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Annals of Oncology,2018,29(3):632-639
2018年03月01日
Background MYC is a well-established cancer driver gene regulating the expression of numerous genes, indicating that polymorphisms in MYC response elements could affect tumorigenesis through altering MYC regulation. We performed integrative multistage study to evaluate the effects of variants in MYC response elements and colorectal cancer (CRC) risk. Patients and methods We systematically integrated ChIP-Seq, DNase-Seq and transcription factor motif data to screen variants with potential ability to affect the MYC binding affinity. Then, we conducted a two-stage case–control study, totally consisting of 4830 CRC cases and 4759 controls in Chinese population to identify risk polymorphisms and interactions. The effects of risk variants were confirmed by functional assays in CRC LoVo, SW480 and HCT15 cells. Results We identified a novel polymorphism rs11777210 in KBTBD11 significantly associated with CRC susceptibility (P = 2.43 × 10−12). Notably, we observed a significant interaction between rs11777210 and MYC nearby rs6983267 (P-multi = 0.003, P-add = 0.005), subjects carrying rs6983267 GG and rs11777210 CC genotypes showing higher susceptibility to CRC (2.83-fold) than those carrying rs6983267 TT and rs11777210 TT genotypes. We further demonstrated that rs6983267 T > G increased MYC expression, and MYC bound to and negatively regulated KBTBD11 expression when the rs11777210 C risk allele was present. KBTBD11 was downregulated in tumor tissues, and KBTBD11 knockdown promoted cell proliferation and inhibited cell apoptosis. Conclusion The rs11777210 is a potential predictive biomarker of CRC susceptibility, and KBTBD11 functions as a putative tumor suppressor in tumorigenesis. Our study highlighted the high CRC risk of people carrying rs6983267 G and rs11777210 C alleles, and provided possible biological mechanism of the interaction.
MYC, genetic variants, risk of colorectal cancer, gene–gene interaction, polymorphism
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Cancer Res.,2018,78(17):5164–72
2018年09月01日
Genome-wide association studies (GWAS) of colorectal cancer have identified several common susceptible variants in gene regulatory regions. However, low-frequency or rare coding risk variants have not been systematically investigated in patients with colorectal cancer from Chinese populations. In this study, we performed an exome-wide association analysis with 1,062 patients with colorectal cancer and 2,184 controls from a Chinese population. Promising associations were further replicated in two replication sets: replication stage I with 2,478 cases and 3,880 controls, and replication stage II with 3,761 cases and 4,058 controls. We identified two variants significantly associated with colorectal cancer risk: a novel rare missense variant in TCF7L2 [rs138649767, OR = 2.08, 95% confidence interval (CI): 1.69–2.57, P = 5.66 × 10−12] and a previous European GWAS-identified 3′-UTR variant in ATF1 (rs11169571, OR = 1.18, 95% CI: 1.13–1.24, P = 1.65 × 10−12). We found a significant interaction between the TCF7L2 missense variant rs138649767 and a previous GWAS-identified regulatory variant rs6983267 in the MYC enhancer (Pinteraction = 0.0002). Functional analysis of this variant revealed that TCF7L2 with rs138649767-A allele harbored the ability to activate the MYC enhancer with rs6983267-G allele and enhance colorectal cancer cell proliferation. In addition, the ATF1 rs11169571 variant significantly correlated with ATF1 expression by affecting hsa-miR-1283 and hsa-miR-520d-5p binding. Further ChIP-seq and gene coexpression analyses showed that oncogenes NRAS and BRAF were activated by ATF1 in colorectal cancer. These results widen our understanding of the molecular basis of colorectal cancer risk and provide insight into pathways that might be targeted to prevent colorectal cancer. Significance: Exome-wide association analysis identifies a rare missense variant in TCF7L2 and a common regulatory variant in ATF1 as susceptibility factors of colorectal cancer.
