|Year : 2015 | Volume
| Issue : 3 | Page : 80-93
Recent Progress in Genetic and Epigenetic Profile of Diffuse Gastric Cancer
Zhengxi He1, Bin Li2
1 Division of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
2 Division of Oncology; Cancer Research Institute of Central South University, Institute of Medical Sciences, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China
|Date of Submission||04-Jan-2015|
|Date of Acceptance||04-Jun-2015|
|Date of Web Publication||30-Jun-2015|
Division of Oncology, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha 410008, Hunan
Source of Support: None, Conflict of Interest: None
Gastric cancer (GC) is the second leading cause of death from cancer worldwide, with 5-year survival rate for about 20% of the affected individuals. Although there is a decrease in the intestinal-type GC (IGC), the incidence of diffuse-type is still increasing, and its progression is notoriously aggressive. Clinically, diffuse GCs (DGCs) propensity for invasion into adjacent tissue, with prominent stromal induction, which presents with linitis plastica, peritoneal implantation and remote metastasis, ends up in dismal prognosis, and translates into poor quality of life. So far, a few molecularly targeted drugs, including HER2 antagonists, have been developed against GC, but most in treating IGC. Thus, DGC constitutes a poor prognosis subgroup of GC with no known promising therapies. Recent genomic characterization of GC by whole-genome and whole-exome sequencing showed that a large number of known cancer-related genes are frequently mutated in gastric malignancies. In the light of this discovery, we did an extensive review of recent literature on progress in genetic and epigenetic profile of DGC. The summary of which makes us believe that it is possible to develop novel therapeutic strategies against this otherwise devastating disease that undergo massive invasion and metastasis.
Keywords: Diffuse gastric cancer, epigenetic, genetic, profile
|How to cite this article:|
He Z, Li B. Recent Progress in Genetic and Epigenetic Profile of Diffuse Gastric Cancer. Cancer Transl Med 2015;1:80-93
| Introduction|| |
Gastric cancer (GC) is a highly prevalent disease, being the third most common cancer and ranking the second in the leading cause of cancer-associated deaths worldwide,  with the highest incidence occurring in East Asia, Central and Eastern Europe, and South Africa in particular. ,, Predisposing factors include Helicobacter pylori infection, smoking, high salt intake, and other dietary factors. In recent meta-analysis, there was no appreciable association established between moderate alcohol drinking and GC risk.  While most GC are considered sporadic, it is estimated that 5-10% have a familial component, and 3-5% are associated with inherited cancer predisposition syndromes.  Analysis of its molecular and clinical characteristics showed diffuse GC (DGC), was complicated by histological, etiological, and molecular heterogeneity. Two main functional types are described (Lauren's classification): intestinal adenocarcinoma and diffuse one. In contrast to decreasing intestinal-type GC (IGC), the incidence of DGC is increasing. Linitis plastica, the aggressive form of DGC has a high propensity to invade surrounding tissue and early metastasis ending up in dismal prognosis. Histologically different from IGC, a typical gland-forming adenocarcinoma, DGC displays lack of cellular cohesion, poor cellular differentiation (often with signet ring cell morphology), and highly infiltrating isolated cells. Furthermore, different genetic pathways are thought to play their role in the development of IGC and DGC. IGC is mostly caused by H. pylori infection as the initial insult while DGC seems to be more closely related to the accumulation of genetic and epigenetic alterations. With the emergence of new technologies, such as new generation sequence (NGS) and clustered regularly interspaced short palindromic repeats added with fast advancement in bioinformatics, brighter landscapes of cancer genome and new driver mutations were gradually uncovered in front of us. ,,, From these data, we can see that various epigenetic alterations are involved in stomach carcinogenesis. This article will review the recent progress in genetic and epigenetic profile in respect to DGC.
| Deregulation of Ras Homolog Gene Family Member a Signal Pathway Drive In Diffuse Gastric Cancer Initiation and Progression|| |
Ras homolog gene family member A (RhoA) belongs to the Rho family of small GTPases, a group of Ras-like proteins, responsible for linking a variety of cell surface receptors to different intracellular signaling proteins which impact the structure and dynamics of the actin cytoskeleton, cell migration, cytokinesis, and the cell cycle. , As is the case for Ras and most other small GTPases, RhoA cycles between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound configurations, a molecular switch strictly controlled by the GTP loading activity of guanine nucleotide exchange factors (GEFs). , RhoA is known to play a key role in tumorigenesis and tumor cell invasion in various malignancies. 
Recurrent gain-of-function mutations of Ras homolog gene family member A in diffuse gastric cancer
In 2014, Kakiuchi et al. first reported recurrent nonsynonymous somatic mutations in 25.3% (22/87) of DGC samples in RhoA, based on whole-exome sequencing method. In a separate study, Wang et al.  performed whole-genome sequencing along with DNA copy number and gene expression, detected that RhoA was mutated in 14.3% (14/98) of diffuse-type tumors and in 7.8% (4/51) of mixed or indeterminate type tumors. These studies also showed that no RhoA mutations were identified in intestinal-type tumors (0/185), which indicate the somatic mutation in RhoA were highly specific to DGC subtype.
Most of the RhoA mutations clustered in core effector region or located in the G box (GTP/GDP-binding site), which impair binding of RhoA to its effector proteins or RhoA configuration swift between activation and inactivation, thereby making the corresponding mutants defective in mediating aspects of RhoA signaling. These RhoA mutations were noted in hotspot sites, including Y42C (14/47), G17E (7/47), R5Q/W (8/47), and L57V (4/47). , The most common alteration, Y42C, lies in the effector-binding region of RhoA, which revealed attenuated activation of protein kinase N. 
