In this large UK Biobank cohort study of a total of 7952 incident GI cancer cases, we aimed to investigate the associations between the phenomic features and GI cancers to better understand the molecular pathogenesis of GI tract cancers. The analysis included a total of 441,141 participants in the study, of whom 7,952 (1.8%) were incident cases of GI cancer and 433,189 were healthy controls. The results demonstrated significant associations between certain variables and different types of GI cancers, providing valuable insights into the risk factors and potential biomarkers associated with these cancers. The characteristics of the GI cancer group were substantially different from those of the control group, with the GI cancer group being older, predominantly male, having a higher BMI, and containing a greater proportion of current or former smokers.
The distribution of the top five GI cancers observed in this UK Biobank cohort was found to be consistent with global trends (Arnold et al. 2020; Ferlay et al. 2020). Colorectal cancer (47.01% of the total GI cancer cases) emerged as the most common GI cancer, followed by pancreatic cancer (11.12%), oesophageal cancer (9.91%), gastric cancer (7.59%), and liver cancer (6.50%). This pattern aligns with previous studies and reflects the epidemiology of GI cancers on a global scale, indicating the generalizability of the findings from this cohort to broader populations. As the top five GI cancers in the UK Biobank cohort represented 82% of the entire GI cases, subset analysis focuses on the five out of nine major GI cancer categories.
One of the notable findings in this study was the consistent association of cystatin C and ethnicity with each type of GI cancer. Cystatin C, a biomarker related to kidney function (Kim et al. 2016; Murty et al. 2013), was found to be consistently raised and associated with all GI cancers in this cohort. Participants with higher cystatin C levels exhibited an increased risk of developing GI cancers, suggesting its potential as a prognostic biomarker. This finding is corroborated in previous literature (Breznik et al. 2019; Leto et al. 2018; Song et al. 2023; Wu et al. 2022). Cystatin C exerts a series of complex effects that may result in either an inhibition or a promotion of tumour cell growth and dissemination, as demonstrated by previous research (Breznik et al. 2019; Leto et al. 2018). A recent study discovered a novel mechanism of mast cells inducing endoplasmic reticulum stress in which Cystatin C mediates tumor inhibition during colorectal cancer development (Song et al. 2023). This function of Cystatin C in cancer cells has never been reported and may lead researchers one step closer to understanding the molecular pathogenesis of GI cancers in relation to cystatin C.
Additionally, ethnicity was found to be significantly associated with total GI cancers, with participants of White ethnicity having a higher risk compared to Asians. The influence of ethnicity is also evident in subsets colorectal, pancreatic and oesophageal cancers in this study. Epidemiological studies have examined the association between ethnicity, specifically White and Asian populations, and gastrointestinal malignancies, including colorectal, pancreatic, esophageal, gastric, and liver cancer (Arnold et al. 2020; Ashktorab et al. 2017; Liu et al. 2020; Pardamean et al. 2023; Wang et al. 2022). Similarly, results showed that gender played a role in the difference in GI cancer incidence, particularly gastric and liver cancers, males having 2.8, 2.4 and 1.7 times more likely to get the cancers respectively. This finding is in line with current literature (Cruz et al. 2019; Pardamean et al. 2023; Scherübl 2022).
In addition to sociodemographic characteristics, lifestyle factor particularly smoking status was proven to be associated with certain GI cancers, including liver and oesophageal cancers. Smoking status still remained a significant factor in the multivariate logistic regression analysis for liver cancer. Interestingly, exposure to smoking (including those who had stopped smoking) consistently increased the risk of developing GI cancers. This is supported and demonstrated in other studies as well (Cruz et al. 2019; Pardamean et al. 2023; Shin et al. 2023). Cancer incidence and mortality rate variations are influenced by several factors, including genetic, environmental, lifestyle, and socioeconomic variables (Ashktorab et al. 2017; Liu et al. 2020; Pardamean et al. 2023; Suzuki et al. 2020).
