Aberrant gene methylation in the peritoneal fluid is a risk factor predicting peritoneal recurrence in gastric cancer.
OBJECTIVE
To investigate whether gene methylation in the peritoneal fluid (PF) predicts peritoneal recurrence in gastric cancer patients.


METHODS
The gene methylation of CHFR (checkpoint with forkhead and ring finger domains), p16, RUNX3 (runt-related transcription factor 3), E-cadherin, hMLH1 (mutL homolog 1), ABCG2 (ATP-binding cassette, sub-family G, member 2) and BNIP3 (BCL2/adenovirus E1B 19 kDa interacting protein 3) were analyzed in 80 specimens of PF by quantitative methylation-specific polymerase chain reaction (PCR). Eighty patients were divided into 3 groups; Group A (n = 35): the depth of cancer invasion was less than the muscularis propria; Group B (n = 31): the depth of cancer invasion was beyond the muscularis propria. Both group A and B were diagnosed as no cancer cells in peritoneal cytology and histology; Group C (n = 14): disseminated nodule was histologically diagnosed or cancer cells were cytologically defined in the peritoneal cavity.


RESULTS
The positive rates of methylation in CHFR, E-cadherin and BNIP3 were significantly different among the 3 groups and increased in order of group A, B and C (0%, 0% and 21% in CHFR, P < 0.05; 20%, 45% and 50% in E-cadherin, P < 0.05; 26%, 35% and 71% in BNIP3, P < 0.05). In addition, the multigene methylation rate among CHFR, E-cadherin and BNIP3 was correlated with group A, B and C (9%, 19% and 57%, P < 0.001). Moreover, the prognosis was analyzed in group B, excluding 3 patients who underwent a non-curative resection. Two of the 5 patients with multigene methylation showed peritoneal recurrence after surgery, while those without or with a single gene methylation did not experience recurrence (P < 0.05).


CONCLUSIONS
This study suggested that gene methylation in the PF could detect occult neoplastic cells in the peritoneum and might be a risk factor for peritoneal metastasis.
Hiraki
Masatsugu
M
Department of Surgery, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga 849-8501, Japan.
Kitajima
Yoshihiko
Y
Sato
Seiji
S
Nakamura
Jun
J
Hashiguchi
Kazuyoshi
K
Noshiro
Hirokazu
H
Miyazaki
Kohji
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001202:Ascitic Fluid / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology; D006801:Humans; D053539:Keratin-19 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology / Q000378:metabolism / Q000556:secondary; D010534:Peritoneal Neoplasms / Q000453:epidemiology / Q000378:metabolism / Q000556:secondary*; D000075223:Poly-ADP-Ribose Binding Proteins; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases
C090121:BNIP3 protein, human; D014408:Biomarkers, Tumor; D015820:Cadherins; D002272:Carcinoembryonic Antigen; D018797:Cell Cycle Proteins; D053539:Keratin-19; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011518:Proto-Oncogene Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases