Clinical Manifestations and Genotype of Primary Ciliary Dyskinesia Diagnosed in Korea: Multicenter Study.

PURPOSE: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder that leads to secondary ciliary dysfunction. PCD is a rare disease, and data on it are limited in Korea. This study systematically evaluated the clinical symptoms, diagnostic characteristics, and treatment modalities of pediatric PCD in Korea. METHODS: This Korean nationwide, multicenter study, conducted between January 2000 and August 2022, reviewed the medical records of pediatric patients diagnosed with PCD. Prospective studies have been added to determine whether additional genetic testing is warranted in some patients. RESULTS: Overall, 41 patients were diagnosed with PCD in 15 medical institutions. The mean age at diagnosis was 11.8 ± 5.4 years (range: 0.5 months-18.9 years). Most patients (40/41) were born full term, 15 (36.6%) had neonatal respiratory symptoms, and 12 (29.3%) had a history of admission to the neonatal intensive care unit. The most common complaint (58.5%) was chronic nasal symptoms. Thirty-three patients were diagnosed with transmission electron microscopy (TEM) and 12 patients by genetic studies. TEM mostly identified outer dynein arm defects (alone or combined with inner dynein arm defects, n = 17). The genes with the highest mutation rates were DNAH5 (3 cases) and DNAAF1 (3 cases). Rare genotypes (RPGR, HYDIN, NME5) were found as well. Chest computed tomography revealed bronchiectasis in 33 out of 41 patients. Among them, 15 patients had a PrImary CiliAry DyskinesiA Rule score of over 5 points. CONCLUSIONS: To our knowledge, this is the first multicenter study to report the clinical characteristics, diagnostic methods, and genotypes of PCD in Korea. These results can be used as basic data for further PCD research.

Epigenetic Activation of Tensin 4 Promotes Gastric Cancer Progression.

Gastric cancer (GC) is a complex disease influenced by multiple genetic and epigenetic factors. Chronic inflammation caused by Helicobacter pylori infection and dietary risk factors can result in the accumulation of aberrant DNA methylation in gastric mucosa, which promotes GC development. Tensin 4 (TNS4), a member of the Tensin family of proteins, is localized to focal adhesion sites, which connect the extracellular matrix and cytoskeletal network. We identified upregulation of TNS4 in GC using quantitative reverse transcription PCR with 174 paired samples of GC tumors and adjacent normal tissues. Transcriptional activation of TNS4 occurred even during the early stage of tumor development. TNS4 depletion in GC cell lines that expressed high to moderate levels of TNS4, i.e., SNU-601, KATO III, and MKN74, reduced cell proliferation and migration, whereas ectopic expression of TNS4 in those lines that expressed lower levels of TNS4, i.e., SNU-638, MKN1, and MKN45 increased colony formation and cell migration. The promoter region of TNS4 was hypomethylated in GC cell lines that showed upregulation of TNS4. We also found a significant negative correlation between TNS4 expression and CpG methylation in 250 GC tumors based on The Cancer Genome Atlas (TCGA) data. This study elucidates the epigenetic mechanism of TNS4 activation and functional roles of TNS4 in GC development and progression and suggests a possible approach for future GC treatments.

Association between soy products, fruits, vegetables, and dairy products and gastric cancer risk in Helicobacter pylori-infected subjects: a case-control study in Korea.

