Approximately half of the world's 500,000 new oesophageal squamous-cell carcinoma (ESCC) cases each year occur in China. Here, we show whole-genome sequencing of DNA and RNA in 94 Chinese individuals with ESCC. We identify six mutational signatures (E1–E6), and Signature E4 is unique in ESCC linked to alcohol intake and genetic variants in alcohol-metabolizing enzymes. We discover significantly recurrent mutations in 20 protein-coding genes, 4 long non-coding RNAs and 10 untranslational regions. Functional analyses show six genes that have recurrent copy-number variants in three squamous-cell carcinomas (oesophageal, head and neck and lung) significantly promote cancer cell proliferation, migration and invasion. The most frequently affected genes by structural variation are LRP1B and TTC28. The aberrant cell cycle and PI3K-AKT pathways seem critical in ESCC. These results establish a comprehensive genomic landscape of ESCC and provide potential targets for precision treatment and prevention of the cancer.
In an analysis of ESCC samples and cell lines, we associated increased expression of SLC39A6 with tumor invasiveness, intracellular level of zinc, and patient survival time. ESCC cell lines that overexpress SLC39A6 up-regulate expression MMP1, MMP3, MYC, and SLUG and form metastatic xenograft tumors in mice. Up-regulation of SLC39A6 might be used to determine prognoses of patients with ESCC or as a therapeutic target.
Genetic variation (rs372883C/T) in the 3'-untranslated region of BTB and CNC homology 1 (BACH1) has been associated with pancreatic ductal adenocarcinoma (PDAC) risk in our previous genome-wide association study; however, the action roles of this genetic variation in PDAC remains unknown.Methods:
BACH1 expression was measured by quantitative real-time PCR, Western blot and immunohistochemistry. The effects of BACH1 on cell proliferation and sensitivity to gemcitabine were examined by alteration of BACH1 expression in PDAC cells. Angiogenesis was determined in vitro using a human umbilical vein endothelial cell model. Reporter gene assays were conducted to compare the effects of microRNA-1257 on rs372883 variation. The associations between rs372883 variants and survival time in patients treated with gemcitabine were estimated by logistic regression.Results: We found substantially lower BACH1 expression in PDAC compared with normal pancreatic tissues and the rs372883T allele had significantly lower BACH1 levels than the rs372883C allele in both tumor and normal tissues. Knockdown of BACH1 expression provoked proliferation of PDAC cells and angiogenesis, which might result from upregulation of hemeoxygenase-1 that evokes oncogenic AKT and ERK signaling. The rs372883T>C change inhibits interaction of BACH1 with microRNA-1257, resulting in increased BACH1 expression. PDAC patients with the rs372883T allele were more resistant to gemcitabine and had shorter survival time compared with those with the rs372883C allele.Conclusion: These results shed light on the mechanism underlying the associations of BACH1 rs372883 variation with risk of developing PDAC and differential gemcitabine sensitivity in patients.
BackgroundPancreatic duct adenocarcinoma (PDAC) remains a major health problem because conventional cancer treatments are relatively ineffective against it. Microarray studies have linked many genes to pancreatic cancer, but the available data have not been extensively mined for potential insights into PDAC. This study attempted to identify PDAC-associated genes and signaling pathways based on six microarray-based profiles of gene expression in pancreatic cancer deposited in the gene expression omnibus database.MethodsPathway network methods were used to analyze core pathways in six publicly available pancreatic cancer gene (GSE71989, GSE15471, GSE16515, GSE32676, GSE41368 and GSE28735) expression profiles. Genes potentially linked to PDAC were assessed for potential impact on survival time based on data in The Cancer Genome Atlas and International Cancer Genome Consortium databases, and the expression of one candidate gene (CKS2) and its association with survival was examined in 102 patients with PDAC from our hospital. Effects of CKS2 knockdown were explored in the PDAC cell lines BxPC-3 and CFPAC-1.ResultsThe KEGG signaling pathway called “pathway in cancer” may play an important role in pancreatic cancer development and progression. Five genes (BIRC5, CKS2, ITGA3, ITGA6 and RALA) in this pathway were significantly associated with survival time in patients with PDAC. CKS2 was overexpressed in PDAC samples from our hospital, and higher CKS2 expression in these patients was associated with shorter survival time. CKS2 knockdown substantially inhibited PDAC cell proliferation in vitro.ConclusionsAnalysis integrating existing microarray datasets allowed identification of the “pathway in cancer” as an important signaling pathway in PDAC. This integrative approach may be powerful for identifying genes and pathways involved in cancer.Electronic supplementary materialThe online version of this article (10.1186/s40880-018-0289-9) contains supplementary material, which is available to authorized users.
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