Our results suggest that high intake of caffeine or coffee was associated with an increased risk of ovarian cancer among premenopausal women, but a lower risk among postmenopausal women. We did not observe any association with tea or decaffeinated coffee intake. Two SNPs in CYP19, but no variants in CYP1A1, CYP1A2, and CYP2A6 were associated (one positively and one inversely) with ovarian cancer risk. Several gene-environment interactions were observed among premenopausal but not postmenopausal women.
Our observations regarding a modifying role of menopausal status in the association between coffee and ovarian cancer risk is consistent with what has been described previously for the NHS/NHSII and NECC (4
). We found that the inverse association with coffee was limited to postmenopausal women. The small sample size of the nested-case control in the NHS/NHSII may have limited our ability to detect any significant differences in this analysis; however, in our previous study of the entire NHS/NHSII cohort (n =507 cases), we reported a significant reduction in risk among those in the highest versus lowest quintile of caffeine intake (OR = 0.69; 95% CI 0.50–0.95; P
for trend = 0.02) (4
). Among premenopausal women from the NECC, increasing intake of both caffeine and coffee were positively associated with ovarian cancer (P
for trend = 0.007 and 0.003, respectively). These results are similar to those from the earlier NECC publication (n = 549 cases) (5
To date, five prospective studies and 12 case-control studies have investigated whether coffee is associated with ovarian cancer risk, with conflicting results (3
). Only three studies have specifically evaluated caffeine (20
). In the first, the authors observed an increased risk of ovarian cancer with caffeine intake among both menopausal groups (21
). However, Jordan et al.
reported a significant inverse association that was limited to postmenopausal women (22
). More recently, Song et al.
reported no association between caffeine consumption and ovarian cancer risk (20
). Despite the uncertainty in the literature regarding the role of coffee in etiology of ovarian cancer, the consistency observed between the Jordan et. al
study, the retrospective assessment of the NECC, and the prospective analysis of the NHS collectively suggest that coffee consumption may influence ovarian cancer risk differentially by menopausal status.
Tea consumption did not influence risk of ovarian cancer in this group of women which is in accordance with the majority of published case-control studies; whereas, prospective studies including a study of the entire NHS/NHSII cohort generally have found an inverse association between tea and ovarian cancer (3
). The lack of an association with decaffeinated coffee supports a role of caffeine as the component of coffee mediating the association with ovarian cancer risk.
The biological rationale explaining why the relationship between coffee/caffeine and risk is modified by menopausal status is unclear; however, caffeine may differentially modulate hormone levels among pre- and postmenopausal women. Furthermore, Tworoger et al.
reported that inverse association with caffeine was limited to women who did not use exogenous hormones (4
). Synthetic hormones found in OCs and estrogen replacement therapy have been shown to inhibit CYP1A2-mediated caffeine metabolism in both pre- and postmenopausal women (23
). Consequently, use of exogenous hormones may obscure the possible decrease in risk conferred by caffeine. Thus, it is possible that caffeine or coffee may only exert a protective effect in a low hormonal environment; this possible association should be re-evaluated in future studies.
Coffee or caffeine also may influence endogenous hormone levels. Both have been directly associated with estrone and SHBG levels, and inversely with testosterone (25
) among postmenopausal women whereas in premenopausal women, caffeine appears to be associated with higher SHBG (26
) and 2-hydroxyestrone (OHE) to 16α-OHE ratio (28
), as well as decreased menstrual cycle length (30
). Associations with other forms of estrogen are unclear (27
). Future studies should evaluate whether intakes of caffeine and caffeine-containing beverages are associated with sex hormone levels in pre- and postmenopausal women and among non-exogenous hormone users.
We initially hypothesized that the contrasting associations between coffee and cancer risk in pre- versus postmenopausal women might be explained by variants in genes involved in caffeine or sex hormone metabolism pathways. The cytochrome P450
) genes are a large superfamily of genes that encode Phase I enzymes involved in the oxidative metabolism of numerous exogenous and endogenous compounds including various steroid hormones and caffeine (32
). CYP19, or aromatase, is the key enzyme mediating the conversion of testosterone to estradiol and androstenedione to estrone. Since these CYP enzymes are involved in the metabolism of caffeine, estrogen, or both, we evaluated whether or not polymorphisms in these genes may modify the association between coffee or caffeine intake and risk of ovarian cancer. The CYP1A1, CYP1A2
, or CYP2A6
genotypes were not associated with risk, nor was there any evidence for modification by these genotypes among women with high versus low levels of caffeine, coffee, decaffeinated coffee or tea intake.
CYP1A2 was the most likely mediator of risk with coffee intake since this enzyme is responsible for the metabolism of more than 95% of caffeine, is itself induced by caffeine (33
), and is involved in estrogen metabolism (34
). A common A
polymorphism in the CYP1A2
gene decreases enzyme inducibility and activity, resulting in the slower metabolism of caffeine (35
). We did not see any evidence for effect modification by this genotype. Only one other study evaluated this association and observed an increased risk of ovarian cancer with coffee and caffeine intake only among women carrying both AA
). Nonetheless, these results cannot be directly compared to ours since most women in the Goodman et al.
case-control study were Asian or Pacific Islander whereas our analysis was limited to Caucasian women.