Anthropometric measurement (body mass index classification) showed associations with oesophageal and gastric cancers. In line with the work of other researchers, we demonstrated U-shape relationship between BMI and the three cancers (Jang et al. 2022; Sohn et al. 2020; Tian et al. 2020). This abundant evidence of excess body weight over the past few decades indicates an emphasis on lipid metabolism and mechanisms involved in malignancies (Brown 2022; Fang et al. 2021; Jang et al. 2022; Sohn et al. 2020; Tian et al. 2020). As demonstrated in this study, apolipoprotein A1, apolipoprotein B and HDL cholesterol were associated with oesophageal, gastric and liver cancers. Studies have suggested that apolipoproteins play critical roles in malignancies including GI cancers. Low apolipoprotein A1 level is linked to a high cancer risk, systemic inflammatory response and poorer survival in some cancers, including oesophageal squamous cell carcinoma (He et al. 2022; Shi et al. 2018; Sirniö et al. 2017; Wang et al. 2016). This is in accordance with our study findings. Apolipoprotein A1 is a protein component of HDL cholesterol. Similar to apolipoprotein A1, HDL cholesterol is inversely associated with cancers, as demonstrated in the subset gastric cancer in this study. One of the proposed mechanisms of the opposing role in tumorigenesis of HDL cholesterol is its modulation of cell cycle entry and apoptosis through the mitogen-activated protein kinase-dependent (MAPK) pathway (Ahn et al. 2009). A Korean cross-sectional study also reported the association between reduced HDL/apolipoprotein A1 levels and an increased risk of colorectal cancer (Jung et al. 2015). Emerging evidence suggests that the apolipoprotein A1/HDL axis, involved in lipid metabolism, is dysregulated in cancer. mRNA levels of apolipoprotein A1 were lower in hepatocellular carcinoma compared to normal liver tissue, the primary source of apolipoprotein A1, as determined by Oncomine database microarray data (Georgila et al. 2019). In hepatocellular carcinoma, the mechanisms underlying the transcriptional repression of apolipoprotein A1 remain obscure.
However, this result is consistent with previous reports of decreased apolipoprotein A1 protein levels in malignant liver tissue and hepatocellular carcinoma patient serum (Ai et al. 2006; Mustafa et al. 2013). The decrease in apolipoprotein A1 transcription, intracellular and secreted apolipoprotein A1, and circulating HDL levels in hepatocellular carcinoma suggests that this pathway may have a tumor-suppressing function (Georgila et al. 2019). Several studies have discovered associations between serum apolipoprotein A1/HDL levels and various aspects of the natural progression of various cancer types (Ahn et al. 2009; Pedersen et al. 2020; Ren et al. 2019; Shi et al. 2018). Consistent with the study findings, high apolipoprotein B level was suggested as a risk factor for liver cancer; it is associated with poorer survival post surgery and a larger tumour size (Nault et al. 2020). More in-depth exploration of the genetic information of apolipoproteins may indicate liver malignancy and thus should be further researched on. Mutations of apolipoprotein B is reported to account for almost 10% of all genetic mutations (Nault et al. 2020). Specifically, a non-oncogenetic mutation of apolipoprotein B is observed, which can result in apolipoprotein B inactivation and is associated with the overexpression of oncogenic regulators and the downregulation of tumour suppressors, resulting in poorer survival outcomes. It is hypothesised that mutations that render apolipoprotein B inactive are preferred in tumorigenesis in order to provide more energy for cancer metabolism (He et al. 2022; Ren et al. 2019).
Multivariable logistic regression demonstrated that ionized serum calcium level was inversely associated with the risk of oesophageal cancer (adjusted OR = 0.37, 95% CI: 0.18–0.74; p-value = 0.005). This is in line with studies that established the significance of calcium intake, in particular, as a potential effect modifier of the association between calcium and diseases including gastrointestinal tract neoplasia (Hashemian et al. 2015; Shah et al. 2020a, 2020b). Increasing dietary calcium intake was associated with lower risk of oesophageal cancer (Hashemian et al. 2015; Shah et al. 2020a, 2020b). There seems to be inconsistent findings on the relationship between serum calcium and risk of cancer in current literature. The Swedish AMORIS study exploring GI cancers specifically oesophageal, stomach and CRC cancers, showed positive association between albumin-adjusted serum calcium and risk of these GI cancers (Wulaningsih et al. 2013a). Nevertheless, a study exploring two large European prospective cohorts (including the UK Biobank) corroborated our study findings on ionized serum calcium level and risk of liver and colorectal cancer (Karavasiloglou et al. 2023).
