Prevalence and spectrum of cancer predisposition germline mutations in young patients with the common late-onset cancers.

BACKGROUND: Pathogenic germline variants (PGVs) can play a vital role in the oncogenesis process in carriers. Previous studies have recognized that PGVs contribute to early onset of tumorigenesis in certain cancer types, for example, colorectal cancer and breast cancer. However, the reported prevalence data of cancer-associated PGVs were highly inconsistent due to nonuniform patient cohorts, sequencing methods, and prominent difficulties in pathogenicity interpretation of variants. In addition to the above difficulties, due to the rarity of cases, the prevalence of cancer PGV carriers in young cancer patients affected by late-onset cancer types has not been comprehensively evaluated to date. METHODS: A total of 131 young cancer patients (1-29 years old at diagnosis) were enrolled in this study. The patients were affected by six common late-onset cancer types, namely, lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, and head-neck cancer. Cancer PGVs were identified and analyzed. based on NGS-based targeted sequencing followed by bioinformatic screening and strict further evaluations of variant pathogenicity. RESULTS: Twenty-three cancer PGVs in 21 patients were identified, resulting in an overall PGV prevalence of 16.0% across the six included cancer types, which was approximately double the prevalence reported in a previous pancancer study. Nine of the 23 PGVs are novel, thus expanding the cancer PGV spectrum. Seven of the 23 (30.4%) PGVs are potential therapeutic targets of olaparib, with potential implications for clinical manipulation. Additionally, a small prevalence of somatic mutations of some classic cancer hallmark genes in young patients, in contrast to all-age patients, was revealed. CONCLUSION: This study demonstrates the high prevalence of PGVs in young cancer patients with the common late-onset cancers and the potentially significant clinical implications of cancer PGVs, the findings highlight the value of PGV screening in young patients across lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, or head-neck cancer.

Profiling of the genetic features of Chinese patients with gastric cancer with HRD germline mutations in a large-scale retrospective study.

BACKGROUND: Approximately 10% of gastric cancers (GCs) are associated with strong familial clustering and can be attributed to genetic predisposition. Homologous recombination deficiency (HRD) leads to genomic instability and accumulation of genetic variations, playing an important role in the development and progression of cancer. We aimed to delineate the germline mutation characteristics of patients with HRD-mut GC in Chinese. METHODS: We retrospectively reviewed the genomic sequencing data of 1135 patients with Chinese GC. Patients harbouring at least one loss of function (LoF) germline mutations in BRCA1, BRCA2, ATM, PALB2, BRIP1, CHEK1, CHEK2, FANCA and FANCL were selected for analysis. RESULTS: 89 patients were identified with LoF germline mutations of HRD gene. Germline mutations occurred most commonly in ATM (30.33%), followed by BRIP1 (17.98%), BRCA2 (14.61%), BRCA1 (12.36%), FANCA (10.11%), PALB2 (10.11%), FANCL (6.74%), CHEK1 (3.37%) and CHEK2 (3.37%). 14 out of 89 patients with HRD-mut harboured double mutations in HRD and MMR genes, with the median age of 51.5 years. The decreasing median age would be attributed to five patients with HRD+MMR double-muts harbouring mutations in both HRD and MMR genes. The median age of onset of patients with HRD+MMR double-muts is 47, which is significantly earlier than that of Chinese patients with GC (p=0.0235). CONCLUSION: Our data suggest that carrying both HRD and MMR gene LoF germline mutations may cause early-onset GC. Germline mutations in the HRD gene should be of concern in the study of hereditary GC.

Identification of MET fusions in solid tumors: A multicenter, large scale study in China.

MET amplification and exon 14 skipping are well known as oncogenic drivers in multiple cancer types. However, MET fusions in most cancer types are poorly defined. To explore the profile and analyze the characteristics of MET fusions, a large-cohort study was conducted to screen MET fusions in clinical samples (n = 10 882) using DNA-based NGS. A total of 37 potentially functional MET fusions containing the intact tyrosine kinase domain (TKD) of MET were identified in 36 samples. Further, 15 novel MET fusions were identified in five cancer types, and the incidence of novel MET fusions accounted for 40.5% (15/37). Brain cancer had the highest incidence of MET fusion, with PTPRZ1-MET as the most common fusion (37.0%). All MET breakpoints in brain cancer (n = 27) were also located in intron 1, while those in lung cancer (n = 4) occurred in intron 1, intron 11, intron 14 and exon 14, respectively. The positive consistency of the common fusion group was 100% (11/11), while that of the rare fusion group was 53.8% (7/13). In conclusion, we provided a comprehensive genomic landscape of MET rearrangement and updated the MET fusions database for clinical test. In addition, we revealed that DNA-based NGS might serve as the clinical test for common MET fusions; however, rare MET fusions must be validated by both DNA-based NGS and RNA-based NGS. Prospective trials are necessary to confirm the treatment efficacy of MET inhibitors.

Molecular characterization of genomic breakpoints of ALK rearrangements in non-small cell lung cancer.

ALK rearrangement is called the 'diamond mutation' in non-small cell lung cancer (NSCLC). Accurately identifying patients who are candidates for ALK inhibitors is a key step in making clinical treatment decisions. In this study, a total of 783 ALK rearrangement-positive NSCLC cases were identified by DNA-based next-generation sequencing (NGS), including 731 patients with EML4-ALK and 52 patients with other ALK rearrangements. Diverse genomic breakpoints of ALK rearrangements were identified. Approximately 94.4% (739/783) of the cases carried ALK rearrangements with genomic breakpoints in the introns of ALK and its partner genes, and 2.8% (21/739) of these cases resulted in frameshift transcripts of ALK. Meanwhile, 5.6% (44/783) of the ALK rearrangement-positive cases had breakpoints in the exons that would be expected to result in abnormal transcripts. RNA-based NGS was performed to analyse the aberrant fusions at the transcript level. Some of these rearranged DNAs were not transcribed, and the others were fixed by some mechanisms so that the fusion kinase proteins could be expressed. Altogether, these findings emphasize that, when using DNA-based NGS, functional RNA fusions should be confirmed in cases with uncommon/frameshift rearrangement by RNA-based assays.

PBRM1 presents a potential prognostic marker and therapeutic target in duodenal papillary carcinoma.

BACKGROUND: Due to its rarity, duodenal papillary carcinoma (DPC) is seldom studied as a unique disease and no specific molecular features or treatment guidelines are provided. METHODS: Whole-exome sequencing was performed to gain new insights into the DPC mutation landscape and to identify potential signalling pathways and therapeutic targets. Mechanistically, immunohistochemistry (IHC), immunofluorescence, RNA-seq, ATAC-seq and in vitro cell function experiments were performed to confirm the underlying mechanisms. RESULTS: We described the mutational landscape of DPC for the first time as a group of rare tumours with a high frequency of dysregulation in the chromatin remodelling pathway, particularly PBRM1-inactivating mutations that are significantly higher than duodenal adenocarcinomas and ampullary adenocarcinoma (27% vs. 0% vs. 7%, p < .01). In vitro cell experiments showed that downregulation of PBRM1 expression could significantly promote the cancer progression and epithelial-to-mesenchymal transition via the PBRM1-c-JUN-VIM axis. The IHC data indicated that PBRM1 deficiency (p = .047) and c-JUN expression (p < .001) were significantly associated with poor prognosis. Meanwhile, the downregulation of PBRM1 expression in HUTU-80 cells was sensitive to radiation, which may be due to the suppression of c-JUN by irradiation. CONCLUSIONS: Our findings define a novel molecular subgroup of PBRM1-inactivating mutations in DPC. PBRM1 play an important role in DPC progression and may serve as a potential therapeutic target and prognostic indicator.

Profiling of gene fusion involving targetable genes in Chinese gastric cancer.

