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Vol. 1 , I 19- 124.

/anuarv/1ehruarv 1992 Cancer Epidemiology, Biomarkers & Prevention 1 19

Folate, Vitamin C, and Cervical lntraepithelial Neoplasia1

Juliet VanEenwyk,2 Faith G. Davis, and Neville Colman recommendations, and both of these types of foods are
Department of Epidemiology and Biostatistics, School of Public Health,
good sources of folates.
University of Illinois at Chicago, Chicago, Illinois 6061 2 [1. V., F. G. D.];
and VA Medical Center, Bronx, New York 10468, and Center for Clini-
cal Laboratories, Mount Sinai Medical Center, New York, New York
Introduction
10029 [N. C.] Folic acid, a B-group vitamin, is necessary for normal cell
replication, and cells grown in folate-deficient media
manifest chromosomal abnormalities which correspond
Abstract to those found in many types oftumor cells (1). In relation
A case-control study was designed to assess the to cervical cancer, it has been noted that folate deficiency
relationship between cervical intraepithelial neoplasia can lead to cervical cellular changes which resemble
(CIN) and folate in serum, red blood cells, and diet. neoplastic change (2) and that preneoplastic cervical
The association between CIN and dietary vitamin C cellular changes among users of oral contraceptives me-
gness with folate supplementation (3). Three case-control
was also investigated. Cases were selected from women
studies of folate consumption and cervical cancer (4-6)
with biopsy-confirmed CIN. Controls were age-,
have found little evidence of an association between
race-, and clinic-matched women with normal cervical
folate intake and disease.
(Pap) smears. Study participants completed self-
This investigation assesses the relationship between
administered food frequency (n = 100 matched pairs)
folic acid and CIN.3 The premalignant condition was
and health (n = 102 matched pairs) questionnaires.
chosen to attenuate physiological changes which may
Fasting venous blood samples were collected for serum
ensue from rather than foreshadow disease. It was hy-
(n = 98 matched pairs) and red cell (n 68 matched
pothesized that higher levels of serum and red cell folate
pairs) folate assays. Conditional logistic regression
and higher dietary intake of folate would be associated
models were used to estimate crude odds ratios and
with a reduction in disease. Because folates and vitamin
odds ratios adjusted for smoking, income, number of
C are found in many of the same foods and because
sexual partners, frequency of cervical smear, use of
vitamin C protects folates from oxidative cleavage, die-
spermicidal contraceptive agents, history of genital
tary intake of vitamin C was also assessed.
warts, and Quetelet index. Dietary intake variables
were adjusted for total energy intake prior to logistic
regression. A protective effect of red cell folate was Materials and Methods
evident with adjusted odds ratios (95% confidence Details of case and control selection, serum and dietary
intervals) of 0.1 (0.0-0.4), 0.6 (0.2-2.0), and 0.5 (0.2- measurement procedures, measurement of confounding
1.9) for those in quartiles 4 (highest), 3, and 2 variables, and statistical analysis have been previously
compared to quartile 1 (lowest). Supporting evidence documented (7, 8). These topics are reviewed below.
for the protective effect of folate was provided by Case and Control Selection. Participants were recruited
inverse associations between CIN and folate in both from clinics at Cook County Hospital and University of
serum and diet. An inverse association was also found Illinois Hospital between April 1987 and June 1 989. Cases
between CIN and dietary vitamin C with adjusted odds (n = 102) were selected from women aged 18 to 49 years
ratios (95% confidence intervals) of 0.2 (0.0-0.7), 0.6 with biopsy-confirmed CIN I, II, or Ill. Age- and race-
(0.2-1.6), and 0.6 (0.2-1.8) for those in quartiles 4, 3, matched controls were selected from women who at-
and 2, respectively, compared to quartile 1. These tended the same clinics as the cases and whose Pap
findings support dietary recommendations, such as smears showed no abnormality of a severity greaten than
those of the American Cancer Society, the National or equal to benign atypia. Women who had been preg-
Cancer Institute, and the U.S. Dietary Guidelines, nant or lactating within the past year were excluded from
which allow for adequate intake of folate and vitamin the study because of the potential for folate depletion
C, both of which are found in good quantity in fruits under these circumstances. In this population, pregnant
and vegetables. Increased consumption of legumes and and postpartum women may also be at increased risk for
whole grains is also in accord with current dietary a diagnosis of CIN, since pregnancy brings women into
the clinic where cervical smears are obtained as part of
prenatal care. Women with epilepsy on sickle cell anemia
were also excluded, since these conditions are associated
with low blood folate and with bringing women into the
Re eived 4/t 6/91.
1 Funded in part by a grant froni the American Canc er Society, Illinois
Division, and I)y the State Cancer Plan of the Illinois Cancer Council.
2 To whom requests for reprints should be addressed, at Illinois Depart-
ment of Public Health, Division of Health Statistics and Policy Develop- ‘ The abbreviations used are: CIN, cervical intraepithelial neoplasia; OR,.
ment, 1 01) West RailoIph, Suite 6-600, Chicago, IL 60601. ( rude odds ratio; OR,,, adjuste(l odds ratios; CI, ci)ntidenc(’ interval.
120 Folate, Vitamin C, and Cervical lnlraepithelial Neoplasia

