MicroRNAs (miRNAs) play a critical role in gastric cancer progression and metastasis. This study investigated the role of miRNA-135a in early gastric cancer (EGC) including lymph node (LN) ...metastasis. We examined the correlation between miRNA-135a expression and clinical outcomes in 59 patients who underwent surgery for EGC. Using gastric cancer cell lines, we performed functional and target gene analyses. miRNA-135a expression was down-regulated in 33.9% of patients. These patients showed a significantly more advanced stage (TNM stage ≥ IB, 35.0% vs. 12.8%, p = 0.045) and higher rate of LN metastasis (30.0% vs. 5.1%, p = 0.014) than those with up-regulation of miRNA-135a expression. In a multivariate analysis, down-regulation of miRNA-135a was an independent risk factor for LN metastasis (adjusted odds ratio, 8.04; 95% confidence interval, 1.08-59.81; p = 0.042). Functional analyses using gastric cancer cell lines showed that miRNA-135a suppressed cell viability, epithelial-mesenchymal transition, cell invasion, and migration. ROCK1 was a target of miRNA-135a and its expression was inversely correlated to that of miRNA-135a. ROCK1 expression was significantly increased in EGC patients with LN metastasis than in those without LN metastasis. Our results confirm the tumor-suppressive role of miRNA-135a, and demonstrate its role in LN metastasis in EGC. miRNA-135a and its target gene ROCK1 may be novel therapeutic and prognostic targets for EGC.
Abstract Background & Aims Early-onset gastric cancer, which develops in younger patients than most gastric cancers, is usually detected at advanced stages, has diffuse histologic features, and ...occurs more frequently in women. We investigated somatic genomic alterations associated with the unique characteristics of sporadic diffuse gastric cancers (DGCs) from younger patients. Methods We conducted whole exome and RNA sequence analyses of 80 resected DGC samples from patients 45 years old or younger in Korea. Patients with pathogenic germline mutations in CDH1 , TP53 , and ATM were excluded from the onset of this analysis, given our focus on somatic alterations. We used MutSig2CV to evaluate the significance of mutated genes. We recruited 29 additional early-onset Korean DGC samples and performed SNP6.0 array and targeted sequencing analyses of these 109 early-onset DGC samples (54.1% female, median age of 38 years). We compared the SNP6.0 array and targeted sequencing data of the 109 early-onset DGC samples with those from diffuse-type stomach tumor samples collected from 115 patients in Korea who were 46 years or older (late-onset) at the time of diagnosis (controls; 29.6% female, median age of 67 years). We compared patient survival times among tumors from different subgroups and with different somatic mutations. We performed gene silencing of RHOA or CDH1 in DGC cells with small interfering RNAs for cell-based assays. Results We identified somatic mutations in the following genes in a significant number of early-onset DGCs: the cadherin 1 gene ( CDH1 ), TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1 . None of 109 early-onset DGC cases had pathogenic germline CDH1 mutations. A higher proportion of early-onset DGCs had mutations in CDH1 (42.2%) or TGFBR1 (7.3%) compared with control DGCs (17.4% and 0.9%, respectively) (P<0.001 and 0.014 for CDH1 and TGFBR1 , respectively). In contrast, a smaller proportion of early-onset DGCs contained mutations in RHOA (9.2%) than control DGCs (19.1%) (P=0.033). Late-onset DGCs in the Cancer Genome Atlas also contained less frequent mutations in CDH1 and TGFBR1 and more frequent RHOA mutations, compared with early-onset DGCs. Early-onset DGCs from women contained significantly more mutations in CDH1 or TGFBR1 than early-onset DGCs from men. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times of patients with early-onset DGCs (hazard ratio, 3.4 (95% CI, 1.5–7.7)). RHOA activity was reduced by an R5W substitution—the RHOA mutation most frequently detected in early-onset DGCs. Silencing of CDH1 , but not RHOA , increased migratory activity of DGC cells. Conclusions In an integrative genomic analysis, we found higher proportions of early-onset DGCs to contain somatic mutations in CDH1 or TGFBR1 compared with late-onset DGCs. However, a smaller proportion of early-onset DGCs contained somatic mutations in RHOA than late-onset DGCs. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times of patients, which might account for the aggressive clinical course of early-onset gastric cancer. Female predominance in early-onset gastric cancer may be related to relatively high rates of somatic CDH1 and TGFBR1 mutations in this population.
Background & Aims Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the ...mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen ( PSCA ), but the loci of the other 2 were not investigated. Methods We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants. Results A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 ( MUC1 ) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10−13 ; odds ratio OR, 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 ( P = 1.43 × 10−11 ; OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38). Conclusions MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.
Background and Objectives
Additional surgery should be done after non‐curative endoscopic resection (ER) in early gastric cancer (EGC) due to the risk of lymph node metastasis (LNM). However, the ...distribution pattern of LNM in these patients is complicated and unpredictable. The aim of this study is to identify any different distribution patterns of LNM in patients with EGC who underwent additional surgery after non‐curative (ER) comparing to those without ER.
