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* = Presenting author

P720 Increased mitochondrial DNA copy number and higher expression of energy metabolic genes predict ulcerative colitis carcinogenesis

T. Tanaka*1, T. Kobunai2, T. Watanabe1

1University of Tokyo, Division of Surgical Oncology, Department of Surgery, Tokyo, Japan, 2Translational Research Laboratory, Taiho Pharmaceutical Co, Ltd, Tokyo, Japan

Background

Ulcerative colitis (UC) is a type of inflammatory bowel disease, and UC-associated cancer, especially the advanced type, affects patient outcomes. Therefore, clinical or molecular methods for the early detection of colitic cancer are needed. Genetic alteration of mitochondrial DNA (mtDNA) has attracted attention as a target for age-related diseases and malignancies. In this study, we examined the copy-number change in mtDNA during UC carcinogenesis and determined if the mtDNA copy-number variation was predictive of UC-associated adenocarcinoma development.

Methods

We studied 17 patients with UC-associated adenocarcinoma (UC-Ca) and 16 without UC-associated adenocarcinoma (UC-non-Ca). The mtDNA copy number in the non-dysplastic mucosa of both groups was quantified. We used an array-based digital polymerase chain reaction (PCR) assay because, by directly counting the target molecules, this technique can achieve absolute quantification without reference to standards, and it is more sensitive to small changes, compared with the quantitative polymerase chain reaction assay. Simultaneously, gene expression related to mitochondrial energy metabolism was determined using the PCR array.

Results

We observed a higher mtDNA copy number in the non-dysplastic mucosa of the UC-Ca group compared with the UC-non-Ca group (484.2 vs 747.7 copies/cell; p = 0.022), as shown in Figure 1. The sensitivity, specificity, positive predictive value, and negative predictive value for the detection of UC-associated adenocarcinoma by mtDNA copy number were 43.8%, 100%, 100%, and 60.9%, respectively. We observed the increased expression of mitochondrial genes related to energy metabolism, together with an increased mtDNA copy number, as shown in the volcano plot of Figure 2 (p < 0.0001, Fisher’s exact test).

Figure 1. mtDNA in UC-Ca mucosa showing increased copy number of mtDNA compared with that of UC-nonCa mucosa (747.7 vs 484.2 copies/cell, p = 0.011). The standard deviation is larger in the UC-Ca group than in the UC-nonCa group (390.5 vs 118.8, p = 0.0001).

Figure 2. Volcano plot for gene expression by mtDNA copy-number status. Fold change; gene expression levels of mtDNA-high/gene expression of mtDNA-low; upper panel, 28 586 QC-passed probes; lower panel, 132 probes for mitochondria-related genes.

Conclusion

Mitochondrial function and its metabolic process play essential roles in UC carcinogenesis and thus are possible risk markers for the development of colitic cancer.