medical system where they are likely to have cervical Measurement of Confounders. RIrti( pants (ompleted a
smears. Women with diabetes were exduded due to the self-administered questionnaire whi h asked aI)out back-
requirenient for ci 1 0-h f,ist. ground, health and pregnin y history, smoking, and sex-
All eligible wonien were requested to participate in ual behavior. Inforniation mroni this questionnaire was
the study. ofeligible
166 cases, 102 were enrolled, used to assess independent contributors to risk of CIN in
yielding a panticipation rate of approximately 61%. To this sample and to control for confounders of the disease-
enroll an equal number of controls, 195 eligible women exposure relationship. Confounders were defined as van-
were approached, giving a participation rate of 52%. ables which have been reported as risk factors in previous
Measurement of Exposure. The food frequency portion studies and variables whose inclusion led to a change of
of the Health Habits and History Questionnaire of the more than 20% in the adjusted odds ratio for the nu-
National Cancer Institute, Division of Cancer Prevention trients of interest.
and Control, version 2. 1 , was used to assess dietary intake Statistical Analysis. OR, and OR,, and 95% CIs were
of folate and vitamin C (9). Participants were asked to estimated using the MCSTRAT program (15), which per-
complete this questionnaire prior to the clinic visit. The forms an iterative conditional maximum-likelihood fit of
conversion of foods on the food frequency questionnaire a logistic regression model. Quartiles for the hematolog-
to nutrients was accomplished via the microcomputer cal measures and calorie-adjusted nutrient intake were
software version 2.2, August 1989, provided by the Na- defined from the distribution of the controls. Those in
tional Cancer Institute, Division of Cancer Prevention the lowest quartile (quartile 1) served as the comparison
and Control (9). The measure of dietary vitamin C ob- group. Adjusted models included independent contrib-
tamed from this procedure includes vitamin C from both utors to risk in this sample, as well as potential confoun-
food and vitamin supplements. There is no provision for dens of the disease-exposure relationship. Tests of trend
including supplemental folates in the dietary folate mea- were achieved by entering quartiles of a given nutrient
sure. Adjustment for total energy intake using the regres- into the logistic model as different values of a single
sion procedure of Willett and Stampfer (10) was used to ordinal variable.
control for over- and underreporting of dietary intake. Pearson product-moment correlation coefficients for
Two participants failed to adequately complete the food the correlation between the natural log of the hemato-
frequency questionnaire, resulting in 100 matched pairs logical measures and calorie-adjusted nutrient and food
available for analysis. intake measures were generated using SAS procedures.
Fasting venous blood samples were collected for Confounding due to intenassay variability was as-
radioassay of serum and red cell folate. Red cell hemo- sessed by including a dichotomous variable in the logistic
lysates were prepared on site by the method of Gutcho models. This variable was (Treated by calculating the
(11). Serum was also aliquoted on site, and all blood mean value for the quality control samples and charact-
samples were stored at -70#{176}C until shipment to the enizing assay groups according to whethen their quality
laboratory on dry ice every 6 to 10 weeks. Assays for control samples were above on below the mean.
serum and red cell folate were conducted by modiuica-
tion of the methods of Waxman et a!. (12) and Longo
and Herbert (13), respectively, using Becton Dickinson Results
Simultrac kits as reagents (14). For the folate assays, the The distribution of cases and controls on demographic
intraassay coefficient of variation was 1 .4-4.6%, and the and nondietary risk factors associated with CIN have
intenassay coefficient of variation was 3.8-8.2% for con- been presented (7, 8). Table 1 shows the OR,,s and 95%
trol samples at the limits of sensitivity of the assay. Low CIs for the nonnutnient variables included in the multi-
levels were associated with the highest coefficients of vanial)le conditional logistic regression models. Increased
variation. All laboratory personnel were unaware of case OR,,s were associated with current smoking status, more
or control status of the blood samples. than t’te year between cervical smears, any use of con-
Failure to withdraw blood from four women resulted traceptive spermicidal foams or gels, and a self-reported
in serum measures for 98 matched pains. Inadequate on- history of genital warts. An inverse association was ob-
site preparation of the red cell hemolysates resulted in served between OddS of disease and monthly income
unreliable data from the first 28 cases and 14 controls, bracket in $400 increments to $2000. Quartile of Que-
leading to the exclusion of 28 matched pairs from the telet index (kg/m2) and number of sexual partners were
final red cell folate analyses. Failure to collect a lavender- not independent contributors to risk after adjustment for
top tube from one woman and missing red cell data from the other variables. However, these variables were me-
one woman resulted in the exclusion of an additional tamed in the final model, because they were considered
two pairs, leaving 68 matched observations for the red to be potential confoundens of the disease-exposure
cell folate analyses. relationship. Use of oral contraceptives and parity have
Because more cases were enrolled at the beginning been reported to relate to both folate status and risk for
of the study and more controls enrolled toward the end CIN. However, since these factors were not independent
of the study period, there was a disparity in the allocation contributors to risk in this sample and their inclusion in
of case and control blood samples to the laboratory assay the logistic models did not alter the adjusted estimates,
groups. To enable control for confounding due to be- they were not included in the final models. Excessive
tween-nun variability, two quality control samples of alcohol consumption is associated with lowered blood
pooled blood were included in 1 1 of the 16 shipments. folates. Controlling for this variable (lid not alter the
These 1 1 batches accounted for 88% of the serum and findings and it is not included in the adjusted models.
100% of red cell samples included in the logistic models. Table 2 shows the quartiles of serum and red (Tell
Laboratory personnel were unaware of the inclusion of folate. The number of cases and controls in each quartile
these samples. and the percentage with deficiencies are also presented.
Cancer Epidemiology, Biomarkers & Prevention 121

