Promoter DNA methylation, which occurs on cytosine nucleotides across CpG islands, results in gene silencing and represents a major epigenetic alteration in human cancer. Methylation‐specific PCR can ...amplify these modifications as markers in cancer cells. In the present work, we rigorously review the published literatures describing DNA methylation in the promoters of critical tumor suppressor genes; detection of promoter DNA methylation in various body fluids permits early detection of cancer cells during perioperative courses of clinical treatment. The latest whole‐genome comprehensive explorations identified excellent epigenetic biomarkers that could be detected at high frequency with high specificity; these biomarkers, which are designated highly relevant methylation genes (HRMG), permit the discrimination of tumor tissues from the corresponding normal tissues; these markers are also associated with unique cancer phenotypes, including dismal prognosis. In humans, HRMG include the CDO1, GSHR, RASSF1 and SFRP1 genes, with these markers permitting discrimination depending on the organs tested. The combination of several HRMG increased the early detection of cancer and exhibited reliable surveillance potential in human body fluids. Cancer clinics using such epigenetic biomarkers are entering a new era of enhanced decision‐making with the potential for improved cancer prognosis.
This is a review paper describing molecular diagnostics of cancer using DNA methylation. DNA methylation has been recently focused on in relation to liquid biopsy in various cancers. It is a promising candidate to improve cancer treatment and patient prognosis.
Chemotherapy is indispensable for gastric cancer. For unresectable and/or recurrent gastric cancer, first‐line chemotherapy consists of multidrug regimens including oral 5‐FU agents such as S1/Xeloda ...and platinum preparations, as well as Trastuzumab, which is effective in HER2‐positive cases. Second‐ and third‐line chemotherapy regimens include taxanes, Ramucirumab (R‐mab), and Nivolumab (N‐mab), which have different mechanisms of action from first‐line chemotherapy. R‐mab is molecularly targeted to vascular endothelial growth factor receptor 2 in the host cells, but its indication is not conditional. For resectable gastric cancer, in Eastern countries, postoperative adjuvant chemotherapy has been successful, including S1, Docetaxel/S1 (DS), and Xeloda/Oxaliplatin (Xelox) regimens, whereas, in Western countries, the 5‐FU/Leucovorin/Oxaliplatin/Docetaxel (FLOT) regimen was recently shown to be effective in the perioperative chemotherapy setting. Most recently, however, in Eastern countries, perioperative SOX was demonstrated to be effective in specific advanced gastric cancer. For stage IV gastric cancer, new therapeutic strategies have been proposed such as neoadjuvant chemotherapy and conversion surgery, and cures can be conditionally obtained. Recent genomic understanding of gastric cancer proposed a diversity of molecular targets by molecular profiling. Such optimized chemotherapy regimens, according to the specific clinical situations, have been rigorously established for the best survival of advanced gastric cancer.
History and emerging chemotherapy regimens in first‐line chemotherapy for unresectable and/or recurrent gastric cancer. Japan‐directed evidence recommends SOX as well as CS regimens the best. Extra‐Japan‐directed evidence recommends Xelox as well as XP or EOX.
Background
The incidence of metachronous multiple gastric cancer (MMGC) after gastrectomy remains unclear. This study evaluated the incidences of MMGC according to specific gastrectomy types, ...including pylorus-preserving gastrectomy (PPG), proximal gastrectomy (PG), and function-preserving gastrectomy (FPG), which was categorized as segmental gastrectomy and local resection.
Methods
We conducted a questionnaire survey of the Japanese Society for Gastro-Surgical Pathophysiology members, who were asked to report their institutional numbers of radical gastrectomy cases for cancer between 2003 and 2012. The cases were categorized according to whether the remnant stomach’s status was followed for > 5 years, confirmation of MMGC, time to diagnosis, and treatment for MMGC. We calculated the “precise incidence” of MMGC by dividing the number of MMGC cases by the number of cases in which the status of remnant stomach was followed up for > 5 years.
