Research Article: Clinical significance of cancer specific methylation of the CDO1 gene in small bowel cancer

Date Published: January 24, 2019

Publisher: Public Library of Science

Author(s): Keita Kojima, Takatoshi Nakamura, Yosuke Ooizumi, Kazuharu Igarashi, Toshimichi Tanaka, Keigo Yokoi, Satoru Ishii, Nobuyuki Nishizawa, Hiroshi Katoh, Yoshimasa Kosaka, Takeo Sato, Masahiko Watanabe, Keishi Yamashita, Aamir Ahmad.


Although small bowel cancer (SBC) is extremely rare, its prognosis is poor, and molecular mechanism of the SBC development remains unclear. The aim of our study is to elucidate whether DNA methylation of the promoter region of the cancer-specific methylation gene, cysteine dioxygenase 1 (CDO1), contributes to the carcinogenic process in SBC. The study group comprised patients with 53 patients with SBC, 107 colorectal cancer (CRC), and other rare tumors of the small intestine such as 4 malignant lymphomas, 2 leiomyosarcomas, and 9 gastrointestinal stromal tumors. We analyzed the extent of methylation in each tissue using quantitative TaqMan methylation-specific PCR for CDO1. Significantly higher CDO1 methylation was observed in cancer tissues compared with non-cancerous mucosa of the small intestine (ROC = 0.96). Among the various clinicopathological factors, positive correlation of CDO1 methylation with tumor diameter was observed (R = 0.31, p = 0.03), and the CDO1 methylation level was a possible prognostic factor for relapse-free survival (p = 0.09). Compared with CRC, SBC had a significantly poorer prognosis (p = 0.007) and displayed a significantly higher CDO1 methylation level (p < 0.0001). Intriguingly, especially in pStage I/II, there were robust prognostic difference between SBC and CRC (p = 0.08 / p < 0.0001), which may reflect CDO1 methylation status (p = 0.02 / p = 0.001). Among small bowel tumors, CDO1 methylation in SBC was higher in order of malignant lymphoma, cancer, and leiomyosarcoma/GIST (p = 0.002) by ANOVA. The CDO1 gene shows extremely cancer-specific hypermethylation, and it can be a prognostic marker in SBC.

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The small intestine consists of the duodenum, jejunum, and ileum, and the total mucosal surface area accounts for about 90% of the total gastrointestinal tract [1]. Nevertheless, small bowel cancer (SBC) is markedly less frequent than other gastrointestinal cancers and it is a very rare disease [1–3]. Its global incidence has been reported as fewer than 1.0 per 100,000 people, when age-standardized to the world population [1, 4]. The general interpretation as to why the incidence of SBC is low is as follows: there is an absence of genetic damage accumulation due to the rapid metabolism of the small intestinal epithelium; there is mucosal immune surveillance by small intestinal lymphatic tissue; and the small bowel avoids contact with carcinogens in food by not stagnating intestinal contents [5, 6]. In the clinical setting, the use of the small intestine endoscope has become prevalent for examination of the small bowel, and in recent years there is a concern regarding an increase in the number of SBC patients [7]. In addition, according to the statistics of small intestinal tumors in the United States in 2009, the 5-year survival rate of patients with SBC who underwent surgical treatment is as low as 32.5%, and has barely changed in the 20 years from 1985 to 2004 [8]. Normal colon and small intestine accumulate similar numbers of somatic mutations with aging [9]. However, due to its very low frequency of occurrence, studies to understand molecular carcinogenesis are still not satisfactory in SBC.

SBC is a disease that is significantly rarer than other gastrointestinal cancers [1]. However, with the recent improvements in diagnostic techniques, the frequency of clinical treatment of SBC has increased. In clinical practice, treatment is usually performed according to the treatment of CRC, although sometimes it is according to the treatment of gastric cancer. While small intestine cancer has been indicated to be similar to CRC, studies on its carcinogenesis mechanism are still insufficient. This study is the first report regarding the relationship between methylation abnormality of the CDO1 gene and SBC.




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