The diffuse morphological phenotype is indicated by early breaking off of signet ring cells through the basement membrane, which requires resistance to anoikis, , followed by the acquisition of highly infiltrative behavior. This ability of RhoA hotspot mutants in DGC to promote escape from anoikis in the organoid culture system is consistent with the critical role of RhoA in this process.  Intriguingly, similar to G17E mutations of RhoA in DGC, G17V mutations were identified to be highly recurrent in 53.3% (24 of 45) of the angioimmunoblastic T cell lymphoma cases, ,,, which demonstrates that, functionally these mutants fail to bind GTP and act in a dominant-negative fashion to inhibit RhoA GTP loading, conferring defective RhoA signaling, and thus promoting lymphoma development. The difference in the RhoA mutational hotspots in GCs and lymphomas raise interesting questions about the organ-specific function of RhoA or other oncoproteins. , Further functional studies on these different RhoA mutants, in animal models, will be necessary to develop new cancer treatments by targeting RhoA pathway.
The results from Rho binding domain assay, to immunoprecipitate RhoA-GTP, showed that both the Y42C and L57V mutants significantly attenuate the GTP-associated form, compared to wild-type protein. The reintroduction of codon 17 or 42 RhoA mutants can rescue cell proliferation effects of RhoA small interfering RNA (siRNA), suggesting the tumor-promoting activity of these RhoA mutants.  However, whether RhoA mutations only inhibit physiologic RhoA activity or lead to RhoA gain of function are not yet to study.
Analysis of clinicopathological characteristics identified that RhoA mutation showed a predilection for the antrum and body but not for the cardia. Most of the RhoA-mutant cases were classified as advanced GC (AGC) with tumor cells invading deeper than the muscle layer and most of these advanced cancers were macroscopically defined as having an appearance consistent with Borrmann type III, with poor tumor differentiation. ,,,, RhoA mutations were observed in both classes of tissue and in one intramucosal carcinoma. These seemed to be an early event, suggesting that RhoA mutations might have a key role in the initial stages of cancer progression,  but this finding and the mechanism of RhoA mutation in the initiation of DGC should be confirmed by more studies.
Tumors with RhoA mutations were less likely to have tumor protein p53 (TP53) mutations, ARID1 mutations, and HER-2 amplification.  Immunohistochemical analyses showed that, of the RhoA-mutant DGC cases tested, only a small fraction 4.5% (1/22) had positivity for HER2 staining, suggesting the possibility of using RhoA as a therapeutic target in DGCs that are not responsive to HER2-targeted therapy. 
Overexpression of Ras homolog gene family member A messenger RNA and protein levels
RhoA was frequently overexpressed in GC tissues and cells, compared with normal tissues or gastric epithelial cells. GC displaying increased expression of RhoA is highly correlated with aggressive lymph node metastasis, advanced tumor stage, histologically diffuse-type, and poorer survival.  RhoA-specific siRNA could specifically and stably reduce RhoA expression up to 90% in AGC cells. Both RhoA-specific siRNA and dominant-negative RhoA expressions could significantly inhibit the proliferation and tumorigenicity of AGC cells and enhance chemosensitivity of the cancer cells to adriamycin and 5-fluorouracil. 
Deregulated signal pathway involving Ras homolog gene family member A
Nonsynonymous mutations in RhoGAP or RhoGEF genes
The activities of Rho are regulated positively by GEFs and negatively by GTPase activating proteins (GAPs). In turn, RhoGEFs and RhoGAPs can be regulated by upstream cell surface receptors for guidance cues or adhesion proteins.  RhoGEFs and RhoGAPs far outnumber Rho GTPases. The Drosophila genome contains 6 Rho GTPases, but at least 20 predicted RhoGEFs and as many RhoGAPs. The human genome is predicted to contain 59-77 RhoGAPs.  While it is interesting to speculate on why so many Rho regulators are in the genome, their importance in the function of the human nervous system is highlighted by recent findings that mutations in a RhoGAP and a RhoGEF cause X-linked nonsyndromic mental retardation. , It was reported that some GC cases harbored nonsynonymous mutations in RhoGAP or RhoGEF genes, suggesting that RhoA in combination with its regulatory molecules is frequently mutated in DGC samples 36% (31/87 cases).  Mutations in RhoGAP or RhoGEF genes were not specific to DGC since they were also observed in IGC cases.
Other deregulated RhoA signal pathway
It is well-known that RhoA, which is involved in different deregulated signal pathway, also participates in the pathogenesis of DGC. RhoA activity can be regulated by protein kinases, such as cyclic adenosine 3',5'-monophosphate - dependent protein kinase A (PKA), type I and II cyclic cytidine 3',5'- monophosphate - dependent PKA (protein kinase G I [PKG I] and PKG II), which induce GC progression.  Wnt5a promotes GC cell migration via the PI3K/Akt/GSK3β/RhoA signaling pathway.  Interleukin-6, via activation of the c-Src/RhoA/ROCK signaling pathway, induces AGC cells invasion.  Vincristine imitated amoeboid-like motility by activating GEF-H1/RhoA/ROCK/MLC signaling and then enhanced the invasive ability of AGC cells. 
Lysophosphatidic acid (LPA) and lysophosphatidic sphingosine 1-phosphate (S1P) have been proved to be an important player in GC progression.  The LPA and S1P act through G-protein coupled receptors (GPCRs) which couple to multiple G-proteins and their effectors. These GPCRs are quite efficacious in coupling to the Ga12/13 family of G-proteins, which stimulate GEFs for RhoA. , Neuroepithelial cell transforming gene 1, a GEF, as a novel GA-associated gene, can mediate RhoA activation facilitating LPA-induced cell migration and invasion in GC, triggering translocation of RhoA from the cytosol toward the membrane and the nucleus. ,
To functionally interrogate these novel RhoA mutations found in DGC, Kakiuchi et al. studied several cancer cell lines harboring RhoA mutations: the OE19 cell line (adenocarcinoma of the gastric cardia), the breast cancer cell line BT474, and the colorectal cancer cell line SW948.  They found that RhoA silence with siRNA dramatically inhibits cell proliferation in these RhoA mutation cells, but it shows no effect in the GC cell lines with wild-type RhoA. Moreover, they displayed that reintroduction of the codon 17 or 42 RhoA mutants, instead of wild-type RhoA reintroduction, rescued cell proliferation effects of RhoA siRNA, indicating tumor-promoting activity of these RhoA mutants. These studies demonstrate that, along with CDH1 mutations, RhoA mutations are quite common in DGC but not in other variants of GC. Intriguingly, these results suggest a model whereby wild-type RhoA activity has a tumor suppressive role in the pathophysiology of DGC and that RhoA mutations inhibit this tumor suppressive function, suggesting these mutants are not merely loss of function, but may repress RhoA activity. Nevertheless, it is still unknown that whether RhoA mutations only attenuate the RhoA activity in physiology condition, or these mutations lead to a gain of function. More studies will be needed to investigate novel RhoA mutants and the deleterious efficacy of RhoA in cancer; especially in DGC.  The results from Wang et al.  provide additional insights in the potential role of mutant RhoA. They utilized primary mouse intestinal organoids to study the impact of RhoA mutants Y42C and L57V on anoikis. Animal experiments showed that Y42C or L57V RhoA mutants could enhance organoid reformation. Treatment with Y-27632, Rho-associated protein kinase (ROCK) inhibitor, enhanced colony growth, but wild-type RhoA induction suppressed the colony forming. Thus, inhibition of anoikis may represent a key requirement for DGC.  In other studies, Zandvakili et al. utilized the K-RasG12D Lox-Stop-Lox murine lung cancer model in combination with a conditional RhoA flox/flox and RhoC−/− knockout mouse models and surprisingly found that deletion of RhoA, RhoC or both did not adversely affect normal lung development. Moreover, deletion of RhoA appears to induce a compensatory mechanism that exacerbates adenoma formation. This study suggests that targeting RhoA alone may allow for compensation and a paradoxical exacerbation of neoplasia.  Another finding showed that RhoA plays a central role in the breast cancer cell migration and also in tumorigenesis, differentiation, and as a progression biomarker in ovarian carcinoma. , In summary, RhoA mutation is extremely uncommon in other cancer types, further corroborating the unique role of this gene in driving DGC carcinogenesis. Given that, RhoA has frequently been implicated as having oncogenic potential, ,, the observed tumor suppressor pattern of mutations causing defective RhoA function and frequent concurrent loss of heterozygosity (LOH), or two-hit mutations were unexpected. RhoA plays a crucial role in the proliferation, apoptosis, adhesion, and migration of GC cells. ROCK is an effector protein of RhoA. RhoA/ROCK regulates the plasticity of metastatic gastric carcinoma via mesenchymal-amoeboid transition and mediates plasticity of scirrhous gastric carcinoma motility.  Inhibition of RhoA/ROCK signaling pathway provided a promising perspective in inhibiting cell invasion ability of DGC cells. 
| E-Cadherin Dysfunction Involved in The Pathogenesis of Diffuse Gastric Cancer|| |
E-cadherin is a Ca2 + -dependent cell-cell adhesion molecule essential for the establishment of epithelial architecture and maintenance of cell polarity and differentiation, both during development and in adult life. ,, This single-pass transmembrane glycoprotein is encoded by the CDH1 gene, annotated to the human chromosome 16q22.1 in a cluster along with other cadherins. , The mature E-cadherin protein is organized into three major structural domains: a cytoplasmic domain of about 150 amino add (AA) residues, a single transmembrane domain, and an extracellular domain of about 550 AA, comprising five randomly repeated domains exclusive to cadherins, the so-called EC1-EC5. ,
The epithelial cell-cell adhesion is achieved through homophilic interactions between cadherin molecules, first among adjacent cells (trans-interaction) and then within the same cell by lateral association leading to the formation of zipper-like structures. ,, The cytoplasmic domain of E-cadherin interacts with β-, α-, and γ (plakoglobin)-catenins (βctn, αctn, γctn), with actin-anchored to the actin cytoskeleton, thus establishing the cadherin-catenin complex.  E-cadherin stabilization at the cell membrane and accurate function occurs by association to p120-catenin. The stability of the cadherin-catenin complex, and its linkage to actin filaments, forms the core of the adherens junction (AJ), which is vital to inhibit individual epithelial cell motility and to provide homeostatic tissue architecture. , Genetic or epigenetic alterations in E-cadherin leads to disturbed epithelial cell-cell adhesion and structure, aberrant stromal interactions, as well as altered cell migration and signaling, with ultimate oncogenic potential.  Dysfunction or reduced expression of E-cadherin, mostly due to decreased expression at messenger RNA (mRNA) and protein levels, has been reported in the majority of DGCs. Somatic mutations and deletions of the E-cadherin gene predict poor survival of patients with GC. 