BACKGROUND: Approximately half of all new cases of gastric cancer (GC) and related deaths occur in China. More than 80% of patients with GC are diagnosed at an advanced stage, which results in poor prognosis. Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful, new drugs are still needed for the treatment of GC. Notably, several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors, including GC, such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers. However, gene fusions involving targetable genes have not been well characterized in Chinese patients with GC. AIM: To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC. METHODS: We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC. Clinicopathological characteristics were obtained from their medical records. Genetic alterations, such as single nucleotide variants, indels, amplifications, and gene fusions, were identified using a targeted sequencing panel containing 825 genes. Fusions were validated by fluorescence in situ hybridization (FISH) using break-apart probes. The microsatellite instability (MSI) status was evaluated using MSIsensor from the targeted sequencing panel data. Tumor mutational burden (TMB) was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region. Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC. RESULTS: We found that 1.68% (16/954) of patients harbored 20 fusion events involving targetable genes. RARA fusions (n = 5) were the most common, followed by FGFR2, BRAF, MET, FGFR3, RET, ALK, EGFR, NTRK2, and NRG1 fusions. Two of the RARA fusions, EML4-ALK (E6:E20) and EGFR-SEPTIN14 (E7:E10), have been identified in other tumors but not in GC. Surprisingly, 18 gene fusion events were previously not reported in any cancer types. Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes, such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA- and ligand-binding domains of RARA. Consistent with the results of detection using the targeted sequencing fusion panel, the results of FISH (fluorescence in situ hybridization) confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09, respectively. Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification (P = 0.02); however, there were no significant differences between fusion-positive and fusion-negative patients in age, sex, MSI status, and TMB. CONCLUSION: We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.

The role of NLRP3 inflammasome in digestive system malignancy.

Digestive system malignancies, the most common types of cancer and a major cause of death in the worldwide, are generally characterized by high morbidity, insidious symptoms and poor prognosis. NLRP3 inflammasome, the most studied inflammasome member, is considered to be crucial in tumorigenesis. In this paper, we reviewed its pro-tumorigenic and anti-tumorigenic properties in different types of digestive system malignancy depending on the types of cells, tissues and organs involved, which would provide promising avenue for exploring new anti-cancer therapies.

Genomic and Transcriptional Profiling of Chinese Melanoma Patients Enhanced Potentially Druggable Targets: A Multicenter Study.

BACKGROUND: In contrast to Caucasian melanoma, which has been extensively studied, there are few studies on melanoma in Asian populations. Sporadic studies reported that only 40% of Asian melanoma patients could be druggable, which was much lower than that in Caucasians. More studies are required to refine this conclusion. METHODS: Chinese melanoma patients (n = 469) were sequentially sequenced by DNA-NGS and RNA-NGS. The genomic alterations were determined, and potentially actionable targets were investigated. RESULTS: Patients with potential druggable targets were identified in 75% of Chinese melanoma patients by DNA-NGS based on OncoKB, which was much higher than in a previous Asian study. NRG1 fusions were first identified in melanoma. In addition, up to 11.7% (7/60) of patients in the undruggable group could be recognized as actionable by including RNA-NGS analysis. By comparing the fusion detection rate between DNA-NGS and RNA-NGS, all available samples after DNA-NGS detection were further verified by RNA-NGS. The use of RNA-NGS enhanced the proportion of druggable fusions from 2.56% to 17.27%. In total, the use of RNA-NGS increased the druggable proportion from 75% to 78%. CONCLUSIONS: In this study, we systemically analyzed the actionable landscape of melanoma in the largest Asian cohort. In addition, we first demonstrated how DNA and RNA sequential sequencing is essential in bringing clinical benefits to more patients with melanoma.

Protective effect of sinomenine on isoproterenol-induced cardiac hypertrophy in mice.

To study the effect of sinomenine (Sin) on isoproterenol (Iso, ß-agonist)-induced cardiac hypertrophy (CH), we set up four mouse groups: control, Iso model, Iso+metoprolol (Met, ß blocker) 60 mg/kg and Iso+Sin 120 mg/kg. CH was induced by Iso (s.c. for 28 days) in mice, and Sin or Met were orally administered by gavage for 28 days in total. Left ventricular diastolic anterior wall thickness (LVAWd), left ventricular diastolic posterior wall thickness (LVPWd), left ventricular ejection fraction (LVEF), and short axis shortening (FS) were measured by echocardiography. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) were measured by commercial kits. Lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1ß) were measured by ELISA kits. Histological changes were observed using hematoxylin-eosin (HE) and Masson staining. Protein level of nuclear transcription factor-kappa B (NF-κB) was detected by immunohistochemistry. Compared with the control group, LVAWd, Left ventricular weight index (LVWI) and myocardial fibrosis of the Iso model group significantly increased, as well as NF-κB, LDH, MDA, TNF-α, and IL-1ß levels. However, the activity of T-SOD decreased. Compared with the Iso model group, LVWI of Iso model+Sin or Iso model+Met group was improved, LVAWd, LVPWd and myocardial fibrosis decreased, and NF-κB, LDH, MDA, TNF-α and IL-1ß levels decreased. T-SOD activity also increased. This study reveals that Sin inhibits the activation of NF-κB, lowers the levels of TNF-α and IL-1ß, has anti-oxidative stress effect and inhibits myocardial inflammation in mouse heart, thereby demonstrating its efficacy in preventing Iso induced CH.

