TY - JOUR
T1 - Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability
AU - Toda, Keisuke
AU - Nagasaka, Takeshi
AU - Umeda, Yuzo
AU - Tanaka, Takehiro
AU - Kawai, Takashi
AU - Fuji, Tomokazu
AU - Taniguchi, Fumitaka
AU - Yasui, Kazuya
AU - Kubota, Nobuhito
AU - Takehara, Yuko
AU - Tazawa, Hiroshi
AU - Kagawa, Shunsuke
AU - Sun, Dong Sheng
AU - Nishida, Naoshi
AU - Goel, Ajay
AU - Fujiwara, Toshiyoshi
N1 - Funding Information:
The authors would like to thank Mr. Toru Nakai, Mrs. Tae Yamanishi, and Mr. Akihiro Nyuya for technical assistance and Enago (www.enago.jp) for English language editing. This work was supported by KAKENHI (19390351 and 20590572).
Publisher Copyright:
© 2015, Toda et al.
PY - 2015/7/23
Y1 - 2015/7/23
N2 - Background: The gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in gastric tumorigenesis. Results: In the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH) analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI phenotypes, respectively. More than 5 % methylation in the DCC and UNC5C promoters were found in 45 % (44/98) and 32 % (31/98) gastric cancers, respectively, and in 9 % (9/105) and 5 % (5/105) normal gastric mucosa, respectively. Overall, 70 % (58 of 83 informative cases) and 51 % (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant methylation in the DCC and UNC5C genes, respectively. In total, 77 % (51 of 66 informative cases) of gastric cancers showed cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both DCC and UNC5C were inactivated in 97 % of CIN-positive gastric cancers and in 55 % of CIN-negative gastric cancers. Conclusions: Defect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory pathway in gastric carcinogenesis.
AB - Background: The gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in gastric tumorigenesis. Results: In the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH) analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI phenotypes, respectively. More than 5 % methylation in the DCC and UNC5C promoters were found in 45 % (44/98) and 32 % (31/98) gastric cancers, respectively, and in 9 % (9/105) and 5 % (5/105) normal gastric mucosa, respectively. Overall, 70 % (58 of 83 informative cases) and 51 % (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant methylation in the DCC and UNC5C genes, respectively. In total, 77 % (51 of 66 informative cases) of gastric cancers showed cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both DCC and UNC5C were inactivated in 97 % of CIN-positive gastric cancers and in 55 % of CIN-negative gastric cancers. Conclusions: Defect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory pathway in gastric carcinogenesis.
KW - Chromosomal instability
KW - DCC
KW - Gastric cancer
KW - Methylation
KW - Netrin-1 receptors
KW - UNC5C
UR - http://www.scopus.com/inward/record.url?scp=84937793347&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937793347&partnerID=8YFLogxK
U2 - 10.1186/s13148-015-0096-y
DO - 10.1186/s13148-015-0096-y
M3 - Article
AN - SCOPUS:84937793347
VL - 7
JO - Clinical Epigenetics
JF - Clinical Epigenetics
SN - 1868-7075
IS - 1
M1 - 73
ER -