Germline CDH1 mutations dysfunction of E-cadherin protein
CDH1 is, however, regarded as a classic tumor suppressor gene in gastric carcinogenesis, being involved in the initiation and progression of both sporadic and hereditary forms of GC. , Ever since, increasing evidence has further supported a specific role of E-cadherin in the initiation of DGC, and indeed over 40% of hereditary DGC (HDGC) cases present CDH1 germline mutations. ,,, HDGC, characteristics of germline alterations in CDH1 (E-cadherin) and CTNNA1 (alpha-E-catenin) genes, was considered as an autosomal dominant inherited GC cancer syndrome.  However, contradictorily, CDH1 gene mutations do not contribute in HDGC in Poland.  Hence, ethnicity difference for the significant risk factor of CDH1 gene in HDGC should be further studied. The frequencies of CDH1 somatic mutations in sporadic DGCs can vary from 3% to > 50%. , To date, 122 germline mutations have been described in the CDH1 gene. ,,,, Interestingly, from a set of 122 CDH1 germline mutations, 87.5% arose from low-risk areas, although the majority were of the nonmissence-type, whereas in high-risk areas, missense mutations were predominant 68.8% (11/16).  This finding suggests that the ethnicity of GC patients should be considered a significant risk factor of the disease and confirms that GC indeed presents various clinical, pathological, and molecular features. Strikingly, germline CDH1 mutations are rarely found in countries such as Japan and Korea,  although this effect can be related to the high rates of sporadic GC found in these countries.
The most common types of CDH1 germline mutations are small frameshift insertions and deletions, as well as point mutations with 80% resulting in protein truncation or even complete loss of expression. The remaining 20% of CDH1 germline alterations are of the missense type, which have a deleterious effect on E-cadherin function. ,,,, In addition, large genomic deletions of germline CDH1 was reported in apparently mutation negative HDGC families.  Somatically, E-cadherin mutations are mainly splice site mutations resulting in exon skipping (frequently exons 8 or 9). , Reduced E-cadherin expression determined by immunohistochemical analysis was noted in most GCs, 92% of 60 cases, when compared with their adjacent normal tissue.  Germline mutations in CDH1 have indeed been reported in diffuse early onset GC patients with and without family history of GC, which highlights the importance of recognition of the HDGC syndrome and of testing for CDH1 germline mutations in young individuals with DGC without a family history of the disease. ,
Epigenetic alteration of E-cadherin as second hit in diffuse gastric cancer
Development of DGC in patients harboring CDH1 mutations (hereditary and sporadic) occurs upon a "second hit" mechanism that leads to E-cadherin aberrant or absent expression. In HDGC tumors, hypermethylation of the CDH1 promoter is the important epigenetic event associated with loss of E-cadherin gene expression and is considered the most common mechanism associated to biallelic CDH1 inactivation, accounting for 50-70% of the cases. ,, In sporadic DGC, methylation of CDH1 is more prevalent than mutation of the gene, promoter methylation is also regarded as the most frequent "second hit" inactivation mechanism. ,, Epstein-Barr virus-associated gastric carcinoma (EBV-associated GC) is characterized by concurrent methylation of multiple genes, and DGC is frequently seen among EBV-associated GCs.  Patients with pan gastritis or enlarged-fold gastritis, which are both caused by H. pylori infection, reportedly have an increased risk for DGC. , Notably, the gastric mucosa of enlarged-fold gastritis patients exhibits CDH1 hypermethylation and genome-wide hypomethylation. These data suggest that aberrant DNA methylation is an essential promoter of carcinogenesis in individuals at high-risk for DGC.  Most DGC cases showed the methylation of CDH1 in tumor samples and in matched nonneoplastic mucosa from adjacent and remote foci of DGC, but low incidence of CDH1 promoter methylation was observed in normal gastric mucosa tissue without DGC. High percentage of CDH1 methylation in the nonneoplastic mucosa of sporadic DGC implied that it occurred in the early stage of DGC.  In addition, LOH represents a vital mechanism in metastases from HDGC cases. 
Micro RNAs were involved in the dysregulation of E-cadherin
Micro RNAs (miRNAs) are a new class of small noncoding RNAs with19-25 nucleotides, which are cleaved from 60 to 110-nucleotide pre-miRNA precursors by RNase III Dicer.  Single-stranded miRNAs bind through partial sequence homology to the three untranslated regions of potentially hundreds of target genes and cause degradation of mRNAs and inhibition of translation. Over 30% of human genes are believed to be regulated by this mechanism. While initial studies suggested that miRNAs generally function as tumor suppressors, recent evidence has revealed that they possess either anti-tumorigenic or antioncogenic properties depending on target genes.  miR-200 family were associated with regulation of E-cadherin expression by targeting the transcriptional repressors ZEB1 and ZEB2. ,, miR-103, miR-107, miR-194, and miR-210 were significantly upregulated in sera of both early and advanced-stage DGC-bearing mice compared to the corresponding ones in control group. However, miR-200a, miR-200b, miR-200c, and miR-141 were down-regulated in DGC. ,,, TaqMan quantitative real-time polymerase chain reaction analyses indicated that four of them, miR-103, miR-107, miR-194, and miR-210, were significantly upregulated in sera of both early and advanced-stage DGC-bearing mice compared to the corresponding controls.  The role and mechanism of these miRNA in regulating E-cadherin need to be studied further.