BACKGROUND/OBJECTIVES: Consumption of certain protective foods may help inhibit Helicobacter pylori (H. pylori) associated gastric pathologies. However, studies conducted to assess the efficacy of protective foods in H. pylori-infected subjects are either limited or inconsistent. This study evaluated the association of individual or a combination of protective foods on the incidence of gastric cancer (GC) in H. pylori-positive subjects through a case-control study. MATERIALS/METHODS: Subjects aged 20-79 years were selected from 2 hospitals between December 2002 and September 2006. In total, 134 patients and 212 controls tested positive for H. pylori infection. Among these, we included 82 pairs of cases and controls matched by sex, age (± 5 years), enrollment period (± 1 years), and hospital. RESULTS: A higher intake of soy products was associated with a significantly lower risk of GC than a lower intake of soy products (odds ratio [OR] = 0.37, 95% confidence interval [CI] = 0.14-0.96). Additionally, a higher fruit intake resulted in a significantly lower risk of GC than a lower fruit intake (OR = 0.35, 95% CI = 0.13-0.94). A combination of food groups was evaluated, and a lower risk of GC was observed with a high intake of both soy products and fruits (OR = 0.20, 95% CI = 0.06-0.67), high intake of soy and dairy products (OR = 0.28, 95% CI = 0.10-0.78) and high intake of fruits and dairy products (OR = 0.28, 95% CI = 0.09-0.83). CONCLUSIONS: A high intake of soy products or fruits was associated with a lower risk of GC. A combination of soy products or fruits with dairy products was associated with a lower risk of GC. A balanced intake of soy products, fruits, and dairy products may help reduce GC risk.

Association of Dietary Antioxidant Vitamin Intake and Gastric Cancer Risk According to Smoking Status and Histological Subtypes of Gastric Cancer: A Case-Control Study in Korea.

Smoking is a risk factor for gastric cancer (GC) and causes oxidative stress. Antioxidant vitamins may protect against oxidative stress. This study aimed to determine the association between dietary antioxidant vitamin intake and GC risk according to smoking status and the histological subtype. This case-control study included 286 pairs of patients with GC and controls aged 20-79 years enrolled at two hospitals from 2002 to 2006, matched by age (± 2 years), sex, hospital, and participation period (± 1 years). Dietary information was collected using a quantitative food frequency questionnaire (FFQ). When stratified by smoking status, increased intake of vitamin C (OR = 0.38; 95% CI = 0.17-0.84 for highest vs. lowest; P for trend = 0.033) and folate (OR = 0.28; 95% CI = 0.12-0.64 for highest vs. lowest; P for trend = 0.003) decreased GC risk in nonsmokers. Vitamin C (P for interaction = 0.043) and folate (P for interaction =0.015) levels were significantly associated with smoking status. Similar results were observed in nonsmokers with diffuse and mixed types of GC, but not in those with intestinal type of GC. Therefore, we found an inverse association between higher intake of dietary vitamin C and folate with the risk of GC among nonsmokers. These protective associations were strong in nonsmokers with diffuse and mixed types of GC.

Sex-dependent associations between MAP3K1 gene polymorphisms and soy products with the gastric cancer risk in Korea: a case-control study.

BACKGROUND/OBJECTIVES: The hormone-dependent effect of MAP3K1 gene polymorphisms may explain sex-specific differences in gastric cancer (GC) risk. Phytoestrogens have been shown to interact with this genetic factor. Here, we investigated the association between MAP3K1 gene polymorphisms and GC risk by sex and whether these associations differ depending on soy products intake. METHODS: Participants aged 20-79 years were recruited from two hospitals between December 2002 and September 2006. In all, 440 cases and 485 controls were recruited, among, 246 pairs of cases and controls, matched by sex, age (± 5 years), study admission period (± 1 years), and hospital, were included for the analysis. RESULTS: In dominant model, men with the A allele of rs252902 showed significantly increased GC risk (odd ratio; OR=2.19, 95% confidence interval; CI=1.31-3.64) compared to GG homozygotes. When stratified by intake of soy products, men with the A allele of rs252902 and low intake of soy products showed significantly higher GC risk (OR=3.29, 95% CI=1.55-6.78) than that in GG homozygotes. CONCLUSIONS: Men with the risk allele of MAP3K1 had a significantly increased GC risk compared to GG homozygotes; this trend was more pronounced in those with low intake of soy products.