Results
The responses identified 33,731 cases of gastrectomy. The precise incidences of MMGC were 2.35% after distal gastrectomy (DG), 3.01% after PPG, 6.28% after PG (
p
< 0.001), and 8.21% after FPG (
p
< 0.001). A substantial proportion of MMGCs (36.4%) was found at 5 years after the initial surgery. The rates of MMGC treatment using endoscopic submucosal dissection were 31% after DG, 28.6% after PPG, 50.8% after PG (
p
< 0.001), and 67.9% after FPG (
p
< 0.001).
Conclusions
The incidence of MMGC was 2.4% after DG, and higher incidences were observed for larger stomach remnants. However, the proportion of cases in which MMGC could be treated using endoscopic submucosal dissection was significantly higher after PG and FPG than after DG.
Postoperative pancreatic fistula is one of the most severe complications after gastric cancer surgery, and can cause critical patient conditions leading to surgery‐related death. Fortunately, the ...incidence of postoperative pancreatic fistula after gastrectomy seems to be decreasing with changes in operative procedures. The rate was reported at about 30% after open gastrectomy with Appleby's method in 1997, but lately has improved below 1% for robotic gastrectomy in 2019. For the diagnosis of postoperative pancreatic fistula, drain amylase concentration has been demonstrated to be beneficial and some reports have proposed the optimal cut‐off values of drain amylase to predict major postoperative pancreatic fistula. There have been many reports identifying risk factors for postoperative pancreatic fistula, including overweight patients, pancreatic anatomy, blunt trauma from compression of the pancreas, and thermal injuries caused by the continuous use of energy devices. And importantly, laparoscopic gastrectomy has been shown to be more often associated with postoperative pancreatic fistula than open gastrectomy in the prospective national clinical database in Japan. Hence, further sophistication of surgical techniques to reduce pancreas compression would have great promise in reducing postoperative pancreatic fistula after laparoscopic gastrectomy.
Postoperative pancreatic fistula is recently decreasing with great advancement of surgical technique.
Background
Gastric cancer (GC) patients with peritoneal metastasis are defined as stage IV in the Japanese classification of GC. For patients with peritoneal metastasis limited to positive peritoneal ...lavage cytology (CY1) and/or localized peritoneal metastasis (P1a), gastrectomy followed by S1 monotherapy is one of the most widely accepted therapeutic strategy in Japan. This study investigated the efficacy of preoperative chemotherapy as initial treatment in GC patients with CY1 and/or P1a.
Methods
We retrospectively reviewed GC patients diagnosed with CY1 and/or P1a at 34 institutions in Japan between 2008 and 2012. Selection criteria were: adenocarcinoma, no distant metastasis except CY1 or P1a, and no prior treatment. The subjects were divided into an Initial-Chemotherapy group and an Initial-Surgery group, according to the initial treatment.
Results
A total of 824 patients were collected and 713 eligible patients were identified for this study. As the initial treatment, 150 patients received chemotherapy (Initial-Cx), and 563 patients underwent surgery (Initial-Sx). Initial-Cx regimens were cisplatin plus S1/docetaxel plus cisplatin plus S1/others (
n
= 90/37/23). Both overall survival (OS) and progression-free survival (PFS) were similar between the Initial-Cx and Initial-Sx groups (median OS 24.8 and 24.0 months, HR 1.07, 95% CI 0.87–1.3; median PFS 14.9 and 13.9 months, HR 1.04, 95% CI 0.85–1.27). The 5-year OS rates were 22.3% in the Initial-Cx group and 21.5% in the Initial-Sx group.
Conclusions
Although, the preoperative chemotherapy did not show a survival benefit for GC patients with CY1 and/or P1a, initial-Cx showed favorable survival in patients who converted to P0 and CY0.
