and benign samples, and is reported as area under the ROC curve (AUC). Spearman correlation was used to assess the relationship between circadian genes within tumor samples. Univariable Cox models were completed to assess survival of PDA patients, using the median gene expression level as stratification factor.

Results: In the tumor tissue of PDA patients, compared to their matched adjacent tissue, expression levels of all circadian genes were significantly lower (P<0.05). Benign tissues also expressed significantly (P<0.05) higher levels of all circadian genes when compared to malignant lesions. Spearman correlations of all 10 genes in tumors showed significant correlations of their expression levels ranging from 0.57 to 0.93, p<0.001 in all cases. Univariable survival analysis indicated that Per2 (p=0.004), Per3 (p=0.007), Cry2 (p=0.016), Tim (p=0.016) and CK1E (p=0.024) are significantly related to survival.

Conclusions: Our results reveal for the first time a disturbed transcription of several circadian genes in PDA. Elevation of the gene levels in the benign and matched adjacent tissues may be indicative of their role during the process of tumorigenesis. Altered expression of Per2, Per3, Cry2, Tim and CK1E in PDA provides the basis for future studies to explore their validity as predictive markers of the outcomes and survival in PDA patients.

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