Abstract
BackgroundSmoking and alcohol increase risk for colorectal malignancies. However, colorectal cancer (CRC) is a heterogenic disease and associations with the molecular pathological pathways are unclear.MethodsThis population-based case–control study includes 2444 cases with first-diagnosis CRC and 2475 controls. Tumour tissue was analysed for MSI (microsatellite instability), CIMP (CpG island methylator phenotype), BRAF (B-Raf proto-oncogene serine/threonine kinase gene) and KRAS (Kirsten rat sarcoma viral oncogene homologue gene) mutations. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for associations between alcohol and smoking and CRC molecular subtypes and pathways.ResultsCurrent smoking showed higher ORs for MSI-high (OR = 2.79, 95% CI: 1.86–4.18) compared to MSS (OR = 1.41, 1.14–1.75, p-heterogeneity (p-het) = 0.001), BRAF-mutated (mut) (OR = 2.40, 1.41–4.07) compared to BRAF-wild type (wt) (OR = 1.52, 1.24–1.88, p-het = 0.074), KRAS-wt (OR = 1.70, 1.36–2.13) compared to KRAS-mut (OR = 1.26, 0.95–1.68, p-het = 0.039) and CIMP-high (OR = 2.01, 1.40–2.88) compared to CIMP-low/negative CRC (OR = 1.50, 1.22–1.85, p-het=0.101). Current smoking seemed more strongly associated with sessile serrated pathway (CIMP-high + BRAF-mut; OR = 2.39, 1.27–4.52) than with traditional pathway CRC (MSS + CIMP-low/negative + BRAF-wt; OR = 1.50, 1.16–1.94) and no association was observed with alternate pathway CRC (MSS + CIMP-low/negative + KRAS-wt; OR = 1.08, 0.77–1.43). No heterogeneity was observed in alcohol consumption association by molecular subtypes.ConclusionsIn this large case–control study, smoking was more strongly associated with MSI-high and KRAS-wt CRC and with cases showing features of the sessile serrated pathway. Association patterns were less clear for alcohol consumption.
Highlights
Smoking and alcohol increase risk for colorectal malignancies
Current smoking was associated with a 59% (OR = 1.59, 95% confidence intervals (95% confidence intervals (CIs)): 1.30–1.94) increased risk of colorectal cancer (CRC), while former smoking was associated with a 19% (OR = 1.19, 95% CI: 1.03–1.38) increased risk
More than 29 pack years of smoking were associated with 61% increased CRC risk (OR = 1.61, 95% CI: 1.31–1.99) compared to never smoking
Summary
Smoking and alcohol increase risk for colorectal malignancies. colorectal cancer (CRC) is a heterogenic disease and associations with the molecular pathological pathways are unclear. Tumour tissue was analysed for MSI (microsatellite instability), CIMP (CpG island methylator phenotype), BRAF (B-Raf proto-oncogene serine/threonine kinase gene) and KRAS (Kirsten rat sarcoma viral oncogene homologue gene) mutations. CONCLUSIONS: In this large case–control study, smoking was more strongly associated with MSI-high and KRAS-wt CRC and with cases showing features of the sessile serrated pathway. Sporadic colorectal cancer (CRC), accounting for 95% of CRC cases, is a heterogeneous disease arising from different sets of genetic and epigenetic alterations.[1] The most established underlying molecular pathological subtypes of CRC are characterised by microsatellite instability (MSI) (prevalence 15% in sporadic CRC), CpG island methylator phenotype (CIMP-high, 20%),[2]. Alcohol was not differentially associated with either MSI,[9,18] CIMP, BRAF19–21 or KRAS status.[22]
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