There have been few available prognostic biomarkers in gastric cancer. We rigorously assessed the clinical relevance of promoter DNA methylation of Cysteine dioxygenase type 1 (CDO1) gene, a ...cancer-specific aberration, in human gastric cancer.
Quantitative CDO1 methylation value (TaqMeth V) was initially calculated in 138 gastric cancer patients operated in 2005, and its clinical significance was elucidated. As a subsequent expanded set, 154 gastric cancer patients with pathological stage (pStage) II / III with no postoperative therapy were validated between 2000 and 2010.
(1) Median TaqMeth V of CDO1 gene methylation of gastric cancer was 25.6, ranging from 0 to 120.9. As pStage progressed, CDO1 TaqMeth V became higher (p < 0.0001). (2) The optimal cut-off value was determined to be 32.6; gastric cancer patients with high CDO1 gene methylation showed a significantly worse prognosis than those with low CDO1 gene methylation (p < 0.0001). (3) A multivariate cox proportional hazards model identified high CDO1 gene methylation (p = 0.033) as an independent prognostic factor. (4) The results were recapitulated in the expanded set in pStage III, where high CDO1 gene methylation group had a significantly worse prognosis than low CDO1 gene methylation group (p = 0.0065). Hematogenous metastasis was unique in pStage III with high CDO1 gene methylation (p = 0.0075). (5) Anchorage independent growth was reduced in several gastric cancer cell lines due to forced expression of the CDO1 gene, suggesting that abnormal CDO1 gene expression may represent distant metastatic ability.
Promoter DNA hypermethylation of CDO1 gene was rigorously validated as an important prognostic biomarker in primary gastric cancer with specific stage.
Background
Minimal residual disease of the peritoneum is challenging for early cancer detection in gastric cancer (GC). Utility of PCR amplification of cancer-derived DNA has been considered feasible ...due to its molecular stability, however such markers have never been available in GC clinics. We recently discovered cancer-specific methylation of
CDO1
gene in GC, and investigated the clinical potential to detect the minimal residual disease.
Methods
One hundred and two GC patients were investigated for peritoneal fluid cytology test (CY), and detection level of the promoter DNA methylation of
CDO1
gene was assessed by quantitative methylation specific PCR (Q-MSP) in the sediments (DNA CY).
Results
(1) CY1 was pathologically confirmed in 8 cases, while DNA CY1 was detected in 18 cases. All 8 CY1 were DNA CY1. (2) DNA CY1 was recognized in 14.3, 25.0, 20.0, and 42.9%, in macroscopic Type II, small type III, large type III, and type IV, respectively, while it was not recognized in Type 0/I/V. (3) DNA CY1 was prognostic relevance in gastric cancer (
p
= 0.0004), and its significance was robust among Type III/IV gastric cancer (
p
= 0.006 for overall survival and
p
= 0.0006 for peritoneal recurrence free survival). (4) The peritoneal recurrence was hardly seen in GC patients with potent perioperative chemotherapy among those with DNA CY1.
Conclusions
DNA CY1 detected by Q-MSP for
CDO1
gene promoter DNA methylation has a great potential to detect minimal residual disease of the peritoneum in GC clinics as a novel DNA marker.
This study investigated the clinical characteristics of patients with gastric tube cancer following esophagectomy at our hospital, and to examine the outcomes of gastrectomy versus endoscopic ...submucosal dissection. Of 49 patients who underwent treatment for gastric tube cancer that developed 1 year or more after esophagectomy, 30 patients underwent subsequent gastrectomy (Group A), and 19 patients underwent endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) (Group B). The characteristics and outcomes of these two groups were compared. The interval between esophagectomy and diagnosis of gastric tube cancer ranged from 1 to 30 years. The most common location was the lesser curvature of the lower gastric tube. When the cancer was detected early, EMR or ESD was performed, and the cancer did not recur. In advanced tumors, gastrectomy was performed but the gastric tube was difficult to approach and lymph node dissection was difficult; two patients died as a result of the gastrectomy. In Group A, recurrence occurred most often as axillary lymph node, bone, or liver metastases; in Group B, no recurrence or metastases were observed. In addition to recurrence and metastasis, gastric tube cancer is often observed after esophagectomy. The present findings highlight the importance of early detection of gastric tube cancer after esophagectomy and that the EMR and ESD procedures are safe and have significantly fewer complications compared with gastrectomy. Follow-up examinations should be scheduled with consideration given to the most frequent sites of gastric tube cancer occurrence and the time elapsed since esophagectomy.