are apparent in both the crude and adjusted models. The


Table 1 Adjusted odds ratios and 95% CIs for nonnutrient variables
included in all adjusted logistic regression models
pattern of decreasing ORs with increasing quartile of red
cell folate is also evident in both models.
. . . 95% confidence
Nonnutrient variable Odds ratio Table 4 presents the OR,s, ORaS, and 95% CIs for
interva
dietary intake of folate and vitamin C. Decreasing ORs
Current smoker 2.6 1.2-5.5 with increasing quartile of dietary folate and vitamin C
(yes versus no)
are evident in both the crude and adjusted analyses. For
Income bracket 0.5 0.3-0.8 dietary vitamin C, a statistically significant decrease in
(ordinal, monthly income in the odds ofClN is evident in both the crude and adjusted
$400 increments to $2000)
models for those in the highest quartile of intake relative
Frequency of cervical smear 3.3 1 .3-8.2 to those in the lowest quartile.
(less often than annual versus Associations among the vitamin assays and dietary
annual) measures are shown in Table 5. Among the vitamin
assays, the strongest correlation is between serum and
Use of contraceptive spermici- 2.8 1.3-6.3
dal agents red cell folate. Intakes of dietary vitamin C and dietary
(ever used versus never used) folate are highly correlated with each other, and both of
these measures seem to be derived primarily from the
Self-reported history of genital 3.4 1.1 -10.8
intake of total fruit and citrus fruit. In contrast, the he-
warts
(yes versus no) matological folate measures are modestly correlated with
vegetable intake.
Quetelet index (kg/m2) 0.7 0.5-1.0
(ordinal by quartile)