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Cancer Epidemiol Biomarkers Prev.,2018,27(9):1029–35
2018年09月01日
Background: Telomere dysfunction triggers cellular senescence and constitutes a driving force for cancer initiation. Genetic variants in genes involved in telomere maintenance may contribute to colorectal cancer susceptibility. Methods: In this study, we firstly captured germline mutations in 192 patients with colorectal cancer by sequencing the coding regions of 13 core components implicated in telomere biology. Five potential functional variants were then genotyped and assessed in a case–control set with 3,761 colorectal cancer cases and 3,839 healthy controls. The promising association was replicated in additional 6,765 cases and 6,906 controls. Functional experiments were used to further clarify the potential function of the significant variant and uncover the underlying mechanism in colorectal cancer development. Results: The two-stage association studies showed that a rare missense variant rs149418249 (c.C1520T and p.P507L) in the 11th exon of TPP1 (also known as ACD, gene ID 65057) was significantly associated with colorectal cancer risk with the ORs being 2.90 [95% confidence interval (CI), 1.04–8.07; P = 0.041], 2.50 (95% CI, 1.04–6.04; P = 0.042), and 2.66 (95% CI, 1.36–5.18; P = 0.004) in discovery, replication, and the combined samples, respectively. Further functional annotation indicated that the TPP1 P507L substitution interrupted TPP1–TIN2 interaction, impaired telomerase processivity, and shortened telomere length, which subsequently facilitated cell proliferation and promoted colorectal cancer development. Conclusions: A rare variant P507L in TPP1 confers increased risk of colorectal cancer through interrupting TPP1–TIN2 interaction, impairing telomerase processivity, and shrinking telomere length. Impact: These findings emphasize the important role of telomere dysfunction in colorectal cancer development, and provide new insights about the prevention of this type of cancer.
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nature communications,2018,9():3688
2018年09月11日
Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Here we report an exome-wide investigation using the Illumina Human Exome Beadchip with 943 PDAC cases and 3908 controls in the Chinese population, followed by two independent replicate samples including 2142 cases and 4697 controls. We identify three low-frequency missense variants associated with the PDAC risk: rs34309238 in PKN1 (OR = 1.77, 95% CI: 1.48–2.12, P = 5.35 × 10−10), rs2242241 in DOK2 (OR = 1.85, 95% CI: 1.50–2.27, P = 4.34 × 10−9), and rs183117027 in APOB (OR = 2.34, 95% CI: 1.72–3.16, P = 4.21 × 10−8). Functional analyses show that the PKN1 rs34309238 variant significantly increases the level of phosphorylated PKN1 and thus enhances PDAC cells' proliferation by phosphorylating and activating the FAK/PI3K/AKT pathway. These findings highlight the significance of coding variants in the development of PDAC and provide more insights into the prevention of this disease.
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European Journal of Cancer,2018,93():1-9
2018年04月01日
Multiple single nucleotide polymorphisms (SNPs) have been found to be highly correlated with colorectal cancer (CRC) risk. However, the variants identified thus far only explain a small part of the cases, suggesting the existence of many uncharacterised genetic determinants. In this study, using the multilevel ‘omics’ data provided in The Cancer Genome Atlas, we systematically performed expression quantitative trait locus (eQTL) analysis for CRC and identified nine SNPs with significant effects on mRNA expression (correlation |r| > 0.3 and FDR < 0.01). Then we conducted a two-stage case–control study consisting of 1528 cases and 1528 controls to examine the associations between candidate SNPs and CRC risk. We found that rs27437 in SLC22A5 was significantly correlated with CRC risk in both stages and the combined study (additive model, OR = 1.31, 95%CI = 1.17–1.47, P = 1.97 × 10−6). eQTL analysis showed that rs27437 GG and GA genotypes were associated with lower expression of SLC22A5 compared with the AA genotype. Dual-luciferase reporter assays confirmed that the G risk allele could decrease the expression of luciferase. SLC22A5 was significantly decreased in CRC tumour tissues compared with adjacent normal tissues, indicating that SLC22A5 may play important roles in CRC, and rs27437 in SLC22A5 might serve as a novel biomarker for early detection and prevention of CRC.
Colorectal cancer, SLC22A5, eQTL, Genetic variants
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