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Dietary and supplementary folate intake and prostate cancer risk
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Dietary and Supplementary Folate Intake and Prostate Cancer Risk
by
Xinyu Zhang
A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(Molecular Epidemiology)
May 2020
Folate Intake vs. Prostate Cancer Risk
2
Table of Contents
Introduction ................................................................................................................................... 3
Incidence ......................................................................................................................................... 3
Mortality ......................................................................................................................................... 4
Introduction of Folate ..................................................................................................................... 8
Folate and Cancer Incidence ........................................................................................................... 9
Materials and Methods ............................................................................................................... 10
Study Population ........................................................................................................................... 10
Data Collection ............................................................................................................................. 11
Statistical Analyses ....................................................................................................................... 11
Results .......................................................................................................................................... 12
Table 1 .......................................................................................................................................... 12
Table 2 .......................................................................................................................................... 12
Table 3 .......................................................................................................................................... 13
Table 4 .......................................................................................................................................... 13
Discussion..................................................................................................................................... 14
Conclusion ................................................................................................................................... 18
Tables and Figures ...................................................................................................................... 19
Conflict of Interest ...................................................................................................................... 25
Acknowledgements ..................................................................................................................... 25
References .................................................................................................................................... 26
Folate Intake vs. Prostate Cancer Risk
3
Introduction
Prostate cancer is the most common malignancy among men, except for skin cancer, with an
estimate of 174,540 new cases diagnosed in the United State in 2019 [1]. The prostate is a
glandular organ, surrounding the urethra, and is a part of the male reproductive system. In
prostate cancer, normal glandular cells undergo uncontrolled transformation into cancer cells,
which adopt a different morphology and begin to invade adjacent tissues. Prostate cancer cells
aggregate to form tumor masses, invading local tissues by taking up oxygen and nutrients that
are required for regular cellular functions [2]. Prostate cancer is a heterogeneous disease. The
vast majority type (>95%) is adenocarcinoma [3], which arises from glandular cells. Other rare
types include squamous cell carcinoma, neuroendocrine tumors, small cell carcinoma, and
sarcomas of the prostate. Tumor cells can eventually spread to other remote organs such as
pelvic lymph nodes, bones, and liver, via the bloodstream and the lymphatic system. Migratory
prostate cancer is responsible for causing symptoms and leading to cancer-specific death.
According to American Cancer Society, prostate cancer is the second leading cause of cancer
death in American men, only second to lung cancer. About 1 man in 41 will die of prostate
cancer [4].
Incidence
Prostate cancer strikes men around the world -- it is ranked globally the top five cancers for both
incidence and mortality [5]. GLOBOCAN 2018 reported an estimate of 1.3 million prostate
cancer incidences worldwide, which account for 7.1% of all cancer cases for both genders at all
ages. Prostate cancer has a higher prevalence in developed countries. Incidence rates are highest
in Australia/New Zealand, Northern and Western Europe, and Northern American, and lowest in
Asia. This geographical variation can be attributed, in part, to differences in the availability of
Folate Intake vs. Prostate Cancer Risk
4
diagnostic test such as prostate-specific antigen (PSA) screening. For example, data has shown
an increasing trend for age-adjusted prostate cancer incidence rate in the United States since
1975 [Fig.1]. A large peak of incidences in the early 1990s paralleled with the first introduction
of PSA screening test to the general public. The peak then went down due to the early detection
of positive cases that would have been diagnosed in the future. Moreover, the lower incidence of
prostate cancer in Asia is thought to be associated, in part, with immature PSA screening
programs and underdeveloped national cancer registration systems. In fact, recent studies have
revealed increasing prevalence of latent prostate cancer in most Asian countries because of the
implementation of PSA testing [6].
Mortality
With an estimated 359,000 deaths in 2018, prostate cancer is the fifth-leading cause of cancer
death in men across the world [1]. Prostate cancer patients in developing countries such as the
Caribbean and Middle and Southern Africa experience the highest mortality rates. Compared
with the incidence rates, prostate cancer mortality rates show less regional variation. A steady
decline in prostate cancer mortality rates was observed in most western countries including
North America as well as Northern and Western Europe. Trends in US mortality rates for black
and white Americans show a slight increase from 1975 to 1991, where it began decreasing
[Fig.1][7]. This drop might be explained by the widespread of PSA screening test in the US in
the early 1990s. Patients with lethal cancers detected at early stage by PSA screening are more
likely to be exempt from cancer-specific death. Therefore, early diagnosis and treatment play an
important role in decreasing the incidence and mortality rates caused by prostate cancer.
Folate Intake vs. Prostate Cancer Risk
5
Risk Factors
Although the etiology of prostate cancer remains unknown, the well-established risk factors
enlisted by epidemiological studies are age, race, and family history. Increasing age, African
American race, and positive family history of the disease have been established to be associated
with higher risk of prostate cancer. On the other hand, there has been no major “prostate cancer
gene” that has been discovered, like BRCA1 for breast cancer. Rather, genome-wide association
studies (GWAS) have provided certain genetic predispositions to prostate cancer with small
relative risks [8]. As previously mentioned, prostate cancer is a heterogeneous disease. Its stage
at diagnosis varies from patient to patient. While some men are diagnosed of primary prostate
cancers that are localized within the organ where they originate, other patients experience
aggressive cancers that migrate to target other parts of the body. It is plausible to assume that
different risk factors are associated with primary and aggressive prostate cancer respectively.
Evidence has suggested that age is strongly associated with primary prostate cancer. The disease
is most commonly diagnosed among elderly males (aged 65-74 years), whereas the incidence
rate is drastically lower in men younger than 40 years [5]. Incidence data from GLOBOCAN and
individual cancer registries show that although varied by almost 50-fold across regions, prostate
cancer incidence increases with age [Fig.2][9].
