Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations

Chang, Jiang; Tian, Jianbo; Zhu, Ying; Zhong, Rong; Zhai, Kan; Li, Jiaoyuan; Ke, Juntao; Han, Qiang‐Qiang; Lou, Jiao; Chen, Wei; Zhu, Beibei; Shen, Na; Zhang, Yi; Gong, Yajie; Yang, Yang; Zou, Detang; Peng, Xiaobo; Zhang, Zhi; Zhang, Xuemei; Huang, Kun; Yang, Ming; Wang, Li; Wu, Chen; Lin, Dongxin

doi:10.1038/s41467-018-06136-x

Cited by 32 publications

(31 citation statements)

References 64 publications

(55 reference statements)

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“…Genotype calling was performed using Illumina GenomeStudio software, and cluster plots were manually checked. A systematic quality control was performed to filter unqualified genetic variants and samples . For SNPs selection procedure, first we extracted 951 single nucleotide polymorphisms (SNPs) in 9p21.3 region (19.9‐29 Mb) from our exon chip data set, then we picked out 318 SNPs with a minor allele frequency (MAF) ≥5% among Han Chinese.…”

Section: Methodsmentioning

confidence: 99%

A functional variant rs1537373 in 9p21.3 region is associated with pancreatic cancer risk

Zhu

Tian

et al. 2019

Molecular Carcinogenesis

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9p21.3 has been identified as an unexpected hot point in multiple diseases GWAS including cancers, and we performed a two‐stage case‐control studies integrating functional assay strategy to find the potential functional variants modified susceptibility to pancreatic cancer (PC). An expanded Illumina HumanExome Beadchip of PC including 943 cases and 3908 controls was used to examine 39 tagSNPs in 9p21.3 and the promising single nucleotide polymorphism (SNP) was validated in stage 2 comprising 624 cases and 1048 controls. The strongest signal was rs6475609 (Odds ratio, OR = 0.81, 95% confidence interval, CI = 0.72‐0.91) maps to the long non‐coding RNA ANRIL. Bioinformatics analysis revealed rs1537373 lies in the linkage disequilibrium (LD) block which the rs6475609 tagged might have potential function and was also associated with a decreased risk of PC in both stages (OR = 0.82, 95% CI = 0.75‐0.90 in combined analysis). Dual luciferase reporter assay and the electrophoretic mobility shift assay (EMSA) verified rs1537373 as the best candidate causative variant for influencing the activity of enhancer through differential binding to certain transcription factor. The expression quantitative trait loci (e‐QTL) analysis indicated the genotypes of rs1537373 were associated with expression of CDKN2B gene (P dominant = 6.00 × 10−4). In conclusion, our study provided evidence that rs1537373 in ANRIL may influence transcription factor binding and regulate CDKN2B expression, thus confer the susceptibility to PC.

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Section: Methodsmentioning

confidence: 99%

A functional variant rs1537373 in 9p21.3 region is associated with pancreatic cancer risk

Zhu

Tian

et al. 2019

Molecular Carcinogenesis

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“…It triggers a cascade of response, from cell growth to survival and motility, that drive tumor initiation to progression . Recently, we discovered that a germline variant in PKN1 gene might perturb the PKN1/FAK/PI3K/AKT pathway and lead to pancreatic tumorigenesis . Our study bridged the core elements of PI3K‐AKT signaling with PKN1/FAK, and highlighted the role of the germline variant on this pathway played in PC development.…”

Section: Introductionmentioning

confidence: 77%

A genetic variant in PIK3R1 is associated with pancreatic cancer survival in the Chinese population

Zhu

Gong

et al. 2019

Cancer Medicine

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Pancreatic cancer is one of the deadliest malignancies with few early detection tests or effective therapies. PI3K‐AKT signaling is recognized to modulate cancer progression. We previously identified that a genetic variant in PKN1 increased pancreatic cancer risk through the PKN1/FAK/PI3K/AKT pathway. In order to investigate the associations between genetic variations in that pathway and pancreatic cancer prognosis, we conducted a two‐stage survival analysis in a total of 547 Chinese pancreatic cancer patients. Consequently, a variant, rs13167294 A>C in PIK3R1 , was significantly associated with poor survival in both stages and with hazard ratio being 1.32 (95% CI = 1.13‐1.56, P = 0.0007) in the combined analysis. Function annotation and prediction suggested that genetic variants in this locus might affect overall survival of pancreatic cancer patients by regulating PIK3R1 expression.

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“…DNA was isolated from the blood sample using a TIANamp Blood DNA Kit (TianGen Biotech Co. Ltd.). Then, the DNA was further performed to genotype using the TaqMan methodology instructed by the manufacturers . Negative controls (water samples) were used to ensure genotyping preciseness.…”

Section: Methodsmentioning

confidence: 99%

LIN28A gene polymorphisms modify neuroblastoma susceptibility: A four‐centre case‐control study

Hua

Zhang

et al. 2019

J Cellular Molecular Medi

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Neuroblastoma ranks the most common seen solid tumour in childhood. Overexpression of LIN28A gene has been linked to the development of multiple human malignancies, but the relationship between LIN28A single nucleotide polymorphisms (SNPs) and neuroblastoma susceptibility is still under debate. Herein, we evaluated the correlation of four potentially functional LIN28A SNPs (rs3811464 G>A, rs3811463 T>C, rs34787247 G>A, and rs11247957 G>A) and neuroblastoma susceptibility in 505 neuroblastoma patients and 1070 controls from four independent hospitals in China. The correlation strengths were determined by using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Among these SNPs, rs34787247 G>A exhibited a significant association with increased susceptibility in neuroblastoma (GA vs GG: adjusted OR = 1.30, 95% CI = 1.03‐1.64; AA vs GG: adjusted OR = 2.51, 95% CI = 1.36‐4.64, AA/GA vs GG: adjusted OR = 1.42, 95% CI = 1.12‐1.80, AA vs GG/GA: adjusted OR = 2.39, 95% CI = 1.29‐4.42). Furthermore, the combined analysis of risk genotypes revealed that subjects carrying three risk genotypes (adjusted OR = 1.64, 95% CI = 1.02‐2.63) are more inclined to develop neuroblastoma than those without risk genotype, and so do carriers of 1‐4 risk genotypes (adjusted OR = 1.26, 95% CI = 1.01‐1.56). Stratification analysis further revealed risk effect of rs3811464 G>A, rs34787247 G>A and 1‐4 risk genotypes in some subgroups. Haplotype analysis of these four SNPs yields two haplotypes significantly correlated with increased neuroblastoma susceptibility. Overall, our finding indicated that LIN28A SNPs, especially rs34787247 G>A, may increase neuroblastoma risk.

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Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations

Cited by 32 publications

References 64 publications

A functional variant rs1537373 in 9p21.3 region is associated with pancreatic cancer risk

A functional variant rs1537373 in 9p21.3 region is associated with pancreatic cancer risk

A genetic variant in PIK3R1 is associated with pancreatic cancer survival in the Chinese population

LIN28A gene polymorphisms modify neuroblastoma susceptibility: A four‐centre case‐control study

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