Aberrant Methylation of Somatostatin Receptor 2 Gene Is Initiated in Aged Gastric Mucosa Infected with Helicobacter pylori and Consequential Gene Silencing Is Associated with Establishment of Inflammatory Microenvironment In Vitro Study.

The loss-of-function variants are thought to be associated with inflammation in the stomach. We here aimed to evaluate the extent and role of methylation at the SSTR2 promoter in inflammation and gastric tumor formation. A whole-genome bisulfite sequencing analysis revealed that the SSTR2 promoter was significantly hypermethylated in gastric tumors, dysplasia, and intestinal metaplasia compared to non-tumor tissues from patients with gastric cancer. Using public data, we confirmed SSTR2 promoter methylation in primary gastric tumors and intestinal metaplasia, and even aged gastric mucosae infected with Helicobacter pylori, suggesting that aberrant methylation is initiated in normal gastric mucosa. The loss-of-function of SSTR2 in SNU638 cell-induced cell proliferation in vitro, while stable transfection of SSTR2 in AGS and MKN74 cells inhibited cell proliferation and tumorigenesis in vitro and in vivo. As revealed by a comparison of target genes differentially expressed in these cells with hallmark molecular signatures, inflammation-related pathways were distinctly induced in SSTR2-KO SNU638 cell. By contrast, inflammation-related pathways were inhibited in AGS and MKN74 cells ectopically expressing SSTR2. Collectively, we propose that SSTR2 silencing upon promoter methylation is initiated in aged gastric mucosae infected with H. pylori and promotes the establishment of an inflammatory microenvironment via the intrinsic pathway. These findings provide novel insights into the initiation of gastric carcinogenesis.

Dietary zinc intake and mortality in patients with intestinal-type gastric cancer: A prospective cohort study in Korea.

Purpose: Current evidence regarding the association between zinc intake and gastric cancer (GC)-specific survival in patients with intestinal-type GC is lacking. Therefore, this cohort study investigated the association between zinc intake and GC mortality through follow-up on GC death among patients with intestinal-type GC and whether these effects differ according to the source of zinc intake. Methods: A total of 185 patients with intestinal-type GC were enrolled from two hospitals between 2002 and 2006. Their survival or death was prospectively followed up until December 31, 2016, through a review of medical records and telephone surveys. Results: A total of 178 patients were included and analyzed. The median follow-up period was 7.3 years. In the fully adjusted models, the highest tertile of total zinc intake showed a significantly lower GC mortality than the lowest tertile (hazard ratio, 0.22; 95% confidence interval: 0.08-0.64). In addition, the tertile of total zinc intake showed a dose-response association with GC mortality (p=0.015). Analysis of the source of zinc intake revealed that when zinc intake from staples (rice and noodles), animal, and plant food sources were combined, the results were similar to those of total zinc intake and GC mortality. Conclusion: Zinc intake through various foods may be effective in reducing GC mortality by achieving balance with other nutrients. Our results suggest that zinc improves the survival of patients with intestinal-type GC in Korea.

A high glycemic index and glycemic load increased the risk of gastric cancer: A case-control study in Korea.

Diet is a critical risk factor for gastric cancer, and Koreans consume significantly high amounts of carbohydrates. This study examined the association between carbohydrate intake, glycemic index, and glycemic load and the risk of gastric cancer and whether the association varied based on the general risk factors for gastric cancer. We hypothesized that carbohydrate intake, glycemic index, and glycemic load elevated gastric cancer risk and the relationship differed by the gastric cancer risk factors. This was a case-control study with a total of 307 matched pairs aged 20 to 79 years. Data collection was completed at two hospitals from December 2002 to September 2006. A food frequency questionnaire was applied for dietary assessment. Carbohydrate intake was not related to gastric cancer risk. However, a high glycemic index (odds ratio [OR], 1.88; 95% confidence interval (95% CI), 1.18-2.97) and glycemic load (OR, 2.51; 95% CI, 1.53-4.12) were significantly associated with the elevated risk of gastric cancer. When the relationship between glycemic load and gastric cancer risk was stratified by risk factors for gastric cancer, the gastric cancer risk especially increased among men, ≥65 years, smokers, drinkers, and people with Helicobacter pylori infection. Although there was no association between carbohydrate consumption and gastric cancer, high glycemic index and glycemic load were associated with the increased gastric cancer risk.

