Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants

Summers, Matthew G.; Maughan, Tim; Kaplan, Richard; Law, Philip; Houlston, Richard S.; Escott‐Price, Valentina; Cheadle, Jeremy P.

doi:10.1016/j.ejca.2019.09.024

Cited by 10 publications

(7 citation statements)

References 35 publications

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“…Interestingly, two large meta-analyses were recently conducted to assess the associations between previously reported CRC risk loci and prognosis and found that none of these loci was significantly associated with survival of CRC patients. 9,10 Although there were some pathway-based gene analyses that found some loci accountable for the prognosis of CRC patients, [11][12][13] the previously reported pathways were limited without elaboration on the underlying mechanisms for the observed associations.…”

Section: Introductionmentioning

confidence: 99%

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer

Zhao

Wang

et al. 2021

Intl Journal of Cancer

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Notch signaling pathway plays crucial roles in progression of colorectal cancer (CRC), likely affecting overall survival (OS). In a two‐stage survival analysis of 1116 CRC patients in East China, we found that one locus at MINAR1 out of 133 genes in the Notch signaling pathway was significantly associated with OS (P < 1 × 10−6, false discovery rate < 0.01). This locus containing seven single‐nucleotide polymorphisms (SNPs) in high linkage disequilibrium (R2 = 1) is located on chromosome 15, of which the MINAR1 rs72430409 G allele was associated with a greater death risk (HR = 1.98, 95% CI = 1.55‐2.54, P = 6.8 × 10−8). Further analysis of ChIP‐sequencing data from the encyclopedia of DNA Elements showed that rs72430409 and rs72630408 were potential cis‐regulatory elements for the MINAR1 promoter. Additional expression quantitative trait loci analysis revealed that rs72430409 G>A and rs72630408 A>G were correlated with increased MINAR1 expression levels in both blood cells and colon tissues. Dual luciferase assays revealed that the rs72430409 A allele increased MINAR1 promoter activity. The Cancer Genome Atlas data showed that expression levels of MINAR1 in CRC samples were significantly higher than that in normal colorectal tissue and that high expression of MINAR1 was associated with a shortened OS, likely via activating the epithelial mesenchymal transition (EMT) pathway as shown in the gene‐set enrichment analysis. In vitro, RNAi‐mediated silencing of MINAR1 led to decreased migration and proliferation in CRC cancer cells, and MINAR1 silencing could downregulate the expression of key effector genes in EMT and glycolysis. Larger cohort studies and further experiments are needed to validate our findings.

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Section: Introductionmentioning

confidence: 99%

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer

Zhao

Wang

et al. 2021

Intl Journal of Cancer

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“…However, there is also a genetic component to the disease, which is estimated to explain up to 35% of the heritability in colorectal cancer risk [5,6]. Some studies point to genetic associations with the CRC outcome [7][8][9]. However, evidence is still limited.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the Angiogenesis-Related Genes EFNB2, MMP2 and JAG1 Are Associated with Survival of Colorectal Cancer Patients

Scherer

Deutelmoser

Balavarca

et al. 2020

IJMS

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An individual’s inherited genetic variation may contribute to the ‘angiogenic switch’, which is essential for blood supply and tumor growth of microscopic and macroscopic tumors. Polymorphisms in angiogenesis-related genes potentially predispose to colorectal cancer (CRC) or affect the survival of CRC patients. We investigated the association of 392 single nucleotide polymorphisms (SNPs) in 33 angiogenesis-related genes with CRC risk and survival of CRC patients in 1754 CRC cases and 1781 healthy controls within DACHS (Darmkrebs: Chancen der Verhütung durch Screening), a German population-based case-control study. Odds ratios and 95% confidence intervals (CI) were estimated from unconditional logistic regression to test for genetic associations with CRC risk. The Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% CIs for survival. Multiple testing was adjusted for by a false discovery rate. No variant was associated with CRC risk. Variants in EFNB2, MMP2 and JAG1 were significantly associated with overall survival. The association of the EFNB2 tagging SNP rs9520090 (p < 0.0001) was confirmed in two validation datasets (p-values: 0.01 and 0.05). The associations of the tagging SNPs rs6040062 in JAG1 (p-value 0.0003) and rs2241145 in MMP2 (p-value 0.0005) showed the same direction of association with overall survival in the first and second validation sets, respectively, although they did not reach significance (p-values: 0.09 and 0.25, respectively). EFNB2, MMP2 and JAG1 are known for their functional role in angiogenesis and the present study points to novel evidence for the impact of angiogenesis-related genetic variants on the CRC outcome.

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“…Some studies have suggested that a subset of these may also influence patient survival [ 2 – 7 ] although other studies have not supported these observations [ 8 – 11 ]. We previously studied the relationship between SNP genotype and patient outcome for 83 CRC-risk SNPs [ 12 ] by analysing patients with advanced CRC from the COIN and COIN-B clinical trials [ 13 , 14 ]. A recent meta-analysis of all available GWAS augmented by transcriptome and methylome-wide association studies (TWAS and MWAS, respectively) has identified further loci taking the total number of CRC-risk loci to 258 [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Relationship between 233 colorectal cancer risk loci and survival in 1926 patients with advanced disease

Wills

Houseman

Watts

et al. 2023

BJC Rep

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Background Genome, transcriptome and methylome-wide association studies have identified single-nucleotide polymorphisms (SNPs) or genes at 258 loci associated with colorectal cancer (CRC) risk. We studied the relationship between these and patient outcome. Methods We studied 1926 unrelated patients with advanced CRC from COIN and COIN-B. Of 205 CRC-risk SNPs, 19 were directly genotyped and 162 were imputed, and of 53 risk genes, 52 were tested. An additive Cox model for overall survival was adjusted for known prognostic factors. For nominally significant SNPs or genes, we considered a recessive model with a Bonferroni corrected threshold of P = 2.1 × 10−4. We examined SNPs as expression quantitative trait loci (eQTL) and the relationship between gene expression in colorectal tumours and survival in 597 unrelated patients. Results Eleven SNPs or genes were nominally associated with survival under an additive model. Only rs117079142 mapping to UTP23 and EIF3H (Hazard Ratio [HR] = 2.79, 95% Confidence Intervals [CI] = 1.70–4.58, P = 4.7 × 10−5) and rs9924886 mapping to CDH1 and CDH3 (HR = 1.24, 95% CI = 1.12–1.38, P = 5.2 × 10−5) passed the multiple testing threshold under a recessive model. rs117079142 was an eQTL for UTP23 and rs9924886 for CDH1, CDH3 and ZFP90. Decreased CDH1 expression in CRCs was associated with worse survival (HR = 2.18, 95% CI = 1.3–3.5, P = 1.8 × 10−3). Conclusion rs117079142 and rs9924886 may represent potential prognostic biomarkers for CRC.

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Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants

Cited by 10 publications

References 35 publications

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer

Polymorphisms in the Angiogenesis-Related Genes EFNB2, MMP2 and JAG1 Are Associated with Survival of Colorectal Cancer Patients

Relationship between 233 colorectal cancer risk loci and survival in 1926 patients with advanced disease

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