Colorectal cancer (CRC) is the third most common cancer globally with over 4 million prevalent cases. Nearly 2 million new cases of colorectal cancer were reported worldwide in 2018.(1) It is the third most common cause of cancer in the United States with an estimated 460,714 cases in 2018.(1) It is the second most common cause of death due to cancer worldwide and within the United States (880,000 deaths worldwide and fifty thousand deaths in the United States in 2018).(1) The global burden of CRC is expected to increase by 60% to more than 2.2 million new cases and 1.1 million cancer deaths by 2030.(2) The need for advanced prevention and treatment strategies has increased due to the need to reduce cancer morbidity and mortality for colorectal cancer.
Some of the risk factors linked to increased risk of developing CRC include obesity, sedentary lifestyle, consumption of high-fat, high-meat diets and calorie rich and fiber deficient food.(3) Apart from these known risk factors, inadequate Vitamin D status as assessed by serum 25-hydroxyvitamin D (25(OH)D) concentration has also been identified as a potential risk factor in the pathogenesis of CRC. Vitamin D has been identified as a potential protective factor in the risk of developing CRC. Intake of 1000 IU/day of vitamin D is shown to be associated with 50% lower risk.(4) A meta-analysis using random effects model showed that the hazard ratio for mortality was lower with higher serum vitamin D status.(5) The results of this study suggested regular testing and restoration of vitamin D status to adequacy for lowering the mortality in colorectal cancer.(5)
Vitamin D is a fat-soluble vitamin which has limited dietary sources and is predominantly obtained when exposed to ultraviolet B (UVB) radiation in sunlight.(6) Previtamin D3 is an intermediate product in the production of cholecalciferol. It is formed when UVB light of wavelengths between 295 and 300 nm from sunlight acts on 7-dehydrocholesterol present in the epidermal layers of the skin. It then converts by spontaneous isomerization into cholecalciferol which is converted into the active form of vitamin D through two-step hydroxylation.(6) Availability and exposure to UVB in sunlight is strongly correlated to the concentration of calcidiol and calcitriol levels in blood. UVB exposure and supplemental vitamin D both increase calcitriol in a dose-dependent fashion,(7) and increases in calcitriol have been shown to depend on baseline vitamin D status.(8, 9) In addition, a number of molecular factors may influence levels of serum 25(OH)D, including expression of the APOEε4 allele.(10)
A recent study showed that most patients with a new diagnosis of CRC had deficient levels of serum 25(OH)D.(11) Better survival rates have been observed in patients with higher serum 25(OH)D concentrations compared to those with lower concentrations.(12) Reviews of ecological studies have shown evidence for the association between UVB–vitamin D–cancer to be convincing for several different types of cancer.(13, 14) However, not all studies have shown an increased cancer risk associated with inadequate circulating vitamin D levels. A Mendelian randomization study provided little evidence for the association of vitamin D and risk of several types of cancer.(15)
The DINOMIT model (disjunction, initiation, natural selection, overgrowth, metastasis, involution, and transition) postulates that the anti-cancer effects of vitamin D can occur across these various phases of cancer etiology.(16) Vitamin D plays a protective role in all phases by protecting intercellular gap junctions through regulation of cadherins. Tight junctions prevent cells from separating and reduce the rate of cancer progression and metastasis. The DINOMIT model also postulates the involution of cancer through replenishment of vitamin D. Vitamin D deficiency’s effect on carcinogenesis is modeled as a function of time. With increasing age, the consequence of vitamin D deficiency accumulates longitudinally. Hence, the inverse epidemiological association between vitamin D status and incidence of colorectal cancer is expected to increase with age due to chronicity vitamin D deficiency. Since UVB exposure is strongly correlated to serum concentrations of 25(OH)D in the body, the strength of the inverse association between UVB estimate of a geographical area and the crude incidence rate of colorectal cancer can be studied to assess the longitudinal accumulation of carcinogensis from vitamin D deficiency.
UVB exposure in a geographic area is affected by cloud cover, skin pigmentation, number of hours spent indoors and type of clothing. Influential covariates that can affect CRC incidence include diet, smoking prevalence, life expectancy, and wealth. The primary objective of this study to explore the effect of age on the inverse association between UVB exposure and CRC incidence, while adjusting for influential covariates. We hypothesize that the strength of the inverse association between UVB exposure and CRC incidence increases with age.