Numberofsexual partners 1.0 0.6-1.7 Discussion


(log,-transformed) Issues of Bias. To assess possible bias due to differential
Odds ratio for each variable is adjusted for all of the other variables participation rates of cases and controls, information on
shown. age, ethnic origin, zip code, and type of payment for
medical services was collected for all women asked to
participate in the study. Response rates were lower (P <
0.05) for controls than for cases among women age 18
For comparison, the percentage of women from the to 24 years and among women who paid their own
Second National Health and Nutrition Evaluation Survey medical expenses. Since cases and controls were
in the deficiency ranges for folate are also given (16). The matched on age, the effect of this discordance cannot
women in this sample appear to manifest poorer folate be estimated. It is not known in what direction the deficit
status than anticipated from the findings of the Second of control women who paid for their own medical ex-
National Health and Nutrition Evaluation Survey. penses may have influenced the ORs, since an under-
The OR,s, ORa5, and 95% CIs by quartile of serum representation in that group could result in an overrep-
and red cell folate are presented in Table 3. A decrease resentation in both higher (privately insured) and lower
in odds of CIN is observed for those in the highest (public aid) socioeconomic groups. Adjustment for the
quartile of serum folate relative to those in the lowest nonnutrient factors in the logistic models should mitigate
quartile. However, while the ORa is smaller than the ORE, bias resulting from nonrandom distribution of cases and
the statistical significance of the decreased OR is atten- controls on socioeconomic factors resulting from differ-
uated in the adjusted model. The pattern of decreasing ential response rates.
ORs with increasing quartile of serum folate is also atten- Cases and controls were comparable on the match-
uated after adjustment for nonnutrient factors. The de- ing variables, as well as on educational level, employment
creased odds of disease for those in the highest quartile status, marital status, history of hospitalizations, oral con-
of red cell folate relative to those in the lowest quartile traceptive use, and age at first intercourse. After control-

Table 2 Qua rtiles of serum and red cell folate

Quartile Deficienc y levela


Nutrient
1 2 3 4 Frank Borderline

Serum folate level )ng/ml) 1.3-3.4 3.5-4.4 4.5-6.3 6.4-21.2 <3.0 (15%io) <5.0(41%”)
Controls’ 26 22 25 25 14.3% 61.2%
Cases#{176} 36 23 25 14 23.5% 67.4%

Red cell folate level )ng/ml) 57-126 127-149 150-190 191-325 <140 (13%’) <160)20%’)
Controls’ 17 17 17 17 41.2% 60.3%
Cases’ 26 18 18 6 51.5% 73.5%
a Deficiency levels are those defined by the laboratory.
b The percentages of women from the Second National Health and Nutrition Evaluation Survey who were below deficiency levels (16) are in parentheses.
C Women aged 20-44 years.
d Estimated for women aged 20-64 years (Ref. 16, p. 37).
e The number of cases and controls in each quartile and the percentage below the specified deficiency level are presented.
I Estimated for women aged 20-64 years (Ref. 16, p. 38).
122 Folate, Vitamin C, and Cervical lntraepithelial Neoplasia

Table I Odds ratios, 95% CIs, and tests ot trend for serum and red cell
folate T,il)le 4 Odds ratios, 95% CIs, ,uicl lists of trend for dietary intake of
Icilate .uil vit.iniin C
Quartile Test i)f trend
Nutrient Qu artile Test of trend
1 (low) 2 3 4 (high) P N utrient
1 low) 2 3 4 high) P
Serum folate
OR, 1.0 0.9 0.8 0.4 0.04 Dietary folate
95%CI 0.4-2.0 0.3-1.7 0.2-0.9 OR. 1 .0 1. 1 1)6 0.5 0.03
95% CI 0.5-2.3 0)3 1 .5 01.2- 1.1
()R, 1.0) 0.9 1.1 0.3 0.15
95%CI 0.3-2.6 0.4-3.2 0.1-1.1 OR, 1.0 0.8 0.7 0.4 0.07
95%CI 0.3-1.9 01.2-2.0) 0.1-1.1
Red cell folate
OR, 1.0 0.7 0.8 0.2 0.03 Dietary vitamin C
95%CI 0)3-1.7 0.3-1.9 0.1-0.7 OR, 1 .0) 0.7 0.6 0.2 0.00”
95% CI 0.3 1 .6 0.3 1 .3 O).1 0.5
OR, 1.0 0.5 0.6 0.1 0.01