Striking differences are also observed in prevalence and morality rates of prostate cancer
across racial and ethnic groups. Research has shown that African American men have the highest
prevalence of prostate cancer worldwide and are more likely to develop disease early in life
compare to other racial groups [10]. In the United States, Black men have prostate cancer
incidence and mortality rates that are 3 and 2.4 times higher than Asian and Caucasian men,
respectively. Moreover, Asian/Pacific Islanders and Native Americans have the lowest incidence
Folate Intake vs. Prostate Cancer Risk
6
and mortality rates among all racial ethnic groups [11]. Although black men are at higher risk for
developing prostate cancer than men of other races, the reason behind this difference is yet to be
determined. A number of genetic factors are identified to be responsible for the difference in the
incidence rates. However, it needs further exploration. It is challenging to assess race as an
independent risk factor because it is associated with socioeconomic and educational factors.
Statistics have reported that African Americans who have less than 12 years of education have a
relative risk of prostate cancer death that is 1.51 times (95% CI 1.03–2.22) greater than that of
African Americans with a college education [7]. African Americans from lower socioeconomic
and educational background tend to receive lower quality healthcare. Therefore, they are less
likely to undergo PSA screening for early detection of the disease. Although there is an SES
effect, the racial differences seem to be real. The issue with PSA screening is complicated – most
countries (e.g. European countries) did not adopt screening the same as in the U.S. More studies
need to be done on prostate cancer development across different racial groups.
Although prostate cancer is considered a disease of elderly men, positive family history of
prostate cancer is the risk factor that particularly affects early onset disease. Epidemiological
studies indicate that inherited susceptibility genes are responsible for 5% to 10% of all prostate
cancer, and as much as 30% to 40% of early onset disease [12]. Genes identified to be associated
with hereditary prostate cancer include BRCA1, BRCA2, and HOXB13. Mutations in these
genes impair the function of tumor suppressor proteins, resulting in uncontrolled cell growth and
division that eventually cause prostate cancer [13]. The genetic susceptibility also has a profound
clinical importance. Inherited prostate cancer patients show increased prostate specific antigen
level when compared with patients without positive family history [14]. In addition to inherited
genetic mutations, exposure to similar environmental carcinogens and common lifestyle habits
Folate Intake vs. Prostate Cancer Risk
7
also contribute to men’s risk of developing prostate cancer [15]. For example, high-fat diet,
sedentary lifestyle, excessive alcohol use, and exposure to certain toxic chemicals are believed to
increase the cancer incidence. Furthermore, people in the same household tend to have similar
dietary and activity habits. Therefore, it is important to control diet for confounding factor when
assessing the association between family history and prostate cancer.
Other than age, ethnicity, and familial clustering, social and environmental factors –
particularly diet and nutrition affect the risk of developing prostate cancer. The impact of dietary
and nutritious factors on prostate cancer is gaining more attention from researchers. Some studies
indicated that plant-based foods such as leafy vegetables, soy, and fruits that are rich in vitamins
appear to be beneficial for men with prostate cancer, whereas diet composed of red or processed
meat and foods high in fat could have the opposite effect. American Institute for Cancer
Research combined results from published meta-analyses, concluded that there is limited
suggestive evidence that high consumption of dairy products (400g per day) might increase risk.
[16]. Dairy products are high in calcium, which could promote cell proliferation in the prostate
by downregulating the synthesis of 1,250dihydroxy vitamin D3 [16]. They also found that there
is limited suggestive evidence that low vitamin E and selenium are risk factors. The Prostate
Cancer SLR 2014 identified eight out of twelve studies that report an inverse association
between plasma alpha-tocopherol level and prostate cancer risk. That is, men with lower plasma
alpha-tocopherol concentrations might be at higher risk for developing prostate cancer.
Nevertheless, the evidence supporting the role of diet is limited. The role of diet in lowering
prostate cancer risk needs further investigation. With the growing popularity of multivitamins
and minerals enrich diet all around the world, clarification of nutritious factors in relation to the
Folate Intake vs. Prostate Cancer Risk
8
prostate cancer risk is urgently demanded. Therefore, in this study, my goal is to investigate the
effect of dietary folate intake on prostate cancer risk.
Introduction of Folate
Folate was first isolated from spinach in 1941 and named after the Latin word folium [17]. It is a
naturally occurring B-vitamin that exists in many foods such as dark green vegetables, beans,
peas and nuts. Adequate folate intake is vital for humans due to its essential role in maintaining
regular cell functions. In the cell, folate functions as a metabolic cofactor that carries and
transfers one-carbon units for a series of anabolic and catabolic reactions collectively known as
folate-mediated one-carbon metabolism (OCM) [18]. Folate-mediated OCM is a network of
pathways that take place in the mitochondria, the cytoplasm, and the nucleus. Folate metabolism
in mitochondria is required for the synthesis of formate and glycine [18]. In the cytoplasm, folate
pathway is essential for de novo purine and thymidylate biosynthesis as well as re-methylation of
homocysteine to form methionine [18]. Folic acid, a synthetic form of vitamin B9, has been
used commercially in supplements and added to processed food products to treat dietary folate
deficiency and certain types of anaemia. National Health and Nutrition Examination Survey
reports that 63% of individuals over age 60 take a dietary supplement: 40% take folic-acid
containing multivitamins, 7% B-complex vitamins, and 2% folic acid supplements [19]. The
Institute of Medicine recommends an upper intake level for folic acid of 1000 ug/day for adults
and between 300 – 400 ug/day for children between the age of 1 to 8 years [20]. However, the
clinical significance of the upper intake levels is not well established. So are the potential side
effects associated with the high dosage. One of the important goals in folate research involves
characterizing its role in modulating cancer development.
Folate Intake vs. Prostate Cancer Risk
9
Folate and Cancer Incidence
An accumulating body of epidemiological, clinical, and experimental evidence suggests that
folate may have both inhibitory and promoting effects on cancer development. Studies have
demonstrated increased risk, no effect, and decreased risk. Kim et al. summarized results from a
series of epidemiologic and clinical studies, indicating that individuals with the highest dietary
folate intake have a 40% increased colon cancer risk when compared those with the lowest
intake [21]. Recent studies regarding folate intake found little or no association between folate
intake and breast cancer. Chen at el. Showed a U-shaped dose-effect relationship between dietary
folate intake and breast cancer risk [22]. There was a significantly decreased breast cancer risk
with dietary folate intake between 153 and 400 mcg compared with those < 153 mcg. However,
dietary folate intake >400 mcg failed to reduce the risk significantly [22]. A randomized
controlled trial investigating the potential anti-neoplastic effect of supplementary folic acid, in
subjects with a history of colorectal adenoma, reported a 67% increased risk of advanced lesions
with supplementation when compared to placebo [23]. No protective effect of folate intake for
risk of ovarian cancer when comparing highest with lowest quantiles of folate intake [24]. It is
expected that folate, a B-vitamin that is essential in DNA synthesis, repair, and methylation, has
a complex relationship with prostate cancer. Results from an in-vitro study indicated that mild
folate depletion (100 nM) could lead to genetic and epigenetic instability that contribute to
proliferation of prostate cancer cells derived from mice [25]. Th role of folate in human prostate
cancer risk development remains uncertain. Therefore, the purpose of this case-control study is
to further investigate the association of dietary folate intake with risk of prostate cancer.
Folate Intake vs. Prostate Cancer Risk
10
Materials and Methods
Study Population
Study subjects were participants in the California Collaborative Prostate Cancer Study, a
population-based multiethnic case-control study conducted between 1997 and 2005, enriched for
aggressive prostate cancer cases, which has been described in detail previously [26,27]. Briefly,
cases were identified from the Los Angeles County Cancer Surveillance Program and the Los
Angeles County (LAC) and the Greater Bay Area (SFBA) Cancer Registries. A total of 1857
cases completed the interview, including 500 African Americans and 1,357 Whites. Advanced
prostate cancer was defined according to SEER (Surveillance Epidemiology and End Results)
1995 pathologic and clinical extent of disease codes 41-85. Of the 1,857 cases, 1,140 were
diagnosed with advanced stage and 717 were diagnosed with localized disease. Controls were
frequency-matched to the expected distribution of cases on race/ethnicity and ten-year age group.
In LAC, controls were ascertained by a standard neighborhood walk algorithm that specifies an
obligatory sequence of residences to be surveyed for eligible control subjects [28]. A
participating control was found within 40 residences in more than 90% of case neighborhoods
surveyed. In SFBA, controls were identified through random digit dialing and random selections
from among beneficiaries of the Health Care Financing Administration. A total of 1,096 controls
completed the interview, including 240 African Americans and 865 Whites.
Blood or mouthwash samples were obtained for 1,140 advanced cases, 717 localized
cases, and 1,096 controls. Biospecimens were not collected from localized cases in SFBA.
All study participants provided written informed consent. The protocol was approved by
the Institutional Review Boards of the University of Southern California and the Cancer
Prevention Institute of California.
Folate Intake vs. Prostate Cancer Risk
11
Data Collection
Trained professional interviewers conducted home visits and administered a structured
questionnaire on demographic background, medical history, body size, lifestyle factors
(including physical activity, alcohol consumption, smoking), and family history of prostate
cancer. Three measurements of standing height and two measurements of weight were taken and
averaged. Usual dietary intake during the reference year (defined as the calendar year before
diagnosis for cases and the year before selection into the study for controls) was assessed using a
74-item food frequency questionnaire (FFQ) adapted from Block’s 1995 Health Habits and
History Questionnaire, which has been validated in middle-aged and older men [29,30,31,32].
The FFQ assessed for each food item the frequency of consumption and portion size, using food
models and utensils. Daily intake of specific nutrients, including folate, was estimated using the
DIETSYS software. Intake of folic acid supplementation during the reference year was assessed
by questions on use (number of tablets per week) of multivitamins and folic acid pills.
Statistical Analyses
Chi-square tests were used to test for departures of genotype frequencies from Hardy-Weinberg
Equilibrium among controls. To control for differences in race/ethnicity, socio-economic status
(SES) and case/control ratio across study sites, we created a variable that classified subjects
according to study site, SES quintile and race/ethnicity, as described previously [26] and fit
conditional logistic regression models to estimate odds ratios (OR) and 95% confidence intervals
(CI). Models were adjusted for age (continuous variable) and first-degree family history of
prostate cancer (yes, no) as potential confounders. We also checked for potential confounding by
PSA screening during the five years prior to the reference year. Reliable screening data were
Folate Intake vs. Prostate Cancer Risk
12
available only for SFBA cases and controls, and there was no evidence of confounding by PSA
screening.
Dose-response trends were assessed by including quartiles as an ordinal value in the
conditional logistical regression models. Cross-product terms were included and a 1 degree of
freedom likelihood ratio test was used to evaluate effect modification. Separate analyses were
performed for cases with localized and advanced stage disease.
Results
Table 1
Socioeconomic characteristics, dietary patterns and anthropometric measures of cases and
controls are shown in Table 1. Age of diagnosis was 3 to 5 years earlier for cases with advanced
stage versus localized disease. Blacks were less educated and of lower socioeconomic status
than Whites. Cases were more likely to have a family history of prostate cancer. Dietary Folate
intake was similar among Whites and Blacks, however, more Whites took supplements
containing folate. Forty-three percent (1,355) of all subjects were Non-Drinkers. Among men
who drank, cases consumed more than controls. Whites were the more ‘moderate drinkers.
(<12.7 g/d)’. African Americans consumed more alcohol per day than Whites, however, more
Blacks were Non-Drinkers.
Table 2
Dietary Folate intake and prostate cancer risk
After adjusting for age, first degree family history of prostate cancer and multivitamin use,
increasing intake of dietary folate was associated with increasing risk of prostate cancer.
Folate Intake vs. Prostate Cancer Risk
13
Compared to those consuming <342 mcg/day (lowest quartile), those in the upper quartile (> 632
mcg/day) were at approximately 48% increased risk. This was similar for localized and
advanced disease (p trend = 0.002 and 0.001, respectively), and for Blacks and Whites.
Table 3
Total Folate intake and prostate cancer risk
After adjusting for age, first degree family history of prostate cancer and multivitamin use,
increasing total folate intake was associated with increasing prostate cancer risk. Those in the
upper quartile of folate intake were at approximately twofold increased risk for prostate cancer
compared to those in the lowest quartile (OR=1.82, 95% CI =1.37, 2.43). In both localized and
aggressive stages, the effect was similar. The effect appeared stronger among African
Americans than among Whites.
Table 4
Alcohol Consumption and prostate cancer risk
Current alcohol consumption was adjusted for age, first degree family history of prostate cancer
and multivitamin use. Among regular consumers of alcohol, there increasing consumption was
associated with increasing risk. Compared to those in the lowest tertile (< 12.7 g/day,
approximately one drink), those in the highest tertile (31.8 g/day, approximately 3 drinks) were
at approximately 40% increased risk for prostate cancer. Those diagnosed with Nonaggressive
and Advanced disease showed a similar pattern. The effect appeared stronger in Whites than in
Blacks. Non-drinkers were at significantly increased risk compared to the lowest tertile of
alcohol consumption overall, but this was seen only among whites, and not among African
Folate Intake vs. Prostate Cancer Risk
14
Americans. There was no interaction between alcohol and folate, and alcohol was not a
confounder of the relationship between folate and prostate cancer risk.
Discussion
This case-control study examining dietary and total folate intake in relation to prostate cancer
risk was conducted among a population of folate sufficient subjects. We observed a significantly
increased risk of overall prostate cancer with increasing dietary (OR=1.48, 95% CI 1.19-1.85)
and total folate intake (OR=1.82, 95% CI 1.37-2.43). The risk effect of folate was observed in
both localized and advanced disease. Although the effect of total folate intake appeared stronger
among Black men (OR=3.02, 95% CI 1.67- 5.45) than among White men (OR=1.56, 95% CI
1.12- 2.18), the racial difference was not as profound in dietary folate intake (Black OR=1.53,
95% CI 0.99-2.37; White OR=1.49, 95% CI 1.15-1.93). The associations were adjusted for
confounding factors including age, family history of prostate cancer, and multivitamin use.
Furthermore, alcohol consumption was found to have a positive association with prostate cancer
risk among regular drinkers. The disease risk was boosted by 40% among heavy drinkers
compare to the reference (OR = 1.39, 95% CI 1.09-1.76). Those diagnosed with nonaggressive
and advanced disease showed a similar pattern and the effect appeared stronger in Whites than in
Blacks. Non-drinkers were at a significantly higher risk when compared to the lowest tertile of
alcohol consumption overall. However, this was only seen among Whites (OR=1.55, 95%CI
1.23-1.94), but not African Americans (OR = 0.95, 95% CI 0.62-1.46).
The incentive for the current analysis originated from the results of a randomized clinical
trial (RCT), which studied prostate cancer occurrence in a placebo-controlled trial of aspirin and
folic acid supplementation. During 10 years of follow-up of 643 men who were randomly
Folate Intake vs. Prostate Cancer Risk
15
assigned to placebo or folic acid (1 mg/day), the estimated probability of being diagnosed with
prostate cancer was 9.7% (95% CI 6.5%-14.5%) in the folic acid group and 3.3% (95% CI 1.7%-
6.4%) in the placebo group [33]. The age-adjusted hazard ratio was 2.63 (95% CI 1.23-5.65)
[33]. In contrast to the positive association between folic acid supplementation and prostate
cancer risk in the RCT, there was a non-significant inverse association of the cancer risk with
baseline dietary folate intake (HR= 0.65, 95% CI 0.35-1.20), and with plasma folate (HR=0.42,
95% CI 0.17-1.04) among non-multivitamin users [33]. Baseline folate intake in the RCT
(mean=320 ug/day, SD=147) was lower than in our study (mean=512 ug/day, SD=242). The
general recommended folate intake is 400 ug/day, which is higher than the mean intake in the
RCT, but lower than that in the current study. Our study demonstrated an increased risk of
prostate cancer with higher folate intake, which is consistent with the results of the RCT.
Some previous observational studies had suggested dietary folate as a protective factor against
prostate cancer. Shannon et al. analyzed 140 prostate cancer cases and 250 biopsy negative
controls as well as 240 PSA normal clinic controls, concluded that when compared to PSA
normal controls, men on the highest quartile of dietary folate consumption (> 669 ug/day) has
significantly lower risk of prostate cancer (OR= 0.19, 95% CI 0.06 -0.56) and specifically high-
grade prostate cancer (OR = 0.08, 95% CI 0.02- 0.39) [34]. An Italian case-control study
reported an OR of 0.61 (95% CI 0.43-0.86) for the highest quintile of dietary folate (> 316
ug/day) for patients with less advanced cancer (Gleason scores < 7), and an OR of 0.47 (95% CI
0.32-0.69) for patients with Gleason scores of 7 or higher. [35]. These results, although focusing
on dietary folate intake, cannot be directly compared to ours’ because even their highest quintile
of folate intake is very low, especially in the Italian study, and is considered deficient when
compare to the general recommendation (400 ug/day) or to our study (mean = 512ug/day). This
Folate Intake vs. Prostate Cancer Risk
16
might due to the lack of food fortification in Europe. Moreover, Shannon’s study was based on a
much smaller sample size, the findings need to be confirmed with a bigger study.
Two meta-analyses published in 2014 have found inconsistent effects of dietary and circulating
folate levels on prostate cancer risk. The dietary folate meta-analysis comprising 11 studies
reported an OR of 0.97 (95% CI 0.89-1.06) [36]. Wang’s meta-analysis of 10 prospective studies
indicated a summary RR of 1.02 (95% CI 0.95-1.09) [37]. However, they both suggested a
positive association of serum folate levels with prostate cancer risk. The OR of the blood folate
meta-analysis by M. Tio is 1.43 (95% CI 1.06-1.93), and the RR of the Wang meta-analysis is
1.21 (95% CI 1.05-1.39). Dose-response meta-analysis indicated that every 5nM increase in
serum folate levels was associated with an increased risk of prostate cancer (RR = 1.04, 95%CI
1.0-1.07) [37]. Evidence from clinical trials indicates that serum folate levels generally correlate
with dietary folate intake. Increasing mean dietary folate intake results in a mean increase in
serum folate [38]. The disparity between the circulating folate and the dietary folate intake meta-
analyses may result from nonspecific dietary and serum folate levels validation [36]. In both
meta-analyses, dietary folate intake was measured by a one-time food frequency questionnaire,
which failed consider change in lifestyle factors (i.e. diet) over time. Direct verification of serum
and dietary folate level could be included in the future study to provide a more comprehensive
result.
Our major findings are also consistent with those of the more recent epidemiological
studies. A nested case-control design based on 6875 cases and 8104 controls from six cohort
studies found a small positive association of circulating folate with prostate cancer risk
(OR=1.13, 95% CI 1.02-1.26) [39]. This association was strengthened after adjusting for tumor
grade: men with higher serum folate levels were at a greater risk of high-grade disease
Folate Intake vs. Prostate Cancer Risk
17
(OR=2.30, 95% CI 1.28-4.12) [39]. No association was found for the low-grade disease. The
study involved mean serum folate concentrations ranged from 5.7 nmol/L to 16.9 nmol/L, which
is within the normal range proposed by WHO in 1968 [40]. Another Norwegian nested case-
control study observed that serum folate level was modestly associated with prostate cancer risk
(OR = 1.15, 95% CI 0.97- 1.37) [41]. More specifically, this association was among individuals
who are greater than 50 years old (OR = 1.40, 95% CI 1.07-1.84), whereas no association was
observed among those under 50 years, because prostate cancer rarely occurs among men under
50 [41]. The serum folate concentration varied from 8.65 to 23.40 nmol/L, which is higher than
that in Price study aforementioned. Results of these studies are consistent with our findings,
suggesting high folate as a risk factor in prostate cancer incidence.
A Swedish cohort study in 2019 proposed that high folate levels may protect against
prostate cancer and lower folate levels may increase risk of metastatic prostate cancer. 8.783 men
participated in the study were followed up for 13 years. Serum folate levels were categorized as
low (<5 nmol/L), normal (5-32 nmol/L) and high levels (>32nmol/L). Compare with the normal
level (5-32 nmol/L), a positive association of serum folate <5 nmol/L with metastatic prostate
cancer (HR=5.25, 95% CI 1.29-21.41), and an inverse association of folate >32 nmol/L with
high-risk prostate cancer risk (HR=0.12, 95% CI 0.02-0.90) were observed [42]. This indicates
that folate may act as both promoter and inhibitor in occurrence of prostate cancer. Furthermore,
an Australian study suggested a weak inverse U-shaped relationship between incidence of
prostate cancer and folate intake. According to the study, the hazard ratios associated with the
second, third, and fourth quintile, compared to the reference, are 1.02, 1.08, and 1.21,
respectively [43]. However, the hazard ratio was the same for the lowest and highest quintiles of
folate intake (215 and 444 ug/day, respectively). The dietary folate intake in the Australian study
Folate Intake vs. Prostate Cancer Risk
18
is much lower compared to that in other studies (quintiles: 215, 271, 315, 364, and 444 ug/day).
The highest quintile was similar to the lowest of our study. It could be that the intake in our study
is too high to pick up the protective effect of increasing folate.
The current study’s limitation includes frequency questionnaires used for dietary folate
intake; assessing may be subject to error. Categorization by population characteristics and folate
intake directly influence the result of the study on this subject. In the current analysis, we divided
the populations into four groups of total folate intake: < 438 ug/day, 438-696 ug/day, 697-
911ug/day, and > 911 ug/day. We further analyzed the ORs among different racial groups. Not
only Caucasians, African Americans were included to enrich the current study. Localized
/advanced disease was also analyzed separately. Compare to the previous epidemiologic studies
which mainly focus on European/ Caucasian populations, our study is a good reference for future
studies that interest in studying the association of high folate with prostate cancer risk among
African Americans.
Conclusion
In conclusion, this study found a significant positive association between dietary folate intake
and prostate cancer risk. Our findings contribute additional support to previous studies
suggesting that high folate intake may be a risk factor in prostate cancer occurrence.