The different direction of the association between the UK Biobank and EPIC cohorts, and the AMORIS study was attributed to differences in study design and the degree of adjustment for confounding variables (Karavasiloglou et al. 2023). It is worthwhile to discuss on this study’s focus on serum calcium measurement rather than dietary calcium intake. Serum calcium indicates extracellular calcium homeostasis and is mainly regulated by vitamin D and parathyroid hormone. Consequently, abnormalities in serum calcium level may reflect an error in its regulation pathways instead of dietary calcium deficiency. This may result in distinct associations between calcium in the diet and serum and carcinogenesis (Karavasiloglou et al. 2023; Peacock 2010; Wulaningsih et al. 2013a). Besides calcium, phosphate is also found to be inversely associated with liver cancer (adjusted OR = 0.36; 95% CI: 0.22–0.58; p-value = 0.001). There is little research on phosphate and cancers, with inconsistent trends among the studies and/or cancers (Brown 2022; Wulaningsih et al. 2013b; Yan et al. 2022). It is accepted that altered levels of phosphate have been linked to the onset of cancer, but with uncertainties on the pathophysiology behind it. More in-depth studies are warranted to better understand the positive and inverse correlation observed between calcium and phosphate levels, and the risk of cancers. This will shed light on the involvement of calcium and phosphate metabolism, and potentially related important hormonal factors and cancer.
Additionally, hematological markers including monocyte and eosinophils were related to some GI cancers. Monocytes and eosinophils are a type of white blood cell. Interestingly, there are scarce research on the association of eosinophils and monocytes in GI cancer. Despite that, the value of immune-related markers in cancers are acknowledged. Previous studies focused mainly on pre-operative values of these circulating cells, however, changes in the immune profile may occur months or years prior to cancer diagnosis due to its role in the etiopathegenesis of tumours (Zhou et al. 2022). White blood cells were previously found to be associated with increased risk of colorectal, lung and breast cancer (Allin et al. 2016). Preclinical data showed that eosinophils have both pro-tumorigenic and anti-tumorigenic properties, via direct and indirect mechanisms. This varying outcomes in different studies imply that the role of eosinophils and their mediators may differ depending on the cancer type (Reichman et al. 2016; Sibille et al. 2022; Varricchi et al. 2018).
These findings provide valuable insights into the associations between various factors and GI cancers within the UK Biobank cohort. The identification of significant associations can contribute to our understanding of the underlying mechanisms and risk factors involved in the development of GI cancers. The consistent association of cystatin C with different types of GI cancers suggest its potential as a promising biomarker for early detection and risk stratification.
Notable strengths of this study include its prospective study design involving a large sample size, a lengthy follow-up period and evaluation of a comprehensive list of covariates. In addition, all biochemistry markers were measured using well-established and validated methods, ensuring accuracy and reliability throughout the study. This study, is however, not without its limitations. The study population was derived from a single cohort in the United Kingdom, which may limit the generalizability of the results to other populations. However, a valid assessment of exposure-disease relationships do not necessitate that the study sample to be representative of the general population (Batty et al. 2020; Manolio and Collins 2010). In addition, the study relied on self-reported lifestyle data, which introduces the possibility of recall bias. To validate and expand upon these findings, additional research with diverse populations and rigorous data acquisition techniques is required. In addition, in terms of study data, no information was available regarding potential confounding variables such as vitamin D and/or calcium supplementation. In addition, we were unable to explain the effect of dietary calcium on gastrointestinal carcinogenesis, as suggested by biological studies.
In conclusion, this study identified several significant associations between various factors and GI cancers using the UK Biobank cohort. A marker Cystatin C, and ethnicity emerged as a consistent biomarker associated with different types of GI cancers. The findings provide valuable insights into the potential diagnostic and therapeutic targets for GI cancers, emphasizing the importance of personalized approaches in cancer prevention, early detection, and treatment strategies. In order to provide more in-depth understanding of how these factors were associated with GI cancers and shed light on the molecular pathogenesis of GI cancers, future research should employ a multi-modal approach exploring the genomics and proteomics of the UK Biobank cohort. This will allow validation of the study findings and enhance understanding on the underlying mechanisms linking these factors to GI cancer development.