Gastric Cancer Risk Was Associated with Dietary Factors Irritating the Stomach Wall: A Case-Control Study in Korea.

The incidence of gastric cancer is high in Korea, and dietary factors are important risk factors for gastric cancer. This study examined whether gastric cancer risk was related to dietary factors that directly irritate the stomach wall. This case−control study consisted of 308 matched pairs of gastric cancer cases and controls recruited from 2002 to 2006 at two hospitals in Korea. Dietary assessments were completed using a food frequency questionnaire and a dietary habit questionnaire. Gastric cancer risk was increased for high meal frequency of >3 vs. low meal frequency of ≤3 times per day, overeating vs. not overeating, and preferred vs. not preferred spicy or salty foods. Furthermore, participants with dietary factors of high meal frequency, overeating, and preference for spicy or salty foods elevated the risk of gastric cancer compared to those with low meal frequency, not overeating, and not preferring spicy or salty foods, simultaneously. In conclusion, gastric cancer risk was significantly increased in people with dietary factors that irritate the stomach wall, such as high meal frequency, overeating, and preference for spicy or salty foods.

The Associations of Dietary Intake of High Sodium and Low Zinc with Gastric Cancer Mortality: A Prospective Cohort Study in Korea.

Sodium and zinc display opposite effects on immune cells, such as regulatory T cells (Tregs) and T helper 17 cells (Th17), resulting in an altered immune response. Immune cells have a pivotal role in regulating tumor progression, which may affect gastric cancer (GC) mortality. Thus, this cohort study investigated the associations between the combination of sodium and zinc intake and GC mortality and whether these associations differ by histological type by following up deaths of GC cases in Korea. A total of 490 patients with GC were enrolled between 2002 and 2006. Survival or death was prospectively followed up until December 31, 2016. Finally, 300 patients with the two main histological types of GC were included; 99 GC deaths occurred during a median follow-up period of 7.1 years. Patients with high sodium and low zinc intake had a significantly higher GC mortality than those with low sodium and high zinc intake (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.09-3.93). However, no significant association was found between the histological types of GC. In conclusion, we found that high sodium and low zinc intake may worsen the survival rate of patients with GC.

Erratum: Dietary Intake of Soy Products, Vegetables, and Dairy Products and Gastric Cancer Survival according to Histological Subtype: a Long-term Prospective Cohort Study.

[This corrects the article on p. 403 in vol. 21, PMID: 35079442.].

Gastric Cancer and the Daily Intake of the Major Dish Groups Contributing to Sodium Intake: A Case-Control Study in Korea.

Studies on the association between gastric cancer (GC) and the intake of soup-based dish groups (noodles and dumplings, soups, and stews), which are sodium-contributing foods, in Korea are insufficient, and the results of studies on the intake of pickled vegetables such as kimchi are inconsistent. This study aimed to determine the association between the incidence of GC and the daily intake of high-sodium dish groups (noodles and dumplings, soups, stews, and pickled vegetables) and whether these associations differ depending on behavioral risk factors for GC. In this case-control study, subjects aged 20-79 years were recruited from two hospitals between December 2002 and September 2006. A total of 440 cases and 485 controls were recruited, of which 307 pairs were matched and included for the analysis. In our results, a higher intake of noodles and dumplings was associated with a significantly increased incidence of GC. In the participants who consumed past or current alcohol, a higher intake of noodles and dumplings was associated with a significantly increased incidence of GC. Our results suggest that efforts to reduce the daily sodium intake from noodles and dumplings are needed to prevent and reduce the incidence of GC.

