Genotype-Based Gene Expression in Colon Tissue-Prediction Accuracy and Relationship with the Prognosis of Colorectal Cancer Patients

Heike Deutelmoser, Justo Lorenzo Bermejo, Axel Benner, Korbinian Weigl, Hanla A Park, Mariam Haffa, Esther Herpel, Martin Schneider, Cornelia M Ulrich, Michael Hoffmeister, Jenny Chang-Claude, Hermann Brenner, Dominique Scherer, Heike Deutelmoser, Justo Lorenzo Bermejo, Axel Benner, Korbinian Weigl, Hanla A Park, Mariam Haffa, Esther Herpel, Martin Schneider, Cornelia M Ulrich, Michael Hoffmeister, Jenny Chang-Claude, Hermann Brenner, Dominique Scherer

Abstract

Colorectal cancer (CRC) survival has environmental and inherited components. The expression of specific genes can be inferred based on individual genotypes-so called expression quantitative trait loci. In this study, we used the PrediXcan method to predict gene expression in normal colon tissue using individual genotype data from 91 CRC patients and examined the correlation ρ between predicted and measured gene expression levels. Out of 5434 predicted genes, 58% showed a negative ρ value and only 16% presented a ρ higher than 0.10. We subsequently investigated the association between genotype-based gene expression in colon tissue for genes with ρ > 0.10 and survival of 4436 CRC patients. We identified an inverse association between the predicted expression of ARID3B and CRC-specific survival for patients with a body mass index greater than or equal to 30 kg/m2 (HR (hazard ratio) = 0.66 for an expression higher vs. lower than the median, p = 0.005). This association was validated using genotype and clinical data from the UK Biobank (HR = 0.74, p = 0.04). In addition to the identification of ARID3B expression in normal colon tissue as a candidate prognostic biomarker for obese CRC patients, our study illustrates the challenges of genotype-based prediction of gene expression, and the advantage of reassessing the prediction accuracy in a subset of the study population using measured gene expression data.

Keywords: PrediXcan; colorectal cancer; genotype-based gene expression; survival.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Data overview for the examination of the correlation ρ between predicted and measured gene expression. Abbreviations: CRC: colorectal cancer; SNPs: single nucleotide polymorphisms.
Figure 2
Figure 2
(a) Scatter plot of the mean measured versus the mean predicted expression values for 5434 genes with estimated Spearman correlation coefficients ρ < 0 in red, 0 ≤ ρ ≤ 0.1 in black, and ρ > 0.1 in green; (b,c) measured versus predicted expression values for the genes TRIM4 (b), and PYGL (c). The linear regression lines are also shown with their corresponding 95% confidence bands.
Figure 3
Figure 3
(a,b) Volcano plots showing the results from survival analyses of 852 CRC patients with a BMI ≥ 30, and 863 genes with a correlation between predicted and measured expression values higher than 0.10. The blue dots indicate results for the gene ARID3B. (a) Overall survival; (b) CRC-specific survival; (c,d) cumulative probability of death due to CRC for patients with a low (lower than the median) and high (higher than the median) ARID3B expression based on individual genotypes for patients with BMI ≥ 30. The number of CRC patients at risk is shown in the lower part of each panel; (c) Aalen-Johansen probability curves in the identification cohort (“Darmkrebs: Chancen der Verhuetung durch Screening” (DACHS) study); (d) Aalen–Johansen probability curves in the validation cohort (UK Biobank). Abbreviations: CRC: colorectal cancer.

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Source: PubMed

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