Methods
Patients who underwent surgery for EGC between 2001 and 2016 were included. Enrolled patients were divided into two groups, those who underwent additional surgery after non‐curative ER and those who underwent direct surgery without a history of ER. Demographics, tumor characteristics and LNM distribution pattern were analyzed.
Results
Among 4295 patients with EGC, 404 patients had a history of preoperative ER, and 3891 patients did not. After the application of exclusion criteria, 23 (7.1%) of 322 patients undergoing additional surgery had LNM. The additional surgery group showed less LNM, fewer nodal stations and more restricted distribution pattern of LNM.
Conclusions
The distribution pattern of LNM in EGC is complicated. However, more restricted locoregional LNM could be expected in cases of additional surgery after non‐curative ER than after direct surgery.
Background/Aims
The operative link for gastritis assessment (OLGA) and operative link on gastric intestinal metaplasia assessment (OLGIM) staging systems are recommended to assess the severity of ...gastritis, but the optimal biopsy sites have not been clearly defined. We aimed to investigate whether the scoring of the OLGA and OLGIM stages was affected by the use of different biopsy sites.
Methods
Between 2014 and 2015, to determine OLGA and OLGIM stages, seven biopsy samples were obtained from the antrum (lesser and greater curvatures LG of the antrum and lesser curvature of the angle) and corpus (LG and anterior and posterior walls AP) in 247 patients diagnosed with gastritis, gastric adenoma, or adenocarcinoma. The OLGA and OLGIM stages were scored using four different protocols: antrum + angle + corpus LG, antrum + angle + corpus AP, antrum + corpus LG, and antrum + corpus AP. High‐risk group included patients who had OLGA or OLGIM stages III and IV.
Results
For the OLGA stage, the angle + antrum + corpus LG protocol placed more patients in the high‐risk group (64.4%) than the angle + antrum + corpus AP (55.5%, P < .001), antrum+corpus LG (59.5%, P = .031), and antrum + corpus AP (47.8%, P < .001) protocols. Likewise, for the OLGIM stage, the angle + antrum + corpus LG protocol placed more patients in the high‐risk group (48.6%) than the angle + antrum + corpus AP (46.2%, P = .134), antrum + corpus LG (36.8%, P < .001), and antrum + corpus AP (37.2%, P < .001) protocols.
Conclusions
To prevent underestimation of OLGA and OLGIM stages, it is necessary to include an angle biopsy, and to obtain corpus biopsy specimens from lesser and greater curvature sites rather than from anterior and posterior wall sites.
Surgery plus peri-operative/adjuvant chemotherapy is the standard of care for locally advanced GC/GEJC, though with unsatisfactory results. dMMR/MSI-high tumors have better prognosis and scant ...benefit from chemotherapy as compared to pMMR/MSS ones. The differential outcome of therapies in terms of safety and efficacy according to sex is still debated in GC/GEJC patients.
We previously performed an individual patient data pooled analysis of MAGIC, CLASSIC, ITACA-S, and ARTIST trials including GC/GEJC patients treated with surgery alone or surgery plus peri-operative/adjuvant chemotherapy to assess the value of MSI status. We performed a secondary analysis investigating the prognostic and predictive role of sex (female versus male) in the pooled analysis dataset in the overall population and patients stratified for MSI status (MSI-high versus MSS/MSI-low). Disease-free (DFS) and overall survival (OS) were calculated.
Patients with MSI-high tumors had improved survival as compared to MSS/MSI-low ones irrespective of sex, whereas in those with MSS/MSI-low tumors, females had numerically longer OS and DFS (5-year OS was 63.2% versus 57.6%, HR 0.842; p = 0.058, and 5-year DFS was 55.8% versus 50.8%, HR 0.850; p = 0.0504 in female versus male patients). The numerical difference for the detrimental effect of chemotherapy in MSI-high GC was higher in females than males, while the significant benefit of chemotherapy over surgery alone was confirmed in MSS/MSI-low GC irrespective of sex.
This pooled analysis including four randomized trials highlights a relevant impact of sex in the prognosis and treatment efficacy of MSI-high and MSS/MSI-low non-metastatic GC/GEJC.
•Role of sex in individual patient data analysis on MSI/MSS resectable gastric cancer.•MSI-high GC patients have better prognosis than MSS/MSI-low ones irrespective of sex.•In MSS/MSI-low GC females had non-significantly improved DFS and OS than males.•MSI-high GC females had a higher trend of detriment from multimodal therapy than males.
Papillary gastric cancer (GC) is classified as differentiated adenocarcinoma, together with well-differentiated (WD) and moderately differentiated (MD) adenocarcinoma. This study evaluated the risk ...of lymph node metastasis (LNM) in submucosal (SM) invasive papillary GC compared with other differentiated early GC types.
This retrospective study involved three tertiary hospitals and enrolled 1,798 lesions with differentiated SM invasive GC treated with curative gastrectomy between March 2001 and December 2012. All pathology slides were reviewed, and clinicopathologic findings associated with LNM, including tumor size, location, gross type, ulceration, depth and width of SM invasion, and lymphovascular invasion (LVI), were analyzed.
