Association between antibiotic use during early life and early‐onset colorectal cancer risk overall and according to polygenic risk and FUT2 genotypes

Abstract

Early‐onset colorectal cancer (EOCRC) has been increasing worldwide. Potential risk factors may have occurred in childhood or adolescence. We investigated the associations between early‐life factors and EOCRC risk, with a particular focus on long‐term or recurrent antibiotic use (LRAU) and its interaction with genetic factors. Data on the UK Biobank participants recruited between 2006 and 2010 and followed up to February 2022 were used. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) of the associations between LRAU during early life and EOCRC risk overall and by polygenic risk score (constructed by 127 CRC‐related genetic variants) and Fucosyltransferase 2 (FUT2), a gut microbiota regulatory gene. We also assessed the associations for early‐onset colorectal adenomas, as precursor lesion of CRC, to examine the effect of LRAU during early‐life and genetic factors on colorectal carcinogenesis. A total of 113 256 participants were included in the analysis, with 165 EOCRC cases and 719 EOCRA cases. LRAU was nominally associated with increased risk of early‐onset CRC (OR = 1.48, 95% CI = 1.01‐2.17, P = .046) and adenomas (OR = 1.40, 95% CI = 1.17‐1.68, P < .001). When stratified by genetic polymorphisms of FUT2, LRAU appeared to confer a comparatively greater risk for early‐onset adenomas among participants with rs281377 TT genotype (OR = 1.10, 95% CI = 0.79‐1.52, P = .587, for CC genotype; OR = 1.75, 95% CI = 1.16‐2.64, P = .008, for TT genotype; Pinteraction = .089). Our study suggested that LRAU during early life is associated with increased risk of early‐onset CRC and adenomas, and the association for adenomas is predominant among individuals with rs281377 TT/CT genotype. Further studies investigating how LRAU contributes together with genetic factors to modify EOCRC risk, particularly concerning the microbiome‐related pathway underlying colorectal carcinogenesis, are warranted.

Risk factors, histopathological landscape, biomarkers, treatment patterns and survival of early‐onset colorectal cancer: A narrative review

“…determined that antibiotics increased EOCRC risk (OR = 1.49, 95% CI 1.07–2.07) after investigating 7,903 CRC cases and 30,418 controls in their US cohort. Further, a study of the UK biobank which is comprised of 113,256 participants ( n = 165 EOCRC cases, n = 719 early‐onset colorectal adenoma cases), found that long‐term or recurrent courses of antibiotics (≥ 3/year) were associated with increased EOCRC risk (OR = 1.48, 95% CI 1.01–2.17, p = 0.046) and adenomas (OR = 1.40, 95% CI 1.17–1.68 , p < 0.001) 15 . The discrepancies between these studies are likely due to the geographical influence on infection prevalence, local sensitivities and resistances, and antimicrobial stewardship between countries.…”

“…There is a significant overlap in the non-modifiable risk factors of EOCRC with LOCRC. For example, in their 2023 systematic review and meta-analysis of 36 studies which included 66,312 participants, Hua et al 6 identified that being male (odds ratio [OR] = 1.20, 95% CI 15 The discrepancies between these studies are likely due to the geographical influence on infection prevalence, local sensitivities and resistances, and antimicrobial stewardship between countries.…”

Early-onset gastrointestinal cancer: An epidemiological reality with great significance and implications

“…Regarding the effect of the therapeutic use of antibiotics during childhood, use which has been etiopathogenetically associated with a multitude of morbid conditions in later adult life ( e.g., inflammatory bowel disease). Jiang et al [ 47 ] found that long-term or recurrent antibiotic use by early life span is associated with an increased risk of early-CRC and adenomas and that the association with adenomas was significantly greater among individuals with the rs281377 TT/CT genotype. However, further studies are needed to investigate how long-term or recurrent antibiotic use contributes (together with genetic factors) to the modification of early-CRC risk, especially regarding the microbiome-related pathway that governs colon carcinogenesis.…”