Promoter DNA methylation of MutL homolog 1 (MLH1) is considered to play a causative role in microsatellite instability (MSI) carcinogenesis in primary gastric cancer, and a high MSI status is ...associated with treatment sensitivity to human cancers. Nevertheless, clinicopathological analysis is defective for MLH1 methylation status in a quantitative manner. We newly developed quantitative methylation specific PCR using a TaqMan probe and applied it to 138 patients with primary gastric cancer who underwent gastrectomy in addition to basic molecular features such as MSI, Epstein Barr virus, and other DNA methylation status. (1) In primary gastric cancer, median methylation value was 0.055, ranging from 0 to 124.3. First, MLH1 hypermethylation was strongly correlated with MSI-High/MSI-Low status and suppressed immunostaining (P < 0.0001). (2) The MLH1 hypermethylation was associated with advanced age (P = 0.0048), antral location (P = 0.0486), synchronous multiple gastric cancer (P = 0.0001), and differentiated histology (P = 0.028). (3) Log-rank plot analysis identified the most relevant cut-off value (0.23) to reflect gentle phenotypes in MLH1 hypermethylation cases (P = 0.0019), especially in advanced gastric cancer (P = 0.0132), which are designated as haploinsufficiency of MSI (MSI-haplo) phenotype in this study. (4) In synchronous multiple gastric cancer, MLH1 hypermethylation was not necessarily confirmed as field cancerization. (5) MSI-haplo defined by MLH1 methylation status represented distinct prognostic phenotype even after molecular classifications. MLH1 hypermethylation designated as MSI-haplo may represent unique prognostic phenotype during gastric carcinogenesis.
Background
Laparoscopy-assisted proximal gastrectomy (LAPG) with esophagogastrostomy using the double-flap technique has been reported to rarely cause gastroesophageal reflux. However, quantitative ...evaluation of the reflux has hardly been performed. The aim of this study was to clarify the superiority of the double-flap technique of LAPG with esophagogastrostomy compared with the OrVil technique in terms of preventing gastroesophageal reflux.
Methods
A total of 40 and 51 patients who underwent LAPG with esophagogastrostomy using the double-flap and OrVil techniques, respectively, for upper one-third gastric cancer were included in this study. Of these, 22 and 13 patients in the double-flap and OrVil groups, respectively, consented to undergo a 24-h impedance-pH monitoring test at 3 months postoperatively. Postoperative complications, including gastroesophageal reflux and anastomotic stricture, were assessed retrospectively.
Results
No significant differences were observed in the patients’ background between both groups, except for a higher D1+ dissection rate observed in double-flap group than in the OrVil group (93% vs 25%,
P
< 0.001). Operative time was significantly longer in the double-flap group than in the OrVil group (353 min vs 280 min,
P
< 0.001). All reflux % time was significantly lower in the double-flap group than in the OrVil group (1.29% vs 2.62%,
P
= 0.043). On the other hand, the proportion of anastomotic stricture requiring endoscopic balloon dilatation was lower in the double-flap group than in the OrVil group but without statistical significance (18% vs 27%;
P
= 0.32).
Conclusions
Despite its longer operative time and still relatively high anastomotic stricture rate, the double-flap technique would be better than the OrVil technique in terms of preventing gastroesophageal reflux in patients who underwent LAPG with esophagogastrostomy.
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