Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer.
BACKGROUND
Patients with advanced gastric cancer (GC) have an adverse prognosis even after curative resection. Development of novel diagnostic and therapeutic approaches for GC is urgently required.


METHODS
The expression and methylation status of DENN/MADD domain-containing protein 2D (DENND2D), a member of the membrane trafficking proteins, were evaluated in 12 GC cell lines and 112 pairs of surgical specimens. Subgroup analysis based on tumor differentiation, location, and morphology was also performed. Expression and distribution of DENND2D protein were determined by immunohistochemistry.


RESULTS
The majority of GC cell lines (75%) and tissues (79%) showed reduced expression of DENND2D mRNA compared with noncancerous gastric tissues. GC tissues showed a significantly lower mean expression level of mRNA and a higher frequency of promoter hypermethylation of DENND2D than corresponding noncancerous tissues. No significant differences in DENND2D mRNA expression and methylation status were found between GC subtypes categorized by tumor differentiation, location, and morphology. The expression patterns of DENND2D protein were confirmed to be consistent with those of DENND2D mRNA. Downregulation of DENND2D mRNA in GC tissues was significantly associated with factors related to more advanced GC and subsequent adverse prognosis. Among 72 patients who underwent R0 resection, downregulation of DENND2D mRNA in GC tissues was an independent prognostic factor and associated with early recurrence.


CONCLUSIONS
Our results suggested that DENND2D is a putative tumor suppressor gene regulated by promoter hypermethylation in GC. Downregulation of DENND2D can serve as a novel tumor biomarker to predict progression and early recurrence of all types of GC.
Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan, m-kanda@med.nagoya-u.ac.jp.
Mitsuro
M
Kanda
Dai
D
Shimizu
Shuji
S
Nomoto
Hideki
H
Takami
Soki
S
Hibino
Hisaharu
H
Oya
Ryoji
R
Hashimoto
Masaya
M
Suenaga
Yoshikuni
Y
Inokawa
Daisuke
D
Kobayashi
Chie
C
Tanaka
Suguru
S
Yamada
Tsutomu
T
Fujii
Goro
G
Nakayama
Hiroyuki
H
Sugimoto
Masahiko
M
Koike
Michitaka
M
Fujiwara
Yasuhiro
Y
Kodera
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D005753:Gastric Mucosa / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
D014408:Biomarkers, Tumor; C582173:DENND2D protein, human; D020662:Guanine Nucleotide Exchange Factors; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins