In this large case–control analysis of DRC using the host-cell reactivation assay, increasing dietary intake of Mg was associated with reduced lung cancer risk ranging from 17 to 53%. In joint effects analysis, subjects with low Mg + suboptimal DRC were at the highest risk for lung cancer. To the best of our knowledge, this is the first study to report that dietary Mg intake is inversely associated with lung cancer risk, that DRC is lower in strata of low Mg intake and that low dietary Mg + suboptimal DRC together are associated with substantial increased risk.
The current research on Mg and lung cancer, including the statistical modeling, is based on biological plausibility. The potential mechanisms by which Mg may protect against lung cancer includes its role in maintaining genetic stability (6
), regulation of cell proliferation (28
), protection against inflammation (11
), maintenance of lung function (29
) and protection against oxidative stress (8
). All these functions of Mg are important in maintaining the integrity of the cell and in the prevention of lung and other cancers. Likewise, we have shown previously that increasing levels of DRC were associated with reduced risk for lung cancer (P
-trend < 0.0001) among men and women (data not shown) (22
In our study, there were substantial increases in lung cancer risk among subjects with low Mg intake + suboptimal DRC compared with high Mg intake + proficient DRC. In particular, these joint effects were more pronounced in subjects who were older, current smokers, had longer duration of smoking, smoked more cigarettes per day, had a family history of cancer in first-degree relatives or were alcohol drinkers, but no difference was evident by vitamin/mineral supplement use. Unfortunately, dosage and frequency of supplementation were unavailable for analysis. The higher risk observed for thinner (BMI ≤ 25) compared with heavier subjects (BMI > 25) () in the low Mg-suboptimal DRC group was similar to findings from earlier research (26
) and may reflect severity of disease.
Cigarette smoke, an established risk factor for lung cancer, is an important source of reactive oxygen species in the lungs; thus individuals with low Mg intake and suboptimal DRC may be unable to combat carcinogenic effects from cigarette smoke. Alcohol can also act as a pro-oxidant in lung tissue (30
). Thus, Mg may function by counteracting oxidative stress induced by alcohol consumption. In animal studies, dietary Mg restriction has significantly increased lipid peroxidation (7
), reduced the activity of superoxide dismutase and catalase (8
) and upregulated genes associated with oxidative stress (31
Two prospective studies reported that dietary Mg intake was inversely associated with risk for colorectal cancer in women (32
). Furthermore, high compared with low serum levels of Mg was associated with significantly lower all-cause cancer mortality in a cohort study (34
We have reported previously that the dietary trace metals, zinc, copper and selenium were associated with reduced risk of lung cancer at the highest quartile of intake (18
). The Mg effect is much stronger than the associations for zinc and selenium, but less than the associations for dietary copper and lung cancer. When individual addition of dietary zinc, copper, carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein–zeaxanthin and lycopene) and folate were made to model 2 (), the magnitude and direction of the association with dietary Mg intake and lung cancer risk remained similar.
When we assessed top food contributors of Mg in our population as risk factors, as expected, we found a significant inverse trend with increased intake of dark bread, banana and nuts with lung cancer risk (data not shown). While these results from food contributors of Mg validate our findings regarding Mg and lung cancer risk, it is also possible that it may not be dietary Mg that is etiologically important, but something else in high Mg foods.
Emphysema, which is strongly influenced by smoking (35
), is a chronic inflammatory condition (36
) and a risk factor for lung cancer (37
). There are experimental (38
) and epidemiological (11
) evidence that Mg has anti-inflammatory properties. For example, in the Women’s Health Study (11
) and National Health and Nutrition Examination Survey (1999–2000) (12
), Mg intake was inversely associated with C-reactive protein levels. In stratified analysis, we observed a significant protective trend for lung cancer with increasing intake of dietary Mg only in subjects who did not report a diagnosis of emphysema (data not shown). Chronic inflammation in emphysema possibly results in a cycle of lung injury and repair that may overwhelm the anti-inflammatory effects of dietary Mg. Nonetheless, the numbers of participants with reported emphysema were too few for meaningful interpretation of the risk estimates from joint effects analysis by the Mg–DRC groups.
We recognize that our study would be strengthened by more objective assessment of Mg status such as serum or intracellular measurements. Unfortunately, biological samples were unavailable for measurement of Mg in our study. However, since our cases were diagnosed at MD Anderson Cancer Center, we were able to identify serum Mg values for most of the cases from medical records. In the parent study, serum Mg values were available for 1103 lung cancer patients with information on clinical stage of the disease, and we found that serum Mg values did not differ between subjects with early stage (n = 289; mean Mg = 1.90 mg/dl) versus late-stage (n = 814; mean Mg = 1.92 mg/dl) lung cancer. In our subset of cases with DRC measurements (n = 1139), serum Mg values were available for 627 patients, and mean serum Mg were as follows: late-stage (n = 528; mean Mg = 2.04 mg/dl) versus early stage lung cancer (n = 199; mean Mg = 1.95 mg/dl).
Like all case–control studies, our study raises concern about recall bias. In an attempt to reduce systematic errors in reporting of dietary intake, the cases were asked to recall their diet the year prior to diagnosis and controls were asked about their diet during the year prior to enrollment into the study. In the current analysis, total calories, a marker of total intake, did not differ between cases and controls. Further, in our study, the control population consumed comparable daily mean dietary Mg intakes to values reported by National Health and Nutrition Examination Survey, 1999–2000, a national sample of USA population (39
). Nevertheless, underreporting or overreporting problems associated with certain types of food cannot be totally ruled out.
The FFQ is practical for large epidemiology studies such as ours, but its use may introduce measurement errors (40
), leading to biased estimates of the association between a given dietary factor and cancer. It has been argued that because of misclassification errors, the FFQ is not always able to detect weak associations (42
), thereby attenuating the true association. In an effort to improve the accuracy, our interviewers were trained in FFQ administration, whereas FFQ responses were reviewed by staff nutritionists; and portion sizes were assessed with visual aids. Despite the above-mentioned limitations, the FFQ has been shown to reliably classify individuals by quartile of intake (44
). Among the top 10 food contributors to Mg (data not shown), no single food was a major contributor of Mg content of the diet, but several foods contributed small amounts of intake. Our participants resided in the Houston area; and although the DIETSYS + Plus database constitutes a wide cross section of foods, we did not have data to compare Mg composition of foods in the Houston area.
Another important limitation of this study is the lack of information on the frequency and duration of use of dietary supplements containing Mg. It is well known that several multivitamin/mineral supplements with different brand names contain varying amounts of Mg. For these reasons, the current analysis is focused only on dietary Mg intake.
Regarding the DRC assay, the issues of intra- and interassay variation and reproducibility have been addressed in earlier publications of the assay development (45
). The DRC assay uses primary, viable lymphocytes that are obtained from a frozen sample of lymphocytes that were isolated from ~20 cc fresh blood sample, enabling us to perform the assay only in duplicates per sample. Therefore, it is not possible at this time to generate the coefficient of variation for each sample with triplicates. Also, the blood was drawn one time after cancer diagnosis but before any treatment and any blood drawn after the treatment may not be comparable with the one drawn before the treatment.
Dietary minerals in lung cancer risk remain an understudied area of research. Our findings suggest that Mg from food sources in the typical USA diet offers protection against lung cancer and that Mg intake and DRC together modulate risk. These intriguing results need to be confirmed in prospective studies. Assessment of the role of Mg intake and tissue levels and lung cancer mortality would complete the evidence-based research picture for this essential mineral.