.,Adtusted
qu(’ncy
95%

of cervical
CI

for current
sniear
smoking
(annual
status,
0.2- 1 .9

monthly
versus less often),
0.2-2.0

personal
00b_04

income.
any use ot sperniicidal
Ire-
.,Adjusted
OR;’
95% Cl

br calories prior
1 .0

to Iogistb
0.2
(1.6
-1 .8
regression
0.2

using
01.6
1 .6

Iine,ir
0.0)’
0.2

regression
- 0.7
0.03

contraceptive agents, sell-reported history of genital warts, quartile of procedures ) 1 0). The logistic moh’I inc luck’s acljustnient for current
Quetelet index, and natural log of number ot sexual partners. smoking status, monthly personal incoilic’, frequency of cervical smear
b <0.05. annual versus less (ifteii), any use ut sI)ernliciclal cc)ntraceptive agents.
self-reported history of genital s’arts, qu,irtile of Quetelet index, and
natural log of number of sexual p.irtic’rs.
,‘ <0.005.

( <0.05.

ling for smoking and income, cases and controls were


also comparable on number of sexual partners and parity.
The similarity of the cases and controls on these factors
and the selection of all participants from clinics serving lower quartiles of serum and
red cell folate are a result
primarily low-income individuals suggests that the sam- of folate sequestration dysplastic
by the cells.
pIe was selected from a high-risk population. The ability Similarly, while anorexia is often a symptom of those
to generalize the study findings to other populations may with cancer, it has not been documented as a feature of
be limited. CIN. It is unlikely that cases exhibited either poorer folate
With control for assay group, the statistically signifi- status or lower intake of vitamin C as the result of dietary
cant decrease in the OR, for those in the highest quartile intake depression in sick patients with poor appetites.
of serum folates was attenuated. This adjustment did not Additionally, because participants were asked to record
substantively modify the dose gradient results or the their average frequency of consumption over the last 5
findings for ned cell folates. Because of the unequal years, the potential for reported dietary intake reflecting
distribution of cases and controls in the assay groups, a changes subsequent to the onset of disease seems un-
dichotomous variable was used to control for interassay likely. Nonetheless, given the case-control design of this
variability. While this procedure crudely adjusts for assay study, the possibility that the lower levels of serum folate,
group, residual confounding may be present and the
red cell folate, and dietary vitamin C for the cases resulted
possibility of bias cannot be entirely excluded.
from the disease process cannot be ruled out.
Bias in the findings for the red cell folate may have
Levels of serum retinyl palmitate indicated high lev-
resulted from the exclusion of the 34 pairs from the
els of compliance with the fasting requirement among
analyses. On the dietary and serum folate measures, the
both cases and controls. For the 98 pairs included in the
controls who were excluded were similar to those in-
serum folate assays, one control and two cases had levels
cluded. However, the distribution of excluded cases by
of retinyl palmitate indicative of nonfasting. Therefore,
quartile of both dietary and serum folate differed from
bias due to differential compliance among cases and
that of cases included in the red cell folate analyses, with
controls regarding fasting is unlikely.
more than the expected number of cases in the highest
quartiles and fewer than expected in the lowest quartiles. Hematological and Dietary Factors. Red cell folate shows
To the extent that the serum and dietary folate measures a strong, statistically significant inverse association with

reflect red cell folate, the findings for red cell folates may CIN. Additionally, the estimates of effect for both serum
be overstated. and dietary folate offer supporting evidence for the role
Folate deficiency has been reported in patients with of inadequate folate nutritional status in the development
a diversity of malignancies (1 7). The question of whether of CIN.
this is a cause or a consequence of cancer remains Some of the difference in the findings for the folate
unanswered. However, it has been suggested that be- variables may be attributable to characteristics of the
cause tumors exhibit rapid cell multiplication, those with measurements. Greater variability is expected in the
cancer may be at increased risk for folate deficiency (18). serum compared to the red cell folate measure, because
Although CIN may represent an early stage of the neo- serum folate indicates short-term changes in folate bal-
plastic process, the length of time required for the pro- ance, while red cell folate reflects changes over several
gression from CIN I and II to cancer (19) argues against months (16). For folates, there is a greater potential for
rapid cell multiplication at this stage of the disease. Since misclassification from dietary intake measures compared
79% of the cases were diagnosed with CIN I or II, it to laboratory data because of inaccuracies in reporting
seems unlikely that the elevated ORs for those in the and converting food to nutrients, the destruction of fo-
Cancer Epidemiology, Biomarkers & Prevention 123

Table 5 Correlationa among vitamin assays” and dietary intake


misincorporated uracil, but which are futile in the low-
measures thymine environment of folate deficiency (22).
Folate assays Dietar y intake
That folate may play an antitumonigenic role by
preventing preneoplastic epithelial cellular changes is
Red cell Serum Folate Vitamin C
suggested in both the Butterworth et a!. study (3) and the
Folate assays preliminary results of a chemopreventive trial with men
Red cell folate 0.61 d
at high risk of lung cancer (23). The findings from the
Serum folate
latter study indicate regression of bronchial squamous
Nutrient intake metaplasia with folic acid and vitamin B12 supplementa-
Folate 027d 0.22” 0.55” tion. Folate supplementation has also been reported to
Vitamin C 0.14 0.22” be protective against the development of colon cancer
and dysplasia in patients with chronic ulcerative colitis
Food intake
Total fruit 0.00 0.02 0.60” 0.66” (24).
Citrus fruit -0.01 0.03 062d 065d
Evidence for an inverse association between dietary
Total vegetables 0.21’ 0.14’ 0.14’ 0.12 vitamin C and risk of CIN is consistent with the findings
025d
Vegetables excluding 0.19’ 0.19’ 0.12
from a similar investigation (25). Of an additional three
rice and potatoes
studies, one found a statistically significant inverse asso-
a Pearson product-moment correlations.
b Hematological measures have been Iog,-transformed. ciation between dietary vitamin C and invasive cervical
C Dietary intake measures were adjusted for total energy intake using cancer (5); one found no association between vitamin C
linear regression methodology (10) prior to correlation procedure. intake and invasive cervical cancer (6); and one was
d p < 0.005.
suggestive of an increase in risk of cervical carcinoma in
‘ P 0.05.
situ with decreased consumption of vitamin C (4). The
evidence of an inverse association between CIN and
vitamin C is also consistent with the finding of lower
levels of serum vitamin C in women with CIN than in
lates during food preparation, and differential absorption age- and clinic-matched controls (26). This latter study,
of folates from diverse food sources. however, failed to control for several possible confoun-
The findings of this study are consistent with those dens, including smoking. The suggestions of an associa-
of Butterworth et a!. (3), who noted higher levels of both tion, combined with the inconsistencies of previous in-
serum and red cell folate in women with cervical dys- vestigations, indicate the need for further research on
plasia versus hospital employee controls. Due to the lack the relationship ofvitamin C to cervical dysplasia. Vitamin
of statistically significant results possibly related to the C functions as an antioxidant and enhances cellular im-
relatively small sample size of 34 cases and 40 controls, munity, both of which may play a role in cancer preven-
Butterworth’s findings remain suggestive. Brock et a!. (4) tion (27).
noted an inverse association between folate intake and Due t the relatively high correlations between the
cervical carcinoma in situ on crude analysis. This protec- folate and vitamin C measures, it is not possible to
tive effect disappeared in the adjusted model, which delineate the relative importance of these nutrients as
included nonnutnient risk factors, as well as dietary cano- possible preventive agents in the etiology of CIN. When
tene, retinol, vitamin C, and energy. However, the valid- quartiles of dietary vitamin C and red cell folate are
ity of simultaneous addition of dietary folate and vitamin entered simultaneously into a logistic model with the
C into a logistic regression model must be questioned, nonnutnient variables, there continues to be a statistically
given the generally high correlation between the two significant protective effect evident for those in the high-
measures (Table 5 and Ref. 20). Of two studies on in- est quartiles of both measures, and a dose gradient is
vasive cervical cancer and folate intake, one (5) showed evident. The decreases in odds of CIN for those in the
an inverse association between dietary folate and disease highest quartiles of red cell folate and dietary vitamin C
in an analysis which did not control for other risk factors, are also evident controlling for quartile of serum a-
and the second (6) revealed a protective effect for folate carotene, /3-carotene, lycopene, and lutein.
among heavy smokers. These two studies focused on That dietary intake of folate is highly correlated with
white women whose socioeconomic status and risk of fruits, while the serum and red cell folate measures are
disease are not described. Therefore, these samples may more strongly correlated with vegetables, may indicate
have differed in a significant fashion from that of the an inadequacy in the dietary folate measure.
present study, which included primarily low-income, Although it was not part of the study design, serum
nonwhite women from a population at high risk of vitamin B2 assays were conducted simultaneously with
disease. the folate assays. A preliminary review of these analyses
Two of the many mechanisms suggested for folate suggests that vitamin B12 may play a role in a subset of
deficiency causing altered DNA and subsequent carci- women with cervical dysplasia. However, controlling for
nogenesis are based on the observed misincorporation quartile ofvitamin B12 did not substantively alter the odds
of uracil into DNA in place of thymine, the de novo ratios associated with serum and red cell folate.
synthesis of which is folate dependent. One theory sug- The findings from this study support dietary recom-
gests that this leads to methyl-poor regions in the DNA mendations, such as those of the American Cancer So-
strand, which preclude the coiling necessary for the ciety, the National Cancer Institute, and the U.S. Dietary
proper configuration of the DNA molecule (21). The Guidelines, which allow for adequate intake of folate and
second hypothesis proposes that efficient DNA repair vitamin C, both of which are found in good quantity in
mechanisms cause chromosome breakage through me- fruit and vegetables. Increased consumption of legumes
peated excision-repair cycles, which aim at removing the and whole grains is also in accord with current dietary
124 Folate, Vitamin C, and Cervical lntraepithelial Neoplasia