Folate Intake vs. Prostate Cancer Risk
19
Tables and Figures
Table 1. Characteristics of Prostate Cancer Cases and Controls
Controls All Cases† Cases
N=1,096 N=1,914 N=1,857
Localized Advanced
N=717 N=1140
Categories N (%) N (%) N (%) N (%)
Race Blacks Whites Blacks Whites Blacks Whites Blacks Whites
N=240 N=856 N=527 N = 1,387 N=265 N=452 N = 235 N = 905
Age (years)
<=49 14 (6%) 40 (5%) 25 (5%) 34 (2%) 11 (4%) 7 (2%) 13 (6%) 27 (3%)
50-59 61 (25%) 248 (29%)
129 (24%) 313 (23%)
52 (20%) 63 (14%)
69 (29%) 247 (27%)
60-69 104 (43%) 337 (39%) 214 (41%) 553 (40%) 108 (41%) 160 (35%) 99 (42%) 382 (42%)
70-79 57 (24%) 202 (24%) 140 (27%) 413 (30%) 78 (29%) 181 (40%) 52 (22%) 223 (25%)
>=80 4 (2%) 29 (3%) 19 (4%) 74 (5%) 16 (6%) 41 (9%) 2 (<1%) 26 (3%)
mean (SD) 64 (8.9) 64 (9.1) 65 (8.8) 66 (8.7) 66 (8.8) 69 (8.5) 63 (8.5) 64 (8.4)
Education
High School or
less 98 (41%) 186 (22%)
238 (45%) 443 (32%)
116 (44%) 160 (35%)
109 (46%) 270 (30%)
College Degree/
College 92 (38%) 235 (27%)
183 (35%) 354 (26%)
104 (39%) 115 (25%)
71 (30%) 236 (26%)
Post Graduate 49 (20%) 432 (50%) 103 (20%) 572 (42%) 44 (17%) 175 (39%) 55 (23%) 396 (44%)
Unknown 1 (<1%) 3 (<1%) 3 (<1%) 6 (<1%) 1 (<1%) 2 (<1%) 0 (0%) 3 (<1%)
Socio-economic
Status
(census tract-
based)
1 = Low 48 (20%) 54 (6%) 165 (31%) 143 (10%) 92 (35%) 54 (12%) 64 (27%) 79 (9%)
2 68 (28%) 68 (8%)
127 (24%) 153 (11%)
68 (26%) 61 (14%)
51 (22%) 89 (10%)
3 56 (23%) 145 (17%) 117 (22%) 219 (16%) 55 (21%) 65 (14%) 56 (24%) 151 (17%)
4 45 (19%) 229 (27%)
72 (14%) 291 (21%)
30 (11%)
103
(23%)
41 (17%) 186 (21%)
5= High 23 (10%) 360 (42%)
44 (8%) 570 (41%)
20 (8%)
169
(37%)
23 (10%) 400 (44%)
Body Mass Index
(BMI)
<25 51 (21%) 235 (28%)
136 (26%) 360 (26%)
60 (23%)
137
(30%) 66 (28%)
220 (24%)
25.0 – 29.9 110 (46%) 387 (45%)
236 (45%) 695 (50%)
123 (47%)
232
(51%) 104 (44%)
451 (50%)
>=30 78 (33%) 232 (27%)
152 (29%) 323 (23%)
81 (31%)
82
(18%) 64 (27%)
234 (26%)
Folate Intake vs. Prostate Cancer Risk
20
Family History of
Prostate
Cancer
Yes 28 (12%) 111 (13%)
125 (24%) 253 (18%)
61 (23%)
89
(20%)
57 (24%) 163 (18%)
No 212 (12%) 745 (87%)
400 (76%) 1,123 (82%)
204 (77%)
363
(80%)
178 (75%) 742 (81%)
Unknown 0 (0%) 0 (0%) 2 (<1%) 0 (0%) 0 (0%) 0 (%) 0 (0%) 0 (0%)
Folate Intake Mean/SD Mean/SD Mean/SD Mean/SD
Total Folate
(µcg/d) 632 (343) 744 (374)
759 (446) 752 (362)
785 (453)
742
(343)
736 (449) 752 (369)
Dietary Folate
(µcg/d) 491 (240) 518 (243)
559 (274) 561 (255)
565 (276)
546
(235)
556 (275) 563 (261)
Supplement Fol
(µcg/d) 140 (210) 226 (265)
200 (349 ) 191 (252)
220 (366)
196
(243)
179 (337 ) 189 (256)
Multivitamin/Folate
400 µcg/d Folic
Acid N (%) N (%) N (%)
N (%)
Yes 72 (30%) 400 (47%) 186 (35%) 561 (40%) 100 (38%)
193
(43%)
75 (32%)
352 (39%)
No 168 (70% 456 (53%) 341 (65%) 826 (60%) 165 (62%)
259
(57%)
160 (68%)
553 (61%)
Table 1a. Characteristics of Alcohol for Prostate Cancer Cases and Controls
Alcohol
Consumption N (%) N (%) N (%)
N (%)
Non drinker
129
(54%) 319 (38%) 267 (51%) 640 (46%) 136 (51%) 228 (50%)
117 (50%)
401 (44%)
<=12.672 g/d
46
(19%) 258 (30%) 93 (18%) 300 (22%) 37 (14%) 90 (20%)
49 (21%)
207 (23%)
>12.672 –
31.776 g/d 21 ( 9%) 132 (15%) 42 ( 8%) 196 (14%) 23 ( 9%) 63 (14%)
18 ( 8%)
132 (15%)
> 31.776 g/d
44
(18%) 147 (17%) 125 (24%) 251 (18%) 69 (26%) 71 (16%)
51 (22%)
165 (18%)
Mean/SD Mean/SD Mean/SD Mean/SD Mean/SD Mean/SD Mean/SD Mean/SD
grams/day
(among drinkers) 22.6 (23.7) 19.9 (19.5)
30.0 (31.0)
22.1 (21.7) 33.1 (33.0) 22.9 (22.5)
27.8 (29.5)
21.9 (21.4)
†All Cases include 57 cases with undiagnosed prostate
cancer stage Rev 8-31-13
Folate Intake vs. Prostate Cancer Risk
21
TABLE 2. Dietary Folate Intake and Prostate Cancer Risk
All Ethnicities Controls All Cases vs. Controls Localized Cases vs. Controls Advanced Cases vs. Controls
N=1096 N=1857 N=717 N=1140
Dietary Folate † N (%) N (%)
OR (95%
CI) N (%) OR (95% CI) N (%) OR (95% CI)
