Interplay between Genome, Metabolome and Microbiome in Colorectal Cancer

Background: Colorectal cancer (CRC), a major health concern, is developed depending on environmental, genetic and microbial factors. The microbiome and metabolome have been analyzed to study their role in CRC. However, the interplay of host genetics with those layers in CRC remains unclear. Methods: 120 individuals were sequenced and association analyses were carried out for adenoma and CRC risk, and for selected components of the microbiome and metabolome. The epistasis between genes located in cholesterol pathways was analyzed; modifiable risk factors were studied using Mendelian randomization; and the three omic layers were used to integrate their data and to build risk prediction models. Results: We detected genetic variants that were associated to components of metabolome or microbiome and adenoma or CRC risk (e.g., in LINC01605, PROKR2 and CCSER1 genes). In addition, we found interactions between genes of cholesterol metabolism, and HDL cholesterol levels affected adenoma (p = 0.0448) and CRC (p = 0.0148) risk. The combination of the three omic layers to build risk prediction models reached high AUC values (>0.91). Conclusions: The use of the three omic layers allowed for the finding of biological mechanisms related to the development of adenoma and CRC, and each layer provided complementary information to build risk prediction models.

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1227Colorectal cancer risk prediction models incorporating lifestyle and biomarker data: Results from the EPIC cohort

International Journal of Epidemiology ◽

10.1093/ije/dyab168.027 ◽

2021 ◽

Vol 50 (Supplement_1) ◽

Author(s):

Krasimira Aleksandrova ◽

Robin Reichmann ◽

Mazda Jenab ◽

Sabina Rinaldi ◽

Rudolf Kaaks ◽

...

Keyword(s):

Colorectal Cancer ◽

High Risk ◽

Risk Prediction ◽

Prediction Models ◽

Lifestyle Factors ◽

Health Concern ◽

Incidence Density ◽

Processed Meat ◽

Risk Prediction Models ◽

Biomarker Data

Abstract Background Colorectal cancer represents a major public health concern and there is a worrying tendency of increasing incidence rates among younger people in the last decades. Risk stratification of high-risk individuals may aid targeted disease prevention. We therefore aimed to evaluate the predictive value of a wide range of lifestyle and biomarker variables using data within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods A range of lifestyle, anthropometric and dietary variables in 329,885 participants in the EPIC cohort were evaluated as potential predictors for risk of colorectal cancer over 10 years. Biomarker measurements of 41 parameters were available for 1,320 CRC cases and 1,320 controls selected using incidence density matching. Best sets of predictors were selected using elastic net regularization with bootstrapping. Random survival forest was applied as a novel technique to validate the set of selected predictors taking variable interactions into account. Results The results suggested a set of lifestyle factors including age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary that showed good discrimination (Harrell's C-index: 0.710) and excellent calibration. The analyses further revealed a set of biomarkers that increased the predictive performance beyond age, sex and lifestyle factors. Conclusions Risk prediction models based on lifestyle and biomarker data may prove useful in the identification of individuals at high risk for colorectal cancer. Key messages Risk prediction models incorporating lifestyle and biomarker data could contribute to developing strategies for targeted colorectal cancer prevention.

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Polygenic risk prediction models for colorectal cancer: a systematic review

BMC Cancer ◽

10.1186/s12885-021-09143-2 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Michele Sassano ◽

Marco Mariani ◽

Gianluigi Quaranta ◽

Roberta Pastorino ◽

Stefania Boccia

Keyword(s):

Colorectal Cancer ◽

Risk Factors ◽

Systematic Review ◽

Prediction Model ◽

Risk Prediction ◽

Genetic Variants ◽

Prediction Models ◽

Risk Prediction Models ◽

Discriminatory Accuracy ◽

Traditional Risk Factors

Abstract Background Risk prediction models incorporating single nucleotide polymorphisms (SNPs) could lead to individualized prevention of colorectal cancer (CRC). However, the added value of incorporating SNPs into models with only traditional risk factors is still not clear. Hence, our primary aim was to summarize literature on risk prediction models including genetic variants for CRC, while our secondary aim was to evaluate the improvement of discriminatory accuracy when adding SNPs to a prediction model with only traditional risk factors. Methods We conducted a systematic review on prediction models incorporating multiple SNPs for CRC risk prediction. We tested whether a significant trend in the increase of Area Under Curve (AUC) according to the number of SNPs could be observed, and estimated the correlation between AUC improvement and number of SNPs. We estimated pooled AUC improvement for SNP-enhanced models compared with non-SNP-enhanced models using random effects meta-analysis, and conducted meta-regression to investigate the association of specific factors with AUC improvement. Results We included 33 studies, 78.79% using genetic risk scores to combine genetic data. We found no significant trend in AUC improvement according to the number of SNPs (p for trend = 0.774), and no correlation between the number of SNPs and AUC improvement (p = 0.695). Pooled AUC improvement was 0.040 (95% CI: 0.035, 0.045), and the number of cases in the study and the AUC of the starting model were inversely associated with AUC improvement obtained when adding SNPs to a prediction model. In addition, models constructed in Asian individuals achieved better AUC improvement with the incorporation of SNPs compared with those developed among individuals of European ancestry. Conclusions Though not conclusive, our results provide insights on factors influencing discriminatory accuracy of SNP-enhanced models. Genetic variants might be useful to inform stratified CRC screening in the future, but further research is needed.

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