STK31 upregulation is associated with chromatin remodeling in gastric cancer and induction of tumorigenicity in a xenograft mouse model.

Pathological changes in the epigenetic landscape of chromatin are hallmarks of cancer. Our previous study showed that global methylation of promoters may increase or decrease during the transition from gastric mucosa to intestinal metaplasia (IM) to gastric cancer (GC). Here, CpG hypomethylation of the serine/threonine kinase STK31 promoter in IM and GC was detected in a reduced representation bisulfite sequencing database. STK31 hypomethylation, which resulted in its upregulation in 120 cases of primary GC, was confirmed. Using public genome­wide histone modification data, upregulation of STK31 promoter activity was detected in primary GC but not in normal mucosae, suggesting that STK31 may be repressed in gastric mucosa but activated in GC as a consequence of hypomethylation­associated chromatin remodeling. STK31 knockdown suppressed the proliferation, colony formation and migration activities of GC cells in vitro, whereas stable overexpression of STK31 promoted the proliferation, colony formation, and migration activities of GC cells in vitro and tumorigenesis in nude mice. Patients with GC in which STK31 was upregulated exhibited significantly shorter survival times in a combined cohort. Thus, activation of STK31 by chromatin remodeling may be associated with gastric carcinogenesis and also may help predict GC prognosis.

Dietary Intake of Soy Products, Vegetables, and Dairy Products and Gastric Cancer Survival according to Histological Subtype: a Long-term Prospective Cohort Study.

PURPOSE: Owing to differences in the general characteristics of gastric cancer (GC) according to histological type, the association of GC risk factors, such as diet, may also differ depending on the histological type. We investigated the associations between individual and combined intake of soy products, vegetables, and dairy products and GC mortality by following up cases of death among Korean GC cases and whether these associations differ according to the histological type. MATERIALS AND METHODS: A total of 508 GC cases were enrolled from two hospitals between 2002 and 2006. Their survival or death was prospectively followed up until December 31, 2016, through a review of medical records and telephonic surveys. Finally, 300 GC cases classified as intestinal- or diffuse-type GC cases were included. The median follow-up period was 7.1 years. RESULTS: In the fully adjusted model, a high intake of soy products (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.19-0.96) and the combination of soy products and vegetables (HR, 0.34; 95% CI, 0.12-0.96) or soy products and dairy products (HR, 0.37; 95% CI, 0.14-0.98) decreased the mortality from intestinal-type GC. In particular, patients consuming various potentially protective foods (HR, 0.23; 95% CI, 0.06-0.83) showed a highly significant association with a lower mortality from intestinal-type GC. However, no significant association was found with diffuse-type GC. CONCLUSIONS: High intake of potentially protective foods, including soy products, vegetables, and dairy products, may help increase survival in intestinal-type GC.

LAD1 expression is associated with the metastatic potential of colorectal cancer cells.

BACKGROUND: Anchoring filament protein ladinin-1 (LAD1) was related to the aggressive progression of breast, lung, laryngeal and thyroid cancers. However, the association of LAD1 with colorectal cancer remained unknown. Here, to determine the relationship of LAD1 with colorectal cancer progression, we explored the effect of LAD1 loss on the malignant features of colorectal cancer cells. METHODS: We constructed LAD1-depleted cell lines and examined the effect of LAD1 deficiency on the phenotypic and molecular features of colorectal cancer cells in vitro. The function of LAD1 in metastasis in vivo was examined by establishing a spleen-to-liver metastasis mouse model. LAD1 protein expression in colorectal cancer patient specimens was assessed by immunohistochemistry of tumor microarrays. RESULTS: We found that LAD1 was abundant in most colorectal cancer cells. In addition, high expression of LAD1 significantly correlated with poor patient outcome. LAD1 depletion inhibited the migration and invasion of two different colorectal cancer cell lines, SW620 and Caco-2, without affecting their proliferation. In addition, LAD1 loss led to defects in liver metastasis of SW620 cells in the mouse model. Immunohistochemistry of colorectal cancer tissues revealed LAD1 enrichment in metastatic tissues compared to that in primary tumor and normal tissues. CONCLUSION: These results suggest that LAD1 expression is associated with the metastatic progression of colorectal cancer by promoting the migration and invasion of cancer cells.