The proportion of SM papillary GC was 2.8% (n=51). SM papillary GC was associated with larger tumor size and deeper and wider SM invasion than other differentiated GC types. LNM was significantly higher in the papillary type than in the MD and WD types. LNM was found in 27.5% of SM papillary GC patients (WD: 9.0%, MD: 21.2%). LVI was the only significant risk factor for LNM in SM papillary GC. The depth or width of SM invasion was not associated with LNM in papillary GC. Lower third location or elevated gross appearance was significantly associated with LVI.
SM papillary GC had the highest LNM rate, with features different from those of other differentiated SM invasive GCs. The treatment strategy for SM papillary GC should be carefully approached, especially for lesions located in the lower third or of the elevated gross type.
Treatment strategy for early gastric cancer depends on the probability of lymph node metastasis. The aim of this study is to develop a nomogram predicting lymph node metastasis in early gastric ...cancer using clinicopathological factors and biomarkers.
A literature review was performed to identify biomarkers related to lymph node metastasis in gastric cancer. Seven markers were selected and immunohistochemistry was performed in 336 early gastric cancer tissues. Based on the multivariable analysis, a prediction model including clinicopatholgical factors and biomarkers was developed, and benefit of adding biomarkers was evaluated using the area under the receiver operating curve and net reclassification improvement. Functional study in gastric cancer cell line was performed to evaluate mechanism of biomarker.
Of the seven biomarkers studied, α1 catenin and CD44v6 were significantly associated with lymph node metastasis. A conventional prediction model, including tumor size, histological type, lymphatic blood vessel invasion, and depth of invasion, was developed. Then, a new prediction model including both clinicopathological factors and CD44v6 was developed. Net reclassification improvement analysis revealed a significant improvement of predictive performance by the addition of CD44v6, and a similar result was shown in the internal validation using bootstrapping. Prediction nomograms were then constructed based on these models. In the functional study, CD44v6 was revealed to affect cell proliferation, migration and invasion.
Overexpression of CD44v6 was a significant predictor of lymph node metastasis in early gastric cancer. The prediction nomograms incorporating CD44v6 can be useful to determine treatment plans in patients with early gastric cancer.
Background
Discrepancies in the clinicopathologic parameters pre- and post-endoscopic submucosal dissection (ESD) sometimes necessitate additional surgical resection. The aim of this study was to ...assess such discrepancies in clinicopathologic parameters before and after ESD in the context of reducing the risk of failure of curative ESD.
Methods
Data on 712 early gastric cancer patients were prospectively collected from 12 university hospitals nationwide. The inclusion criteria were differentiated carcinoma <3 cm in size, no ulceration, submucosal invasion <500 μm, and no metastasis. Clinicopathologic factors were compared retrospectively.
Results
The discrepancy rate was 20.1 % (148/737) and the most common cause of discrepancy was tumor size (64 cases, 8.7 %). Ulceration, undifferentiated histology, and SM2 invasion were found in 34 (4.6 %), 18 (2.4 %), and 51 cases (6.9 %), respectively. Lymphovascular invasion (LVI) was observed in 34 cases (4.6 %). Cases with lesions exceeding 3 cm in size showed more frequent submucosal invasion, an elevated gross morphology, and upper and middle locations (
p
< 0.05). In the cases with ulceration, depth of invasion (DOI) was deeper than in the cases without ulceration (
p
= 0.005). Differentiation was correlated with DOI and LVI (
p
= 0.021 and 0.007). DOI was correlated with tumor size, ulceration, differentiation, LVI, gross type, and location. There were statistically significant differences between mucosal cancer cases and submucosal cancer cases in tumor size, differentiation, ulceration, LVI, and location.
Conclusions
The overall discrepancy rate was 20.1 %. To reduce this rate, it is necessary to evaluate the DOI very cautiously, because it is correlated with other parameters. In particular, careful checking for SM-invasive cancer is required due to the high incidence of LVI irrespective of the depth of submucosal invasion.
Background
Few results regarding the long-term survival from laparoscopy-assisted total gastrectomy (LATG) have been reported. The purpose of this study was to investigate the feasibility of LATG in ...terms of long-term survival and morbidity.
Methods
A case–control study was conducted on 100 cases of LATG and 348 cases of open total gastrectomy (OTG) performed for treating clinical stage I (cT1N0, cT1N1, and cT2N0) gastric cancer from August 2003 to December 2008 at the National Cancer Center of Korea. The clinicopathological characteristics, surgical outcomes, and complications were compared between the LATG and OTG groups. The overall survival rate and disease-free survival rate were analyzed using a Cox proportional hazards model for multivariate analysis.
Results
The rate of postoperative complications was 27 %, the most common being anastomotic stenosis from LATG (9 %). There were no significant differences in surgical outcomes and complications between the LATG and OTG groups except for a longer operating time for LATG. Survival rates were also similar between groups; the hazard ratio of LATG versus OTG was 0.43 (95 % confidence interval CI = 0.15–1.20;
p
= 0.107) for overall survival and 0.47 (95 % CI = 0.19–1.18;
p
= 0.106) for disease-free survival.
Conclusion
LATG may be a feasible procedure with acceptable complications and long-term survival rate for clinical stage I gastric cancer.
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