CDH1 polymorphisms and haplotypes in sporadic diffuse gastric cancer
E-cadherin (CDH1) genetic variations may be involved in invasion and metastasis of various cancers by altering gene transcriptional activity of epithelial cells.  In a study on Taiwanese population, the frequency of 160A allele was significantly higher in DGC cases, but it was not significantly different in IGC cases, compared to controls. Two sets of three-marker haplotypes (−160C → A, 48 + 6 T → C, 2076C → T and − 160C → A, 1937-13 T → C, 2253C → T) were associated with the risk of DGC, which suggested that the CDH1 − 160C → A promoter polymorphism and haplotypes play significant roles in cancer risk for sporadic DGC.  Plasma CDH1 levels may serve as a risk marker against GC and CA genotype of rs26160 and CG genotype of rs17690554 were associated with the risk of DGC, compared with their wild genotypes in Chinese population. 
Aberrant regulation of E-cadherin trafficking pathways
Aberrant regulation of E-cadherin trafficking pathways lead to disruption of its function and consequently, to pathophysiological conditions, such as malignant transformation and cancer metastases. Recent findings showed that 2 HDGC-associated E-cadherin missense mutations can lead to folding defects and premature proteasome-dependent endoplasmic reticulum-associated degradation. Drosophila DnaJ (Hsp40) homolog, subfamily B, member 4 (DNAJB4), the human homolog of DnaJ-1, influences E-cadherin localization and stability even in the absence of E-cadherin endogenous promoter, suggesting a posttranscriptional level of regulation. Increased expression of DNAJB4 leads to stabilization of WT E-cadherin in the plasma membrane. The expression of DNAJB4 and E-cadherin is concomitantly decreased in human gastric carcinomas.  Aberrant N-glycosylation modifications associated with E-cadherin deregulation was reported in human GCs.  Abnormal activation of proto-oncogenes, including c-Met, Src and Rack1, have also been shown to result in increased phosphorylation of tyrosine residues in the cytoplasmic domain of E-cadherin, leading to the recruitment of Hakai and subsequent ubiquitin-degradation of E-cadherin. ,,,, Of the newly identified HDGC-associated mutations (E185V, S232C, and L583R), L583R is predicted to be destabilizing. This mutation is not functional in vitro, exhibits shorter half-life and is unable to mature, due to premature proteasome-dependent degradation. E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo. 
Deregulated network of signaling pathways intersects with E-cadherin
Increasing evidence suggests that a network of signaling pathways intersects with E-cadherin and these are known to involve a multitude of molecules including epidermal growth factor receptor (EGFR), Notch-1, Bcl-2, Rho family members, and matrix metalloproteinases. , Abnormal activation of the Hedgehog signaling pathway markedly increased Gli-1 expression and then augmented Snail expression and consequently decreased E-cadherin expression. 
In conclusion, E-cadherin is responsible for maintaining intact cell-cell adhesion. Aberrant E-cadherin will, therefore, promote deregulation of E-cadherin-mediated signaling pathways, having an impact on cell-cell adhesion, migration, invasion, and survival. As with EGFR, other pathways relevant for cell motility such as Src kinase and p38 mitogen-activated protein kinases have been shown to be aberrantly activated as a consequence of HDGC-related E-cadherin mutations.  E-cadherin has also been shown to be involved in apoptosis and cell survival. Functional loss of E-cadherin renders cells more resistant to apoptotic stimuli. E-cadherin impairment is able to increase cell survival through Notch-dependent up-regulation of Bcl-2.  However, the E-cadherin mutants do not induce the activation of the Wnt pathway in a Bctn-dependent way. 
Of note, CDH1 mutations have been seen in up to 50% of sporadic lobular breast cancer.  Pathological similarities between diffuse gastric and lobular breast carcinomas such as high mucin content with associated signet ring features and loss of E-cadherin on immunohistochemistry hint at a common molecular mechanism. ,,
| DNA and Histone Methylation in Diffuse Gastric Cancer|| |
DGC changes in gene expression like other diseases. The changes can be generated not only by genetic and environmental factors but also by epigenetic factors. Epigenetic alterations of chromatin include DNA methylation and histone modifications, which can affect gene-expression profiles. Identification of the factors that contribute to individual cancers is a prerequisite to a full understanding of cancer mechanisms and the development of customized cancer therapies. Recent studies have revealed diverse mechanisms by which chromatin modifiers; including writers, erasers, and readers of the aforementioned modifications, contribute to the formation and progression of cancer.
As in other types of cancer, numerous studies have shown that key players in GC are regulated by changes in DNA methylation patterns at their promoter CpG islands, that is, hyper- or hypo-methylation [Table 1]. DNA hypermethylation, which refers to the gain of methylation at a locus, originally unmethylated, usually results in stable transcriptional silencing, which functions in regulating gene expression. , In DGC, few studies have shown that promoter hypomethylation is associated with the activation of proto-oncogenes. In particular, Shin et al.  reported that the hypomethylation of the MOS promoter in GC was associated with tumor invasion, lymph node metastasis, and the diffuse-type. These genes include tumor-suppressor genes, oncogenes, and genes that are involved in tumor progression and metastasis. In addition, recent findings demonstrated changes in the DNA methylation patterns of miRNA genes in GC tissue; samples have revealed more complexity in the epigenetic regulation of GC.