CYP2A6 is involved in the biotransformation of nicotine (38
), coumarin (39
) and the metabolic activation of various carcinogens (40
). CYP2A6 also metabolizes 1,7-dimethylxanthine, the primary metabolite of caffeine (41
). Many variants in the CYP2A6
gene have been identified that explain the inter-individual variation in enzymatic activity; however, their frequency in Caucasians is low (43
). Five prior studies have examined the association between ovarian cancer and the Msp1
polymorphism in CYP1A1
and all reported no association, similar to our study (45
). However, Terry et al.
did report an elevated risk of ovarian cancer among women with the Ile/Val
variant who consumed > 204.5 mg of caffeine per day (47
). Comparable with our findings, they did not report such an interaction with the Msp1
variant and caffeine intake.
Only one of the CYP19
haplotypes estimated from the htSNPs was associated with ovarian cancer risk. Since there were no significant associations overall or with the other individual haplotypes, the significant inverse association in block 3 likely is due to chance. Interestingly, the two CYP19
, which were independently associated with ovarian cancer risk in our study, have been previously shown to be significantly associated with endogenous estradiol and estrone levels among postmenopausal women (50
). Levels of circulating estradiol and estrone were 12 to 17% higher among individuals who were homozygous variant for either SNP compared to wildtype (P
for trend ≥ 1.3 × 10−10
). Furthermore, a significant 10% to 20% increase in postmenopausal estrogen levels were noted for heterozygous and homozygous carriers of the two-SNP haplotype compared with non-carriers (P
for trend = 4.4 × 10−15
). Because the latter study was comprised of a multi-ethnic cohort and we limited our study population to white women, the minor allele frequency of CYP19027
differed between the two groups. Thus, we repeated our analysis such that the reference allele of the two SNPs corresponded to that of the Haiman et al.
paper (due to differing ethnic distributions) and showed a higher risk of ovarian cancer among women who were homozygous variant for the A
alelle (OR = 1.12; 95% CI 0.90–1.38; P
for trend = 0.05) for the CYP19027
SNP. We also examined the association with the two-SNP haplotype and found that women with both the A
risk alleles had a 13% increased risk of ovarian cancer compared to women with both the wild-type alleles (OR = 1.13; 95% CI 1.00–1.27). Despite the numerous statistical comparisons in our study, these are important preliminary results since these variants exert a functional effect on endogenous estrogen levels, and thus elevated estrogen levels may explain the increased risk of ovarian cancer we observed. While this provides biological plausibility for our observations, replication is required in future studies.
One study evaluated whether allelic variants of CYP19, CYP1A2
were associated with the risk of hormone-dependent cancers among Caucasian women from Russia (48
). The authors reported no association between the CYP19
and CYP1A1 Msp1
polymorphisms and risk, and an inverse association between the CYP1A2 AA
genotype and risk. A major limitation of this study is that the authors did not distinguish between endometrial and ovarian tumor types in their analysis. Among premenopausal women, we reported significant interactions between caffeine intake and three of the CYP19
htSNPs; however, it is unclear by what mechanism these variants in CYP19
may alter the association between caffeine and ovarian cancer risk. Thus, our results should be interpreted with caution.
There are several limitations to the present study. There were very few premenopausal cases in the NHS/NHSII due to the age of the cohort. Nonetheless, there were a sufficient number of premenopausal cases in the NECC (n = 510) for the analysis of the gene-environment interactions. In the NECC, the FFQ was completed in the cases following their diagnosis. This retrospective assessment of coffee intake is subject to recall bias and misclassification of the exposure variables; however, this is unlikely since the results of the NECC were similar to those in the prospective analysis of the NHS/NHSII (4
). We used cumulative updating for the NHS/NHSII but could not take into account duration of intake among women in the NECC. The current analysis was limited to white women and may not generalizable to other populations of different ancestries. Given the large number of SNPs and gene-environment interactions that were evaluated, our positive findings may be attributed to chance.
A major strength of our study was the ability to evaluate the association between a common exposure and ovarian cancer risk using a large study population that included 1352 cases and 1847 controls. Furthermore, we controlled for the majority of the known or suspected risk factors for ovarian cancer thus decreasing the influence of confounding. The prospective nature of the NHS/NHSII allowed for the detailed collection of unbiased dietary and risk factor information.
These data further suggest that menopausal status modifies the association between coffee consumption and ovarian cancer risk and that genetic variation in CYP19013 and CYP19027 may be implicated in the etiology of ovarian cancer; however few, if any, diet-genotype interactions exist. Because coffee is such a common exposure, clarifying its role is critical especially since the data supporting nutritional or lifestyle factors in the prevention of ovarian cancer is scarce. Moreover, our results could have important public health implications especially since the inverse association in postmenopausal women was seen with consumption of at least 2.5 cups of coffee per day. Additional studies evaluating mechanisms by which coffee mediates risk are warranted before recommendations are implemented.