Aberrant gene methylation in the peritoneal fluid is a risk factor predicting peritoneal recurrence in gastric cancer

AIM: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 defi ned 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).CONCLUSION: 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.

Methylation-mediated gene silencing as biomarkers of gastric cancer:a review

Despite a decline in the overall incidence of gastric cancer(GC),the disease remains the second most common cause of cancer-related death worldwide and is thus a significant global health problem.The best means of improving the survival of GC patients is to screen for and treat early lesions.However,GC is often diagnosed at an advanced stage and is associated with a poor prognosis.Current diagnostic and therapeutic strategies have not been successful in decreasing the global burden of the disease;therefore,the identification of reliable biomarkers for an early diagnosis,predictive markers of recurrence and survival and markers of drug sensitivity and/or resistance is urgently needed.The initiation and progression of GC depends not only on genetic alterations but also epigenetic changes,such as DNA methylation and histone modification.Aberrant DNA methylation is the most well-defined epigenetic change in human cancers and is associated with inappropriate gene silencing.Therefore,an increasing number of genes methylated at the promoter region have been targeted as possible biomarkers for different purposes,including early detection,classification,the assessment of the tumor prognosis,the development of therapeutic strategies and patient follow-up.This review article summarizes the current understanding and recent evidence regarding DNA methylation markers in GC with a focus on the clinical potential of these markers.

Immunohistochemical and molecular genetic analyses of multiple sporadic gastrointestinal stromal tumors

A 77-year-old Japanese male patient was admitted to our hospital complaining of general fatigue and melena. A gastroduodenal endoscopic examination revealed no def initive localized lesions. However, both a large amount of cruor and blood ? ow from the small intestine into the ascending colon was observed during the colonoscopic examination. At least three tumors, believed to originate from the small intestine, were detected by abdominal computed tomography. Based on these f indings, multiple and hemorrhagic small intestinal tumors were diagnosed and surgical treatment of the tumors planned. During the celiotomy, twelve tumors were found in the small intestine. Intestinal wedge or partial resection was applied. All excised specimens demonstrated morphology of a submucosal tumor and the largest tumor had a delle with coagulation on the mucosal face. In the histological f indings, hematoxylin and eosin staining showed spindlecell morphology. The immunohistochemical examination revealed that the tumor cells were diffusely positive for KIT and CD34. The myenteric plexus layer of the small intestine was focal-positive for KIT and showed no intestinal cells of Cajal hyperplasia. The tumor sequencing results revealed an identical missense mutation in codon 642 of c-kit exon 13 leading to the replacement of lysine by glutamic acid and a silent germ-line mutation in exon 12 of the PDGFRA gene concerning whole blood, normal mucosa and tumors. We concluded that the current subject was categorized as having multiple sporadic-type gastrointestinal stromal tumor with identical mutational types. Although the patient did not receive any adjuvant chemotherapy, there has been no sign of recurrence over the 3 years since the surgery.