Effect of 4,5-diazafluorene derivative on γδ T cell-mediated cytotoxicity against renal cell carcinoma.

AIMS: This study aimed to investigate the effect of previously synthesized 4,5-diazafluorene derivative (14c) on γδ T cell-mediated cytotoxicity against renal cell carcinoma (RCC). MATERIALS AND METHODS: A real-time cell analyzer monitored cell proliferation, and Cell Counting Kit-8 determined cell viability. A reverse transcription-polymerase chain reaction analyzed gene expression, and protein expression was determined by cellular immunofluorescence analysis and Western blot. KEY FINDINGS: The compound 14c induced the expression of immunomodulatory molecules, such as natural killer group 2, member D ligands (NKG2DLs), fibroblast-associated (Fas) death receptor, and tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAILRs) in RCC. In addition, 14c induced DNA damage responses in RCC. Blocking DNA damage by KU-55933 reduced the effect of γδ T cells on 14c-treated RCC, suggesting that DNA damage responses were involved in the augmentation of γδ T cell-mediated cytotoxicity. Treating 786-O cells with a nitrogen-containing bisphosphonate prodrug further enhanced the anti-tumor effect of γδ T cell plus 14c combination treatment. SIGNIFICANCE: The present evidence indicates that 14c induced DNA damage responses in RCC and augmented γδ T cell-mediated cytotoxicity primarily through NKG2D/NKG2DLs pathways, suggesting potential cancer immunotherapy for harnessing γδ T cells and small compounds that induce DNA damage responses.

The new role of riluzole in the treatment of pancreatic cancer through the apoptosis and autophagy pathways.

Pancreatic cancer is always diagnosed at an advanced stage. Hence, chemotherapy becomes the best choice for patients. Therefore, new anticancer drugs for pancreatic cancer are needed. Riluzole (RIL) is mainly used to treat amyotrophic lateral sclerosis clinically, but many previous studies have shown that RIL could inhibit tumors. However, no report has explored the association between RIL and pancreatic cancer. To validate this association, we performed this study. Our data showed that RIL could induce cytotoxicity, block the cell cycle, and inhibit clone formation, apoptosis, and migration in pancreatic cancer cells. Moreover, we demonstrated that RIL could suppress autophagy. However, more experiments will be needed to validate the reliability of our conclusions. In summary, our data suggest that RIL might provide clues for the development of a treatment for human pancreatic cancer in the future.

Upregulation of miRNA­301a­3p promotes tumor progression in gastric cancer by suppressing NKRF and activating NF­κB signaling.

MicroRNA­301a (miRNA/miR­301a) and nuclear factor (NF)­κB signaling play important roles in tumor invasion, migration and progression. However, the role of miRNA­301a­3p in human gastric cancer (GC), and specifically in the activation of NF­κB signaling, remains unclear. The aim of the present study was to investigate miRNA­301a­3p expression in GC progression and the molecular mechanisms as regards the regulation of NF­κB signaling. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was used to detect miRNA­301a­3p expression in GC and paired normal tissues. The association between the expression of miRNA­301a­3p and patient pathological parameters and the prognosis of GC was statistically analyzed using an in situ hybridization (ISH) assay. An MTS assay and a Transwell assay were performed to evaluate the effects of miRNA­301a­3p on the proliferation, invasion and migration of GC cells. RT­qPCR and western blot analysis were used to analyze the association between miRNA­301a­3p and nuclear factor­κB repressing factor (NKRF) expression and the corresponding downstream NF­κB signaling molecules. A luciferase assay was used to verify the target effect of miRNA­301a­3p and NKRF. It was found that miRNA­301a­3p expression was significantly higher in 30 cases of primary GC compared with matched normal tissues. Additionally, the ISH assay indicated that the high expression of miRNA­301a­3p in GC was associated with tumor invasion depth, lymph node metastasis, lymph node invasion and tumor metastasis stage. Patients whose tumors had a higher miRNA­301a­3p expression level exhibited a poorer prognosis. The in vitro assay indicated that miRNA­301a­3p affected the proliferative and invasive ability of GC cells by targeting the expression of NKRF, which then affected NF­κB signaling. Therefore, it was hypothesize that miRNA­301a­3p promotes GC progression and affects the prognosis of patients with GC by targeting NKRF, which in turn, directly influences NF­κB activation.