Hypermethylation of CpG islands results in the silencing of neighboring genes and promoters of tumor-suppressor genes are often methylated in GC patient samples. Widely studied genes with methylation promoters include CDKN2A, TP53, MLH1, runt-related transcription factor 3 (RUNX3), adenomatous polyposis coli, and Ras association (RalGDS/AF-6) domain family member 1. ,,,, In addition, recent studies have identified numerous hypermethylated genes encoding pro-apoptotic or anti-growth proteins (BCL2 L10, BCL6B, BNIP3, DAPK, and FBLN1), transcription factors (GATA4, HOXD10, LMX1A, and SOX17), enzymes (KL), cell-cell interaction or migration-related proteins (ADAMTS9, OPCML, PCDH10, RELN, TIMP3, and VEZT), DNA-repair proteins (XRCC1), signaling molecules (CXCL12, dickkopf Wnt signaling pathway inhibitor 1 [DKK1], DKK3, DLL1, SFRP proteins, and suppressor of cytokine signaling 1 [SOCS1]), an RNA binding-protein (QKI), and others (NDRG2). ,,,,,,,,,,,,,,,,,,,,
Hypermethylation of the aforementioned genes generally promotes GC tumorigenesis and/or metastasis via several mechanisms. DNA methylation of tumor-suppressor genes endows gastric cells with the ability to overcome oncogene-induced senescence as well as apoptosis. For example, down-regulation of DKK1 and SOCS1 reactivates the WNT and STAT3 pathways. ,,
In addition, mapping of the CDH1 promoter has revealed a positive association between hypermethylation and older age, as well as a significant correlation between DNA hypermethylation and the A-allele of the −160 C → A-polymorphism. The A-allele has been described to increase the risk of developing GC in association with the methylation status.  This epigenetic mark was recently associated with tumor location and H. pylori infection in GC. 
Other studies have also described a number of genes that are silenced by hypermethylation in association with H. pylori or EBV infection: APC, SHP1, p14, and CDH1. ,,, According to Chan  the eradication of H. pylori infection significantly reduces the methylation index of the CDH1 promoter. In contrast, it has been shown that a portion of the aberrant DNA methylation induced by H. pylori infection may persist even after the infection has disappeared. , Shin et al.  observed that the methylation levels in MOS remained significantly increased in patients with previous H. pylori infection compared with H. pylori-negative subjects.
Hypomethylation causes de-repression of target genes; several genes involved in tumorigenesis, progression, and metastasis of GCs have been found to be hypomethylated. For example, Kwon et al.  demonstrated that the promoter of achaete-scute family bHLH transcription factor 2, which encodes a basic helix-loop-helix transcription factor, shows hypomethylation in GC samples compared to normal tissues, and high expression levels of this gene are correlated with poor survival rate of GC patients. In addition, the promoter of the well-known oncogene MYC has been shown to undergo hypomethylation in GC.  With lymph node metastasis, Yashiro et al.  showed that demethylation in telomeric repeat binding protein 2 and embryonic stem cell expressed Ras promoters causes reactivation of these genes in GC. 
A recent study by Balassiano et al.  reported that GC patient samples contain hypomethylated promoters of two cancer-associated genes, aldehyde dehydrogenase 2 family and methylenetetrahydrofolate reductase. Finally, an interesting study by Yuasa et al.  showed an association between hypomethylation of blood leukocyte DNA and the risk of GC, indicating that changes in the DNA methylation pattern in nontumor cells in addition to tumor cells themselves can be used as potential prognostic markers in GC.
Micro RNAs promoter methylation
MiRNAs are small noncoding RNAs that can regulate the expression of target genes at the posttranscriptional level. Because a single miRNA can target several mRNAs, dysregulation of miRNAs can effectively affect multiple signaling pathways leading to tumor formation and metastasis. As in other types of cancer, recent studies have identified several miRNAs as frequent targets of DNA methylation in GC. For example, the suppression of several miRNA genes, such as MIR137, MIR210, MIR375 or MIR449, via promoter, methylation have been shown to prevent apoptosis by alleviating the miRNA-induced inhibition of pro-survival pathways such as MAPK1 (by MIR137 and MIR210) and PDK1 (by MIR375) or by inhibiting pro-apoptotic pathways (by MIR449). ,,
Histone modifications including acetylation, methylation, phosphorylation, and ubiquitylation that can directly alter gene expression have been described in several cancer types, but the methylation status of chromatin is still unclear for DGC. It was reported that the inactivation of certain tumor suppressor genes by histone modifications results in a poor prognosis. , Moreover, Li et al.  used GC cell lines to demonstrate that the PRC1 member CBX7 initiated trimethylation of H3K9 at the P16 locus through recruitment and/or activation of the HMT SUV39H2 to the target locus. This finding links two repressive epigenetic landmarks, H3K9me3 formation, and PRC1 binding within the silenced domains in euchromatin and builds up a full pathway for epigenetic inactivation of P16 by histone modifications.
Recently, Angrisano et al.  reported that H. pylori infection is followed by activation of inducible nitric oxide synthase (iNOS) gene expression and chromatin changes at the iNOS promoter (including decreased H3K9 methylation and increased H3K4 methylation).
| Catenin Gene Family Mutations are Rare Events in Diffuse Gastric Cancer|| |
Catenins interact closely with E-cadherin molecules in cells. Recently, a germline truncating allele of α-E-catenin (CTNNA1) was reported in two family members with invasive DGC, and four family members in which intramucosal signet ring cells were detected as part of endoscopic surveillance. The remaining CTNNA1 allele was silenced in the two DGCs from the family that was available for screening, and this was also true for signet ring cells identified in endoscopic biopsies.  No nonsynonymous variants were seen in CTNNA1, CTNNB1, or CTNND1.  Catenin genes are not commonly mutated in non-CDH1 HDGC families.  The reason for the big difference between mutation incidence of E-cadherin and catenin gene is still unknown.
In sharp contrast, the somatic mutation in RhoA and CDH1 were highly specific to the DGC subtype. Frequently affected by mutation, the CDH1, and RhoA signaling pathways are reported to be functionally linked with each other, indicating that dysregulation around these two signaling pathways would contribute to DGC development. ,, Although RhoA mutation mutually coexisted with CDH1 mutation, the interaction between RhoA and E-cadherin was extensively studied and proved to play a vital role in DGC pathogenesis.  As known to play a role in cytoskeletal organization, Rac1 and RhoA, involving Rho GTPases, were shown to be frequently overexpressed in primary gastric carcinoma.  Furthermore, increased RhoA activity, which led to higher migration capacity, was induced by HDGC-associated extracellular E-cadherin missense mutations. , EGFR has been shown to be involved in RhoA activation in an E-cadherin-dependent manner. , Noticeably, mutations at the E-cadherin extracellular domain impair the EGFR/E-cadherin interaction, leading to EGFR activation and enhanced cell motility through activation of RhoA. 
The E-cadherin and Rho GTPases were identified to participate as key players in cell adhesion, cytoskeletal organization, and forms the core of the AJ, which is vital to inhibit individual epithelial cell motility and to provide homeostatic tissue architecture.  These two top perturbed pathways and their interactions lead to a highly invasive behavior of DGC, in which single isolated cancer cells or small collective masses of cancer cells massively infiltrated into adjacent tissue with prominent scirrhous stromal reaction. These findings provide new insights for designing a new and effective treatment for this refractory gastric carcinoma.
| Polymorphism of Prostate Stem Cell Antigen and Mucin 1 Susceptibility To Diffuse Gastric Cancer|| |
In a genome-wide association study (GWAS) on DGC, a prostate stem cell antigen (PSCA) gene encoding a glycosylphosphatidylinositol-anchored cell surface antigen was identified as a GC susceptibility gene in the Japanese population. The second candidate locus identified using the GWAS, 1q22; mucin 1 (MUC1) gene encoding a cell membrane-bound mucin protein, was found as another gene related to DGC. ,
Functional studies demonstrated that rs4072037 in MUC1 affects promoter activity and determine 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. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of GC.  PSCA at 8q23.3 was significantly replicated in diffuse-type but far less significant in intestinal-type. 
In Chinese population, rs2294008 C > T and rs2976392 G > A-polymorphisms in PSCA may contribute to the susceptibility to GC, particular to noncardia or DGC. ,,, An SNP in the PSCA gene (rs2976329) has been reported to be associated with increased risk of DGC in Japanese and Korean populations.  The effect of rs2070803 in MUC1 significantly increased the risk of both IGC and DGCs. 
| Other Abnormal Genome Specialty in Diffuse Gastric Cancer|| |
Using whole-exome sequencing in DGC samples, a few specialty genomes were identified in DGC pathogenesis. Wang et al.  executed the whole-genome sequencing, displayed the distinct genomic characteristics of DGC, including a low number of somatic mutations, and less CIN or demethylation with a high propensity for acquiring promoter CpG island hypermethylation. In DGCs, chromosomes 16, 17, 19, 20, 21, and 22 contained an increased amount of block deletions while chromosomes 3, 7, 8, and 13 showed notably increased duplications. Many tumor suppressor genes, such as CDH1, PLA2G2A, RUNX3, SMAD2, and TP53, are located in extensively deleted chromosomal regions. In addition, the copy numbers of the oncogene MYC, MET, MOS, ZHX2, and MDM2 were frequently amplified leading in their overexpression. A copy number gain of genes encoding calcium channel proteins (CACNG6, CACNG7, and CACNG8) was significantly more common in DGC samples. 
PI3K and TP53, well-known cancer-associated genes, were the most frequently mutated genes in both DGC and IGC. Mutations in two known PI3KCA hotspots (E545K and H1047L) and one nonsynonymous single nucleotide variant (nsSNV) mutation (Q546K) adjacent to the E545K mutation were found in DGC sample. Compared to low frequency (16-17%) of the nsSNVs in PI3KCA in IGC samples, it appears that the relatively high mutation rates of PIK3CA in DGC may reflect the specificity of mutations in this gene to this type of cancer. In addition, a nonsense mutation (R1446*) or a copy number reduction in the ARID1A gene, leading to lower protein expression, was found in EBV-positive DGCs. 
Interestingly, the somatic variations were then mapped onto the Kyoto Encyclopedia of Genes and Genomes pathways database [Table 2]. This analysis revealed that the mutated genes of DGCs were significantly associated with the calcium signaling pathway.
| Related Gene Abnormality Prediction of Peritoneal Dissemination in Diffuse Gastric Cancer|| |
Peritoneal dissemination is a characteristic of DGC. In most patients with scirrhous GC (one of the most aggressive of DGCs) recurrence occurs even after potentially curative resection, most frequently in the form of peritoneal metastasis. Recent studies showed that some alternative gene changes are vulnerable to DGC.
