Dietary patterns, BCMO1 polymorphisms, and primary lung cancer risk in a Han Chinese population: a case-control study in Southeast China

The International Agency for Research on Cancer reported a lung cancer incidence rate of 23.1/100,000 and a lung cancer mortality rate of 19.7/100,000 for 2012 [1]. Although China does not yet have a well-established cancer registry system, the data available for 2015 indicate that lung cancer is the most common and most deadly cancer in China [2]. Because of the poor prognosis and often aggressive nature of lung cancer, the 5-year overall survival rate for lung cancer is only 10–15%, putting a heavy burden on patients, patient’s families, and governments [3]. Although tobacco smoking is the most salient cause of lung cancer, several other risk factors may contribute to the disease [4, 5].

It has been reported that about a third of all tumors may related to dietary factors [6]. Currently, most studies that have examined the influence of dietary factors on lung cancer risk have focused on a single food or a limited combination of certain foods or nutrients, and their results have not been consistent [7‐10]. However, generally, people do not consume single foods or nutrients. Moreover, different categories of foods and nutrients may have interactions with one another. Hence, exploring specific foods and nutrients in isolation is not representative of real-life diets. Consequently, researchers have become interested in examining the influence of dietary patterns and holistic dietary status on lung cancer risk [11‐18]. Although the findings are uncertain, they argue that a diet with high vegetable is related with a reduced risk of lung cancer [19], while a high fat and red meat diet is related with increased risk. However, most of these studies were conducted outside of China, where eating habit vary greatly across different regions. Examination of the possible influence of Chinese dietary patterns on lung cancer is lacking.

Importantly, any observed correlation between dietary patterns and lung cancer could be related to other factors, such as smoking, social-economic status, and physical activity [19]. Although intake of vegetables and fruits has been suggested to reduce the risk of lung cancer [10], β-carotene (BC)—a retinal (form of vitamin A) precursor found in many edible plants—has been suggested to increase the risk of lung cancer in smokers [7], perhaps due to a complex gene-diet interaction. In this regard, Tu and colleagues suggested recently that the association between dietary patterns and lung cancer risk may be modified by genetic background [17].

Dietary BC is cleaved into two retinal molecules by β-carotene-15,15′-monooxygenase (BCMO1) [20]. Single nucleotide morphisms (SNPs) of the human BCMO1 gene, which is located on chromosome 16, have been reported to influence blood concentrations of BC, suggesting that BCMO1 SNPs may affect the efficiency of BC transformation into vitamin A in vivo [21]. If so, then it is possible that BCMO1 SNPs may also influence the effects of dietary patterns on lung cancer risk. To test this hypothesis, we conducted a case-control study to explore the potential influence of three BCMO1 SNPs, namely rs6564851, rs12934922, and rs7501331, on the association between dietary patterns and lung cancer risk in a case-control study of ethnic Han Chinese participants.

Because BC, which is ubiquitous in edible plants, and BC metabolites have important biological functions, BC is generally considered to be a health promoting compound. However, lung exposure to BC in Bcmo1^−/− mice has been reported to alter gene expression in a manner that augments the Gene Ontology terms “oncogenes”, “cell proliferation”, and “cell cycle”. BC has also been reported to have adverse effects on lung tissues in human subjects, including increasing the risk of lung cancer [21, 27, 28]. BC absorption and conversion into retinal is extremely variable across individuals, with as many 45% of the people being classified as low responders to dietary BC [29]. Two BCMO1 coding-region SNPs examined in this study (rs12934922 and rs7501331) were shown previously to result in reduced BCMO1 catalytic activity, confirming that these variants at least contribute to a low-responder phenotype. In vitro biochemical characterization of a double mutant BCMO1 protein encoded by recombinant gene carrying bot the rs12934922 and rs7501331 SNPs indicated that the double mutation reduced catalytic activity of BCMO1 by 57% (P < 0.001) [25]. Meanwhile, the homozygous rs6564851 genotype of BCMO1 has been reported to result in a 48% reduction in the catalytic activity of BCMO1 as reflected by in vivo plasma level data in adult female human volunteers [29].