Sinomenine's protective role and mechanism in stress load-induced heart failure.

OBJECTIVES: This study is designed to investigate the effects and mechanisms of sinomenine (Sin) in stress load-induced heart failure in mice. METHODS: We used aortic constriction (AB) to cause pressure overload as our heart failure model. Sin was received in mice as the treatment group. Cardiac function and structural changes were detected using echocardiography. Heart-lung mass ratios were measured. The serum levels of IL-10 and IL-17 proteins were detected by using ELISA, cardiac hypertrophy markers atrial natriuretic peptide (ANP), myocardial I and III collagen mRNA levels were detected by RT-PCR. Myocardial type I and III collagen protein levels were detected by Western blotting. KEY FINDINGS: Sin significantly improved stress load-induced heart failure (P < 0.05), reduced the heart-lung mass ratio, ANP, collagen-I and -III mRNA and protein levels (P < 0.05); Sin can enhance the ratio of IL-10/IL-17. CONCLUSION: Sin may be a promising drug target to improve heart failure. Its role is related to reduce serum ANP levels, inhibit the mRNA and protein level of type I and III collagen and enhance the ratio of IL-10/IL-17.

miR-618 Suppresses Metastasis in Gastric Cancer by Downregulating the Expression of TGF-ß2.

Recent studies have demonstrated that microRNAs regulate gene expression and are related to cancer progression. Increasing evidence shows that miR-618 plays an important role in a variety of tumors, including thyroid carcinomas, breast cancer and lymphoma cancer. However, no studies have examined the expression or function of miR-618 in gastric cancer (GC). In this study, we examined the effects and molecular mechanisms of miR-618 in GC. We compared the expression levels of miR-618 in 90 paired GC tissues and adjacent noncancerous tissues. Cell cycle, apoptosis and transwell assays were performed in GC cells with miR-618 mimic or inhibitor in vitro. We first used quantitative PCR(qPCR) to show that miR-618 expression levels were downregulated in GC tissues, which showed statistical significance. Next we used transwell assays to prove that miR-618 suppressed the invasion and migration capacity of GC cells. Furthermore, screening of the miRDB and Target Scan Human databases indicated TGF-ß2 as a downstream target of miR-618. In further research, we identified TGF-ß2 as a target gene of miR-618 by the luciferase reporter assay. Western blot analysis confirmed that TGF-ß2 expression was inversely correlated with miR-618 expression. In situ hybridization showed that miR-618 expression level was downregulated in GC tissues. In conclusion, our findings suggest that miR-618 may function as a tumor suppressor in GC and suppresses metastasis in GC by negatively regulating the transcriptional level of TGF-ß2. Anat Rec, 302:931-940, 2019. © 2019 Wiley Periodicals, Inc.

Low FAT4 expression is associated with a poor prognosis in gastric cancer patients.

In this study, we investigated the role of Fat atypical cadherin 4 (FAT4) in gastric cancer (GC) progression. Immunohistochemical analysis showed lower FAT4 expression in tumor tissues from GC patients than in normal gastric epithelium. Lower FAT4 expression was associated with poor prognosis, tumor size and invasion, and lymph node and distant metastases. Multivariate analysis showed that TNM stage, lymph node and distant metastases, Lauren classification, and FAT4 expression were independent prognostic factors in GC. Methylation-specific PCR analysis showed increased FAT4 promoter methylation in GC tumor tissues and cell lines. Higher FAT4 promoter methylation was associated with low FAT4 expression and a poor prognosis. BGC-823 cells showed increased FAT4 expression upon treatment with 5-azacytidine, demethylating agent. FAT4 knockdown in BGC-823 cells led to increased cell proliferation, migration and invasiveness. Moreover, xenografts of BGC-823 cells with FAT4 knockdown showed enhanced tumor growth and metastasis in nude mice. These findings demonstrate that low FAT4 expression is associated with a poor prognosis in GC patients.