<342 mg/day 274 (25%) 369 (20%) 1.0 (ref) 145 (20%) 1.00 (ref) 224 (20%) 1.00 (ref)
342 - 472
mg/day 274 (25%) 418 (23%)
1.14 (0.91,
1.43) 169 (24%) 1.23 (0.91, 1.66) 249 (22%) 1.10 (0.86, 1.42)
473-632 mg/day 274 (25%) 481 (26%)
1.33
(1.06,1.66) 171 (24%) 1.34 (0.99, 1.81) 310 (27%) 1.35 (1.06, 1.73)
> 632 mg/day 274 (25%) 589 (32%)
1.48
(1.19,1.85) 232 (32%) 1.58 (1.18, 2.12) 357 (32%) 1.46 (1.14, 1.87)
p for Trend p=0.001 p = 0.002 p= 0.001
African
Americans N=240 N=500 N=265 N=235
N (%) N (%)
OR (95%
CI) N (%) OR (95% CI) N (%) OR (95% CI)
<342 mg/day 64 (27%) 116 (23%) 1.0 (ref) 60 (23%) 1.00 (ref) 56 (24%) 1.00 (ref)
342 - 472
mg/day 68 (28%) 100 (20%)
0.80 (0.51,
1.25) 54 (20%) 0.83 (0.49, 1.42) 46 (20%) 0.76 (0.45, 1.29)
473-632 mg/day 51 (21%) 122 (24%)
1.29 (0.82,
2.04) 62 (23%) 1.30 (0.76, 2.22) 60 (25%) 1.27 (0.74, 2.16)
> 632 mg/day 57 (24%) 162 (32%)
1.53 (0.99,
2.37) 89 (34%) 1.65 (0.99, 2.74) 73 (31%) 1.40 (0.84, 2.34)
p for Trend p= 0.01 p = 0.02 p = 0.07
White
Americans N=856 N=1357 N=452 N=905
N (%) N (%)
OR (95%
CI) N (%) OR (95% CI N(%) OR (95% CI)
<342 mg/day 210 (24%) 253 (19%) 1.0 (ref) 85 (19%) 1.00 (ref) 168 (19%) 1.00 (ref)
342 - 472
mg/day 206 (24%) 318 (23%)
1.29 (0.99,
1.67) 115 (25%) 1.49 (1.03, 2.15) 203 (22%) 1.22 (0.92, 1.63)
432-632 mg/day 223 (26%) 359 (26%)
1.35 (1.04,
1.74) 109 (24%) 1.38 (0.95, 2.00) 250 (28%) 1.37 (1.32, 1.81)
> 632 mg/day 217 (25%) 427 (31%)
1.49 (1.15,
1.93) 143 (32%) 1.59 (1.10, 2.29) 284 (31%) 1.50 (1.32, 1.98)
p for Trend p= 0.004 p=0.03 p=0.004
Dietary Folate is folate from diet only
All Models adjusted for age, multivitamin use and family history of prostate cancer
Folate Intake vs. Prostate Cancer Risk
22
TABLE 3. Total Folate Intake and Prostate Cancer Risk
All Men Controls All Cases vs. Controls Localized Cases vs. Controls Advanced Cases vs. Controls
N=1096 N=1857 N=717 N=1140
Total Folate
† N (%) N (%) OR (95% CI) N (%) OR (95% CI) N (%) OR (95% CI)
<438
mcg/day 274 (25%) 385 (21%) 1.0 (ref) 151 (21%) 1.00 (ref) 234 (21%) 1.00 (ref)
438 - 696
mcg/day 274 (25%) 520 (28%) 1.46 (1.17, 1.82) 193 (27%) 1.46 (1.08, 1.97) 327 (29%) 1.49 (1.17, 1.90)
697-911
mcg/day 274 (25%) 438 (24%) 1.44 (1.11,1.86) 176 (25%) 1.45 (1.03, 2.05) 262 (23%) 1.47 (1.10, 1.96)
> 911
mcg/day 274 (25%) 514 (28%) 1.82 (1.37,2.43) 197 (27%) 1.77 (1.21, 2.58) 317 (28%) 1.91 (1.39, 2.61)
p for Trend p=0.001 p = 0.006 p= 0.001
African
Americans N=240 N=500 N=265 N=235
N (%) N (%) OR (95% CI) N (%) OR (95% CI) N (%) OR (95% CI)
<438
mcg/day 85 (35%) 120 (24%) 1.0 (ref) 58 (22%) 1.00 (ref) 62 (26%) 1.00 (ref)
438 - 696
mcg/day 61 (25%) 142 (28%) 1.59 (1.05, 2.43) 76 (29%) 1.76 (1.06, 2.91) 66 (28%) 1.44 (0.88, 2.37)
697-911
mcg/day 56 (23%) 101 (20%) 1.46 (0.88, 2.42) 57 (22%) 1.66 (0.92, 2.99) 44 (19%) 1.34 (0.73, 2.48)
> 911
mcg/day 38 (16%) 137 (27%) 3.02 (1.67, 5.45) 74 (28%) 3.11 (1.58, 6.10) 63 (27%) 2.87 (1.44, 5.70)
p for Trend p= 0.001 p = 0.002 p = 0.005
White
Americans N=856 N=1357 N=452 N=905
N (%) N (%) OR (95% CI) N (%) OR (95% CI N(%) OR (95% CI)
<438
mcg/day 189 (22%) 265 (20%) 1.0 (ref) 93 (21%) 1.00 (ref) 172 (19%) 1.00 (ref)
438 - 696
mcg/day 213 (25%) 378 (28%) 1.38 (1.06, 1.79) 117 (26%) 1.28 (0.88, 1.86) 261 (29%) 1.48 (1.11, 1.96)
697-911
mcg/day 218 (25%) 337 (25%) 1.38 (0.82, 1.88) 119 (26%) 1.30(0.85, 1.98) 218 (24%) 1.48 (1.06, 2.05)
> 911
mcg/day 236 (28%) 377 (28%) 1.56 (1.12, 2.18) 123 (27%) 1.36 (0.85, 2.16) 254 (28%) 1.73 (1.21, 2.48)
p for Trend p=0.02 p=0.24 p=0.005
†
Total Folate is dietary folate plus folate supplements
All Models adjusted for age, multivitamin use and first degree family history of prostate cancer
Folate Intake vs. Prostate Cancer Risk
23
TABLE 4. Alcohol Intake and Prostate Cancer Risk
All Men Controls All Cases vs. Controls Localized Cases vs. Controls Advanced Cases vs. Controls
N=1096 N=1857 N=717 N=1140