Regenerating islet-derived family member four, which is observed in many human gastrointestinal (GI) malignancies, was significantly correlated with diffuse-type histopathology and frequent peritoneal recurrence. Multivariate analysis identified RegIV expression as independent prognostic factors for peritoneal recurrence-free survival. Overexpression of RegIV protein was evident in the majority of peritoneal tumors (93.8%). RegIV mRNA, assessed by transcriptase-reverse transcriptase concerted reaction (TRC), could be a predictive marker for peritoneal recurrence after curative operation.  Integrins are relevant for GC diffusion. The A-genotype of rs2269772 (ITGA3) and the C-genotype of rs11902171 (ITGV), was related with DGC histology. Genotyping of rs2269772 (ITGA3) and rs11902171 (ITGV) may be a further asset in the definition of high-risk patients for peritoneal carcinogenesis among those relapsing after curative resection.  Further, study showed that combining information from genotyping of rs699947 (vascular endothelial growth factor A, AC), rs2269772 (ITGA, AA) and tumor histology could allow clinicians to individuate GC at high-risk for recurrence either with peritoneal or hematogenous metastases.  Focal adhesion kinase, a nonreceptor tyrosine kinase, is known to be associated with tumor progression in various tumors. Focal adhesion kinase gene amplification or protein expression was positively associated with perineural invasion and an independent poor prognostic factor. 
Plasminogen activator inhibitor-1 (PAI-1) siRNA significantly decreased peritoneal tumor growth and the formation of bloody ascites in the mouse model of GC, suggesting that PAI-1 maybe a new and effective target for inhibiting DGC peritoneal metastasis.  Enhanced expression of phosphoglycerate kinase 1, an adenosine triphosphate-generating enzyme in the glycolytic pathway and its signaling targets, CXCR4, and beta-catenin, in GC cells promote peritoneal carcinomatosis. 
In conclusion, DGC is composed of noncohesive cells (with or without signet ring cells) in which single isolated cancer cells or small collective masses of cancer cells massively infiltrate into adjacent tissue in a highly invasive manner with prominent scirrhous stromal reactions and is more commonly observed in younger patients. , H. pylori infection has proven to be an interesting target and multiple studies have indicated that H. pylori infection is a necessary, but not a sufficient causal factor in the development of GC.  Fresh fruits and vegetables are associated with a reduced risk of GC but fortification of the diet with ascorbic acid or use of multivitamins does not appear to confer the same protection. Even with many efficient diagnostic tools such as upper GI endoscopy and biopsy, chest/abdomen/pelvic computed tomography (CT), positron emission tomography-CT, HER2-neu testing, and with treatment options such as surgery, chemotherapy, radiotherapy, and targeted therapy, so far, DGC constitutes a poor prognosis subgroup of GC with no known effective molecularly targeted therapies.
Recently, although the complex combination of genetic and epigenetic alterations have been demonstrated to coexist in GC tumor,  the cancer genome Atlas More Details proposed a molecular classification dividing GC into four subtypes: (i) tumors positive for EBV which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1), and PDCD1LG2 (also known as PD-L2); (ii) microsatellite unstable tumors, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signaling proteins; (iii) tumors with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases; and (iv) genomically stable tumors, which are enriched for the diffuse histological variant and mutations of RhoA or fusions involving Rho-family GAPs.  Indeed, recent genomic characterization of GC based on NGS technology showed a few candidate driver genes including RhoA, CDH1 as a gain-of-function mutations in DGC initiation and progression. Other genes such as PI3K, PTEN, MET, MDM2, ITGA, as well as CACNG6, CACNG7, CACNG8, and CNV or SNV were also more frequently associated with DGC. Identification of these molecular subtypes and connecting the Lauren's type will provide a roadmap for patient stratification and trials of targeted therapies. 
Low calcium intake may contribute to GC development. Most genes involved in DGC were dramatically related with the calcium signaling pathway. Aside from a mutation in CDH1, RhoA mutation was detected in DGC. Calcium channel is necessary for RhoA to keep cell cytoskeleton in normal shape and maintain normal cell migration by modulating the activity of the actin-binding proteins cofilin and profilin. Furthermore, calcium is essential for the function of E-cadherin. Loss of E-cadherin-mediated adhesion is involved in the transition from a benign lesion to invasive metastatic cancer. Indeed, exome sequencing assay identified recurrent somatic mutations in cell adhesion in gastric adenocarcinoma.  Hence, calcium-related pathway is an alternative pivotal target for DGC therapy.
Furthermore, the somatic mutations were strongly associated with pathways related to small cell lung cancer. In particular, genes involved in focal adhesion pathways, such as ITGA, PIK3CA, and MET were frequently mutated in DGC. Therefore, a similar target therapy may be designed based on related gene profile between DGC and small cell lung cancer. Based on current studies, it might be possible to develop novel therapeutic strategies against otherwise devastating DGC that undergo massive invasion and metastasis, via specific interference with mutant RhoA or CDH1 through their oncogenic pathways.
This article is an overview of the genomic landscape that highlights the multidimensional perturbations of the DGC genome and epigenome, which occur to an extent seldom seen in IGC and other solid cancers. More driver genes that may have mutated or deregulated in DGC will be discovered and will provide a comprehensive roadmap to facilitate genome-guided personalized therapy and precision medicine in the future. ,,
Financial support and sponsorship
This work was supported by grants from the Natural Scientific Foundation of China (81200366, 81171841) and Province Natural Scientific Foundation of Hunan (No. 14JJ6004) and the Key Subject Education Department of Hunan ((2012)594).
Conflict of interest
There are no conflict of interest.
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[Table 1], [Table 2]