Clinical Significance of Tumor and Immune Cell PD-L1 Expression in Gastric Adenocarcinoma.

BACKGROUND/AIM: The prognostic relevance of programmed cell death ligand-1 (PD-L1) protein expression in gastric cancer (GC) remains controversial. The aims of the present study were to determine the correlations between tumor cell (TC) and immune cell (IC) PD-L1 protein levels with prognosis, and to determine the correlation between PD-L1 expression and different molecular GC subtypes. MATERIALS AND METHODS: TC and IC PD-L1 protein levels were measured in 286 GC patients. The patients were classified according to the Cancer Genome Atlas and Asian Cancer Research Group guidelines using immunohistochemistry and in situ hybridization. RESULTS: TC and IC PD-L1 protein levels were positively correlated with patient survival. TC PD-L1 expression was negatively correlated with tumor grade. TC and IC PD-L1 expression was associated with improved prognosis in Epstein-Barr virus negative (EBV-), microsatellite instability (MSI) rather than microsatellite stability (MSS) subgroup GC patients. CONCLUSION: PD-L1 protein expression in TCs and ICs can be used as a prognostic indicator for GC patients, particularly in the EBV-, MSI, and MSS subgroups.

Methylation of the CDX2 promoter in Helicobacter pylori-infected gastric mucosa increases with age and its rapid demethylation in gastric tumors is associated with upregulated gene expression.

Pathological changes in the epigenetic landscape of chromatin are hallmarks of cancer. The caudal-type homeobox gene CDX2 is not expressed in normal gastric epithelia but rather in adult intestinal epithelia, and it is overexpressed in intestinal metaplasia (IM). However, it remains unclear how CDX2 transcription is suppressed in normal gastric epithelial cells and overexpressed in IM. Here, we demonstrate that methylation of the CDX2 promoter increases with age in Helicobacter pylori-positive, noncancerous gastric tissue, whereas the promoter is demethylated in paired gastric tumors in which CDX2 is upregulated. Moreover, we also found that the CDX2 promoter is demethylated in IM as well as gastric tumor. Immunohistochemistry revealed that CDX2 is present in foci of parts of the gastric mucosae but highly expressed in IM as well as in gastric tumors, suggesting that the elevated level of CDX2 in IM and gastric tumors may be attributable to promoter demethylation. Our data suggest that CDX2 repression may be associated with promoter methylation in noncancerous H. pylori-positive mucosa but its upregulation might be attributable to increased promoter activity mediated by chromatin remodeling during gastric carcinogenesis.

ONECUT2 upregulation is associated with CpG hypomethylation at promoter-proximal DNA in gastric cancer and triggers ACSL5.

Many studies have focused on global hypomethylation or hypermethylation of tumor suppressor genes, but less is known about the impact of promoter hypomethylation of oncogenes. We previously showed that promoter methylation may gradually increase or decrease during the transition from gastric mucosa (GM) to intestinal metaplasia (IM) to gastric cancer (GC). In our study, we focused on regional CpG hypomethylation of the promoter-proximal DNA of the transcription factor ONECUT2 (OC2) in IM and GC cells. We validated the hypomethylation of promoter-proximal DNA of OC2 in 160 primary GCs, in which methylation level correlated negatively with OC2 mRNA level. IM and GC cells stained positively for OC2, whereas GM cells did not. Stable transfection of OC2 in GC cells promoted colony formation, cell migration, invasion and proliferation. Moreover, OC2 knockdown with a short hairpin RNA suppressed tumorigenesis in nude mice. In addition, chromatin immunoprecipitation coupled with DNA sequencing and RNA-seq analyses revealed that OC2 triggered ACSL5, which is strongly expressed in IM of the stomach but not in GM, indicating that OC2 and ACSL5 are early-stage biomarkers for GC. We also observed a high correlation between the levels of OC2 and ACSL5 mRNAs in the GENT database These results suggest that epigenetic alteration of OC2 upregulates its expression, which then activates ACSL5; thus, OC2 is induced in IM by epigenetic alteration and triggers ACSL5 expression, and thus OC2 and ACSL5 may cooperatively promote intestinal differentiation and GC progression.