We speculated that efficiency-reducing BCMO1 SNPs would allow accumulation of BC in vivo, which may support uncontrolled proliferation of lung cells. Our hypothesis that the low BC➔retinal efficiency BCMO1 variant genotypes would thus be associated with lung cancer risk was not supported by the present results. Although the sample size of the current study is not small, the association of BCOM1 polymorphisms can be examined with a larger study with a more comprehensive genotyping on BCOM1 gene. This study was the first, to our knowledge, to examine the relationship between these variants and lung cancer directly. A prior Italian genome-wide association study did reveal an association between rs6564851 and higher than average BC levels, but the authors expected it would nonetheless be associated with a lower risk of cancer [26]. In our study, we observed that the effects of the “high quality protein” pattern was further modified by rs6564851. It showed there may have been some genetic mechanisms need to explore.

Notably, this study had the strength of employing dietary pattern analysis, which can better reveal dietary habit interactions and health benefits than studies of isolated nutrients. The results of a recent meta-analysis suggest that a healthful dietary pattern (a.k.a. a prudent pattern)—characterized by a high intake of vegetables, fruits, white meat, fish, and whole-grain breads and a low intake of red meat, fatty foods, and refined grains—is associated with a reduced lung cancer risk, and thus provide evidence for favoring diet pattern shifts in the general population [19].

The patterns identified in this analysis were reflective of real-world consumption in the Fujian Han population rather than an ideal dietary pattern. A potential criticism of this approach is that the dietary pattern factors are dependent on the study population for their validity. Thus, a different set of patterns may emerge with a different study population, which limits the interpretive value of these dietary patterns. However, it is important to note that our high quality protein (seafood in majority), fruits and vegetables patterns are analogous to patterns that have emerged repeatedly in many studies that used factor analysis to study dietary patterns [30, 31].

Our association findings for four patterns are consistent with findings from previous studies on dietary pattern and lung cancer. Previous factor-analysis studies [15‐17] have related healthful eating to a decreased risk of lung cancer, similar to findings obtained with index-based dietary patterns, supporting the current dietary guidance of increasing consumption of fruits, vegetables, whole grains, lean meats or meat alternatives, and low-fat dairy [11]. In addition, the Mediterranean dietary pattern was thought to be negatively related with risk of lung cancer, whereas a “Western” dietary pattern was found to be associated with lung cancer risk [13].

On the other hand, our study showed a positive relationship between frugal pattern and lung cancer risk, which has not, to our knowledge, been reported previously. The participants in our study with high scores on the frugal pattern showed with a lower income. In Fujian, poor people usually take dried sweet potato and salted vegetables as staple food. This pattern showed increased incidence of lung cancer that suggests that there may have been relationship between economics and lung cancer. However, the potential mechanisms linking strong adherence to frugal pattern with an increased risk of lung cancer are unknown.

Our study had several strengths and limitations. The strengths include our large sample size, which tends to reduce type II errors. Additionally, extensive information on lifestyle factors were collected to enable adjustment for confounding factors. Several potential limitations of the present study should also be considered. Firstly, there was a recruitment bias related to the retrospective case-control study design; however, the results did not appear to be seriously affected by this bias given the HWEs in the control group. Secondly, our study was subject to potential dietary intake recall bias and we do not use 3-day measuring method or other methods to validate for each of the dietary patterns. It exits potential bias on the findings. Nevertheless, the directions and magnitudes of the associations for our patterns were consistent with other prospective studies. Finally, we did not employ a food-frequency questionnaire (FFQ) and thus may have missed the opportunity to capture data on more types of foods. Further studies in large population-based cohorts by using a FFQ are warranted to identify the role of dietary habits in lung cancer in Fujian, China.

In summary, our study adds to the growing evidence indicating that diet plays an important role in lung carcinogenesis, which is often assumed to be caused solely by smoking. In particular, our study suggests that a diet rich in fruits and vegetables may reduce lung cancer risk.