recommendations, and both of these types of foods are 1 1. Longo. D. L., and Herbert, V. Raclioassav for s(’rum and red ( elI
folate. I. Lab. Clin. Med., 87: 138-151, 1976.
good sources of folates.
14. laiob, F., CoIiian, N., and HerI’rt, V. Evaluation of siniult,ineous
radioassav for two vit,imins: folate and vitaiiin B- 1 2. Am. I. Clin. Nutr.,
Acknowledgments 30:616, 1977.
1 5. Naessans, I. M., Offord, K. P., S ott, W. F., md l)aoocl, S. I . The
The authors wish Ic) acknowledge the support c)f Stanley Gall at the
MCSTRAT procedure. In: R. P. Hastings ed.), SUGI Supplemental Library
University of Illinois Hospital, Michael Makii at Cook County Hospital.
User’s Guide, Version 5 Ed., ip. 307- 328. Can,’, NC: SAS Institute, In.,
Eileen McAleer at the Bronx V.A. Hospital, and Ray Murphy at the Illinois
1986.
Department of Public Health. They have appreciated the advice and
(oiiiments of Phyllis Bowen, lack GOIdE)erg, William Haenszel, Frederick 16. Sc’nti, F. R., .10(1 t’ilch, S. lvi. Assessnient (ii tl’ Folate Nutritional
Kviz, and Victoria Persky at the University of Illinois at Chicago. Status of the U.S. Population Based on Data Collected in the Sec ond
National Health and Nutrition Examination Survey 1976- 1 98L). Bethesda,
MD: Life Sciences Research Offices, FASEB, 1984.
References 1 7. Clarnon, C. H., Feld, R., Evans, W. K., Weiner, R. S., Kramer, B. S.,
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