Subepithelial Spread of Early Gastric Signet Ring Cell Carcinoma: How Far They Can Reach?

INTRODUCTION: Although signet ring cell carcinoma (SRC) is a poorly differentiated cancer subtype, recent studies suggest that endoscopic resection can be applied in small, mucosal early gastric SRC. However, other studies report frequent positive lines at the lateral resection margin after endoscopic treatment. Subepithelial spread beneath normal mucosa can exist in SRC, and such lesions may be the cause of positive margins after endoscopic resection. Thus, we conducted a retrospective study in order to evaluate the significance of subepithelial spread in early gastric SRC. METHOD: Medical records of early gastric SRC patients who underwent surgery or endoscopic resection from January 2011 to December 2016 at a single tertiary hospital (Daejeon, South Korea) were reviewed to examine subepithelial spread and clinical datum. Two expert pathologists reviewed all pathologic specimens, and only patients showing a pure SRC component were included. RESULTS: Eighty-six patients were initially enrolled, and subepithelial spread existed in 62 patients (72.1%). The mean distance of subepithelial spread was 1,132.1 µm, and the maximal distance was 6,000 µm. Only discoloration was significantly associated with the presence of a subepithelial spread (p < 0.05, χ2 test, and logistic regression test). Distance of subepithelial spread did not correlate with total lesion size. CONCLUSION: Subepithelial spread of early gastric SRC occurs frequently and can reach up to 6 mm. Lesion discoloration may be associated with the presence of subepithelial spread. Our results suggest that careful decision of the margin is needed when performing endoscopic resection of early gastric SRC.

Identification of a molecular signature of prognostic subtypes in diffuse-type gastric cancer.

BACKGROUND: Although recent advances in high-throughput technology have provided many insights into gastric cancer (GC), few reliable biomarkers for diffuse-type GC have been identified. Here, we aim to identify a prognostic and predictive signature of diffuse-type GC heterogeneity. METHODS: We analyzed RNA-seq-based transcriptome data to identify a molecular signature in 150 gastric tissue samples including 107 diffuse-type GCs. The predictive value of the signature was verified using other diffuse-type GC samples in three independent cohorts (n = 466). Log-rank and Cox regression analyses were used to estimate the association between the signature and prognosis. The signature was also characterized by somatic variant analyses and tissue microarray analysis between diffuse-type GC subtypes. RESULTS: Transcriptomic profiling of RNA-seq data identified a signature which revealed distinct subtypes of diffuse-type GC: the intestinal-like (INT) and core diffuse-type (COD) subtypes. The signature showed high predictability and independent clinical utility in diffuse-type GC prognosis in other patient cohorts (HR 2.058, 95% CI 1.53-2.77, P = 1.76 × 10-6). Integrative mutational and gene expression analyses demonstrated that the COD subtype was responsive to chemotherapy, whereas the INT subtype was responsive to immunotherapy with an immune checkpoint inhibitor (ICI). Tissue microarray analysis showed the practical utility of IGF1 and NXPE2 for predicting diffuse-type GC heterogeneity. CONCLUSIONS: We present a molecular signature that can identify diffuse-type GC patients who display different clinical behaviors as well as responses to chemotherapy or ICI treatment.