Smoking, Genetic Predisposition, and Colorectal Cancer Risk

Abstract

INTRODUCTION: Smoking and genetic predisposition are established risk factors for colorectal cancer (CRC). We aimed to assess and compare their individual and joint impact on CRC risk using the novel approach of genetic risk equivalent (GRE). METHODS: Data were extracted from the Darmkrebs: Chancen der Verhütung durch Screening study, a large population-based case-control study in Germany. A polygenic risk score (PRS) based on 140 CRC-related single nucleotide polymorphisms was derived to quantify genetic risk. Multiple logistic regression was used to estimate the individual and joint impact of smoking and PRS on CRC risk, and to quantify the smoking effect in terms of GRE, the corresponding effect conveyed by a defined difference in PRS percentiles. RESULTS: There were 5,086 patients with CRC and 4,120 controls included. Current smokers had a 48% higher risk of CRC than never smokers (adjusted odds ratio 1.48, 95% confidence interval 1.27–1.72). A PRS above the 90th percentile was significantly associated with a 3.6-, 4.3-, and 6.4-fold increased risk of CRC in never, former, and current smokers, respectively, when compared with a PRS below the 10th percentile in never smokers. The interaction between smoking and PRS on CRC risk did not reach statistical significance (P = 0.53). The effect of smoking was equivalent to the effect of having a 30 percentile higher level of PRS (GRE 30, 95% confidence interval 18–42). DISCUSSION: Both smoking and the PRS carry essentially independent CRC risk information, and their joint consideration provides powerful risk stratification. Abstinence from smoking can compensate for a substantial proportion of genetically determined CRC risk.

Non‐steroidal anti‐inflammatory drugs, polygenic risk score and colorectal cancer risk

“…DNA was extracted from blood samples (in 99.1% of participants) or from buccal cells (in 0.9% of participants). Information about genotyping and imputation of missing genotypes for the study population has been described in detail previously 20,24 . In brief, the following four genotyping arrays were used: Illumina HumanCytoSNP for 49.5% of participants, Illumina HumanOmniExpress for 19.5% of participants, Illumina Infinium OncoArray for 16.8% of participants and the Illumina Infinium Global Screening Array for 14.2% of participants.…”

“…The score was calculated as the sum of risk alleles of the respective variants (0, 1 or 2 copies of the risk allele for genotyped SNPs; imputed dosages for imputed SNPs). Full details of derivation of PRS have been published recently 20,24,26–29 …”

“…Details of the derivation of GRE have recently been described elsewhere 20 . In brief, the GRE was developed based on a well‐established concept of risk and rate advancement periods 30 .…”

“…Thus, the aim of this study was to assess the effect of regular use of aspirin and NSAIDs (including aspirin) on CRC risk at different levels of PRS. We also compared the effects of aspirin and NSAID use with the impact of PRS on CRC risk using the ‘genetic risk equivalents (GRE)’, a recently developed metric for effective risk communication 20 …”

Red and Processed Meat Intake, Polygenic Risk Score, and Colorectal Cancer Risk

“…In this large population-based study from Germany, we aimed to assess the association of red and processed meat intake with CRC risk across various levels of a PRS that incorporates information from 140 independent genetic variants on CRC risk [ 4 ]. Furthermore, we aimed to compare the effects of red and processed meat intake with the impact of genetic predisposition using “genetic risk equivalent” (GRE) [ 11 , 12 ], a recently developed metric aimed at enhancing effective risk communication.…”