PHD3 affects gastric cancer progression by negatively regulating HIF1A.

Prolyl hydroxylase 3 (PHD3) is widely accepted as a tumor suppressor; however, the expression of PHD3 in various cancer types remains controversial. The present study aimed to investigate the association between PHD3 expression and the clinicopathological features of gastric cancer using reverse transcription­quantitative polymerase chain reaction and immunohistochemistry. The effects of PHD3 in gastric cancer cell lines were assessed using western blot analysis and transwell migration assays. The present results revealed that PHD3 expression was increased in adjacent non­cancerous tissue compared with in gastric cancer tissue, and PHD3 overexpression was correlated with the presence of well­differentiated cancer cells, early cancer stage classification and the absence of lymph node metastasis. In vitro experiments demonstrated that PHD3 may act as a negative regulator of hypoxia­inducible factor­1α and vascular endothelial growth factor, both of which participate in tumor angiogenesis. In conclusion, the present results suggested that PHD3 may act as a tumor suppressor in gastric cancer. Therefore, the targeted regulation of PHD3 may have potential as a novel therapeutic approach for the treatment of patients with gastric cancer.

HOXB7 overexpression promotes cell proliferation and correlates with poor prognosis in gastric cancer patients by inducing expression of both AKT and MARKs.

Increased expression of HOXB7 has been reported to correlate with the progression in many cancers. However, the specific mechanism by which it promotes the evolution of gastric cancer (GC) is poorly understood.In this study, we sought to investigate the role of HOXB7 in GC by assessing HOXB7 expression in patient tissue and its correlation to clinical characteristics. We found that GC tissues showed increased expression of HOXB7 and that the HOXB7 expression was significantly associated with Lauren classification, invasion depth, lymphatic metastasis and poor prognosis, and could serve as an independent prognostic factor. To further investigate the role of HOXB7 in GC, we generated stable GC cell lines and both over-expressed and knocked down HOXB7 expression. Over-expression of HOXB7 in GC cell lines enhanced cell proliferation, colony formation, migration and invasion ability, whereas the opposite trends were observed upon reduction of HOXB7 expression by knockdown. These findings were further supported by our in vivo studies which show that HOXB7 expression can affect the GC cells' subcutaneous growth and lung metastases. A Phospho-MAPK Array Kit was used to explore the possible mechanism of HOXB7-induced cell proliferation and invasion. We found that the AKT signaling pathway and the two members of the MAPK pathway, were involved in those promoting effects. In conclusion, our results showed that increased expression of HOXB7 might play an important role in promoting GC proliferation, migration and invasion by inducing both AKT and MAPK pathways, thus resulting in progression of, and poor prognosis in GC patients.

The CDH1 -160C/A polymorphism is associated with breast cancer: evidence from a meta-analysis.

BACKGROUND: Numerous epidemiological studies have evaluated the association between the CDH1 -160C/A polymorphism and the risk of breast cancers. However, these studies have yielded conflicting results. To derive a more precise estimation of this association, this meta-analysis was conducted. METHODS: A comprehensive search using the keywords "CDH1," "E-Cadherin," "polymorphism," "SNP," and "variant" combined with "breast," "cancer," "tumor," or "carcinomas" was conducted. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were appropriately calculated using a fixed effect or random effect model. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 checklist was used for this meta-analysis. RESULTS: Four publications including five studies were identified. It was found that the CDH1 -160C/A polymorphism was significantly associated with breast cancer risk in the dominant model (CA + AA vs. CC: OR = 1.207, 95 % CI = 1.031-1.412, P = 0.019). CONCLUSIONS: Our meta-analysis demonstrated that the -160C/A polymorphism in the CDH1 gene might contribute to breast cancer susceptibility. Further investigations using a much larger sample including different ethnicities are still needed to verify this association.