AbstractPhysical activity (PA) has been identified as an important modifiable risk factor for numerous cancers, with the World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) reporting convincing evidence for a protective role of PA for cancers of the colon, breast and endometrium.
Despite this, evidence suggesting a protective role for PA in upper gastrointestinal (GI) cancer aetiology is more limited, particularly from large-scale prospective studies. Currently, there is a lack of prospective evidence investigating the association between PA and oesophageal and gastric cancers.
There is also a lack of evidence in relation to the underlying biological mechanisms underpinning the previously reported ‘convincing’ associations between PA and cancer risk. For the purposes of this thesis, the associations between PA and colorectal cancer (CRC) risk as potentially mediated by the insulin-like growth factor (IGF) pathway are further investigated using novel mechanistic systematic review methodology.
In order to address these research gaps, two pieces of work were undertaken within this thesis:
1. Firstly, a prospective cohort study investigating self-reported PA, screen-based sedentary behaviour and oesophago-gastric cancer risk was conducted within the UK Biobank. A cohort of 359,033 adults aged 40–69 years were identified between 2006-2010. During a mean 5.5 years of follow-up, 294 oesophageal cancer and 217 gastric cancer cases were diagnosed. PA and screen-based sedentary behaviour levels were not associated with overall oesophageal cancer (high vs low PA; HR 1.18 95% CI 0.85–1.62), (high vs low screen time; HR 1.14 95% CI 0.87–1.49) or gastric cancer risk (high vs low PA; HR 1.28 95% CI 0.82–1.98), (high vs low screen time; HR 1.13
95% CI 0.83–1.55). When compared with low levels, high PA levels were associated with a significantly reduced risk of gastric non-cardia cancer (HR 0.58, 95% CI 0.37– 0.95). Moderate PA levels were associated with a 38% reduced risk of oesophageal
adenocarcinoma (OAC) (HR 0.62, 95% CI 0.43–0.89). This work has been published in the United European Gastroenterology Journal in 2018 (Kunzmann*, Mallon* et al, United European Gastroenterol J. 2018 Oct;6(8):1144-1154; *Joint first authorship)
2. Secondly, a systematic review, utilising the recently developed WCRF-International/University of Bristol methodology for identifying and carrying out systematic reviews of mechanisms of exposure-cancer associations was conducted to assess whether the IGF pathway mediates the association between PA and CRC risk. This review entailed two specific objectives:
• To assess the components of PA, including type, intensity and duration in relation to concentrations of any IGF biomarker related to the IGF pathway.
• To assess the association between circulating IGF components and CRC risk.
Fifty-seven studies assessing domains of PA in relation to concentrations of any IGF biomarker related to the IGF pathway and 19 studies observing biomarkers related to the IGF pathway and CRC risk were identified.
Meta-analyses for part 1 of this review revealed statistically significant decreased levels of IGF-1 in relation to self-report PA (via questionnaire), (SMD -0.08, 95% CI -0.16, 0.00) only. No significant associations between long-term (numerous sessions performed over several weeks/months) and short-term (typically, one short distinct session of PA lasting several minutes/hours) PA interventions with any biomarkers related to the IGF pathway were found.
Meta-analyses comparing the highest vs lowest levels of circulating IGF-1 showed an almost 1.3-fold increased risk of CRC (RR 1.27, 95% CI 1.12-1.45) and a significant 1.7-fold increased risk in CRC (RR 1.69, 95% CI 1.26-2.26) when comparing the highest vs lowest circulating levels of IGF-2.
Overall the work within this MPhil thesis adds to current knowledge regarding a protective role for PA in reducing the risk of some subtypes of upper GI cancer, giving a greater insight into potential mediators in the PA-CRC relationship.
This work provides both novel evidence for PA in upper GI cancer aetiology, as well as a deeper understanding of the underlying mechanisms through which PA may reduce CRC risk, which may prove useful in informing future research in this area.
|Date of Award||Dec 2019|
|Supervisor||Christopher Cardwell (Supervisor), Helen Coleman (Supervisor) & Ruth Hunter (Supervisor)|