Current
Alcohol † N (%) N (%) OR (95% CI) N (%) OR (95% CI) N (%) OR (95% CI)
Non-
Drinker 0
g/d 448 (41%) 882 (48%) 1.38 (1.13, 1.68) 364 (51%) 1.45 (1.11, 1.90) 518 (45%) 1.36 (1.09, 1.69)
Moderate
<=12.672 g/d 304 (28%) 383 (21%) 1.0 (ref) 127 (18%) 1.0 (ref) 256 (22%) 1.0 (ref))
High
>12.672-
<=31.776 g/d 153 (14%) 236 (13%) 1.27 (0.98, 1.64) 86 (12%) 1.55 (1.08, 2.22) 150 (13%) 1.15 (0.86, 1.53)
Very High
> 31.776 g/d 191 (17%) 356 (19%) 1.39 (1.09, 1.76) 140 (14%) 1.59 (1.15, 2.20) 216 (19%) 1.29 (0.99, 1.67)
p for Trend p=0.002 p=0.02 p=0.005
Trend among
drinkers
African
Americans N=240 N=500 N=265 N=235
N (%) N (%) OR (95% CI) N (%) OR (95% CI) N (%) OR (95% CI)
Non-Drinker 129 (54%) 253 (51%) 0.95 (0.62, 1.46) 136 (51%) 1.09 (0.65, 1.85) 117 (50%) 0.85 (0.52, 1.38)
<=12.672 g/d 46 (19%) 86 (17%) 1.0 (ref) 37 (14%) 1.0 (ref) 49 (21%) 1.0 (ref)
>12.672-
<=31.776 21 ( 9%) 41 ( 8%) 1.10 (0.57, 2.11) 23 ( 9%) 1.55 (0.71, 3.37) 18 ( 8%) 0.76 (0.35, 1.65)
> 31.776 g/d 44 (18%) 120 (24%) 1.38 (0.83, 2.30) 69 (26%) 1.91 (1.04, 3.50) 51 (22%) 0.97 (0.54, 1.74)
p for Trend p=0.71 p=0.89 p=0.59
White
Americans N=856 N=1357 N=452 N=905
N (%) N (%) OR (95% CI) N (%) OR (95% CI N(%) OR (95% CI)
Non-Drinker 319 (37%) 629 (46%) 1.55 (1.23, 1.94) 228 (50%) 1.62 (1.18, 2.23) 401 (44%) 1.54 (1.20, 1.96)
<=12.672 g/d 258 (30%) 297 (22%) 1.0 (ref)) 90 (20%) 1.0 (ref)) 207 (23%) 1.0 (ref)
>12.672-
<=31.776 132 (15%) 195 (14%) 1.31 (0.99, 1.74) 63 (14%) 1.51 (1.01, 2.27) 132 (15%) 1.24 (0.91, 1.69)
> 31.776 g/d 147 (17%) 236 (17%) 1.35 (1.03, 1.77) 71 (16%) 1.35 (0.91, 2.01) 165 (18%) 1.35 (1.00, 1.81)
p for Trend p=0.01 p=0.006 p=0.001
†
Current Alcohol is beer, wine and hard liquor grams per day
All Models adjusted for age, multivitamin use and first degree family history of prostate cancer
Folate Intake vs. Prostate Cancer Risk
24
Figure 1. Age-adjusted prostate cancer incidence and mortality (1975-2007) as measured in the
National Cancer Institute Surveillance Epidemiology and End Results program [7].
Figure 2. Age-specific incidence rates for prostate cancer, 2003-2007 [9].
Folate Intake vs. Prostate Cancer Risk
25
Conflict of Interest
The authors declare to have no conflict of interest.
Acknowledgements
I am sincerely grateful to Dr. Sue A. Ingles for guiding me through the data analysis and writing
up of this thesis. I am also thankful to my committee members Dr. Meredith Franklin and Dr.
Mariana for their support and insightful comments.
Folate Intake vs. Prostate Cancer Risk
26
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Creator
Zhang, XinYu
(author)
Core Title
Dietary and supplementary folate intake and prostate cancer risk
School
Keck School of Medicine
Degree
Master of Science
Degree Program
Molecular Epidemiology
Publication Date
02/25/2020
Defense Date
02/25/2020
Publisher
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
folate,folic acid,OAI-PMH Harvest,prostate cancer,Race
Language
English
Contributor
Electronically uploaded by the author
(provenance)
Advisor
Franklin, Meredith (
committee member
), Ingles, Sue (
committee member
), Stern, Mariana (
committee member
)
Creator Email
es6299@gmail.com
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-c89-274755
Unique identifier
UC11673875
Identifier
etd-ZhangXinYu-8210.pdf (filename),usctheses-c89-274755 (legacy record id)
Legacy Identifier
etd-ZhangXinYu-8210.pdf
Dmrecord
274755
Document Type
Thesis
Rights
Zhang, XinYu
Type
texts
Source
University of Southern California
(contributing entity),
University of Southern California Dissertations and Theses
(collection)
Access Conditions
The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...
Repository Name
University of Southern California Digital Library
Repository Location
USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA
Tags
folate
folic acid
prostate cancer