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Health Research Center, Department of Family and Preventive Medicine [M. L. S., K. C., S. E., K-N. M.], and Department of Surgical Pathology [W. S. S.], University of Utah, Salt Lake City, Utah 84108 ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024 [J. D. P.]; University of Minnesota, School of Public Health, Minneapolis, Minnesota 55454-1015 [K. A.]; and Division of Research, Kaiser Permanente Medical Care Program, Oakland, California 94611 [D. S.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Using data from a population-based case-control study of 1836 cases with MSI data and 2410 population-based controls, we evaluated sex, reproductive factors, and hormone exposure in relation to the presence or absence of MSI in tumors. MSI was evaluated by a panel of 10 tetranucleotide repeats, the noncoding mononucleotide repeat BAT-26, and the coding mononucleotide repeat in transforming growth factor ß receptor type II (TGFßRII). Exposure data on reproduction, hormone use, obesity, and physical activity were obtained from an interviewer-administered questionnaire.
Women were less likely then men to have MSI+ tumors at a young age and more likely to have unstable tumors at an older age; we observed a significant interaction (P < 0.01) between age, sex, and MSI. Evaluation of reproductive factors showed that women who had ever been pregnant had half the risk of MSI+ tumors compared with women who had never been pregnant. In complementary fashion, total ovulatory months were associated with an increased risk of MSI+ tumors [odds ratio (OR), 2.1; 95% confidence interval (CI), 1.1–4.0 comparing MSI+ versus MSI- tumors]. Age at first and last pregnancy did not influence the association. The observed associations were strongest among women <60 years of age at the time of diagnosis. Having used oral contraceptives was associated with a lower risk of MSI+ tumors (OR, 0.7; 95% CI, 0.4–1.2); recent users of HRT were at a reduced risk of MSI+ tumors (OR, 0.8; 95% CI, 0.5–1.4); and women who were former HRT users were at an increased risk of MSI+ tumors (OR, 1.8; 95% CI, 1.1–3.0). Obesity and lack of physical activity were associated with an elevated risk of both MSI+ (OR, 1.7; 95% CI, 0.7–3.3) and MSI- (OR, 2.2; 95% CI, 1.7–3.) tumors in men, but only with MSI- (OR, 1.5; 95% CI, 1.1–2.2) tumors in women.
The excess of MSI+ tumors in women is explained by the excess of MSI+ tumors at older ages. Our data suggest that estrogen exposure in women protects against MSI, whereas the lack of estrogen in older women increases risk of instability. HRT in these older women may, again, reduce the risk of unstable tumors. A model for the way in which estrogens (endogenous, exogenous, and obesity-associated) modify the risk of MSI+ tumors is proposed.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Controls, in addition to the eligibility criteria for cases, had no history of colorectal cancer. Controls were selected from eligibility lists for Kaiser Permanente Medical Care Program of Northern California; driver’s license lists for Minnesota; and random-digit dialing, driver’s license lists, or Health Care Finance Administration lists for Utah. These methods have been described in detail (9) . Of all controls selected, 63.7% participated.
Questionnaire Data.
Data were collected by trained and certified interviewers using laptop
computers (10)
. The referent period for the study was the
calendar year, approximately 2 years before the date of diagnosis.
Using this referent period, information was collected on dietary intake
using a detailed diet history questionnaire (11)
.
Demographic factors; physical activity (7)
; body size,
including usual adult height and weight 2 and 5 years before diagnosis;
use of aspirin and/or nonsteroidal anti-inflammatory drugs; cigarette
smoking history; medical history; and reproductive history were
obtained from a standardized questionnaire. A measure of long-term
(past 20 years) levels of vigorous leisure-time physical activity was
used because this was shown to be a sensitive predictor of cancer risk
in this population (9)
. BMI of weight/height
(2)
was used as an indicator of body size.
A detailed reproductive history was obtained from women. The interview included questions on the use of exogenous hormones such as estrogen, progestin, or other female hormones for both contraceptive and noncontraceptive purposes. Dates of first and last use and duration of use of HRT were ascertained. Information also was collected on total number of pregnancies, total amount of time pregnant, number of live births, age at first and last pregnancy, and menstrual history. Total ovulatory months were calculated by subtracting age first menstruated from age at menopause; total months pregnant was subtracted from this number.
Tissue Ascertainment.
Methods for ascertaining tumor tissue and extracting DNA have been
described in detail (12)
. Tumor DNA, obtained from
paraffin blocks, was amplified, and MSI status was determined. From
those on whom we obtained tumor DNA, MSI results were obtained for 98%
of tumor DNA samples. Of the 1836 cases with MSI data, 1510 also had
valid interview data and are included in these analyses. Of these
cases, 689 were women with both MSI status and a complete reproductive
history.
MSI.
Each tumor was evaluated for MSI with a panel of 10 tetranucleotide
repeats used by us in previous studies, the mononucleotide repeat
BAT-26, and a mononucleotide repeat within the coding region of
TGFßRII (13)
. The primer sequences and PCR conditions
for these repeats were as described previously (13, 14, 15, 16)
.
Both tumor DNA and normal DNA were PCR amplified with these 12 primer
sets. MSI for a given primer set was defined as the appearance of one
or more new PCR products either smaller or larger than those produced
from normal DNA; for BAT-26, we required a that a smaller PCR product
be at least 4 bp smaller than the normal. Results from the
tetranucleotide repeat panel were considered to indicate significant
MSI if three or more repeats were unstable. Results were considered to
indicate stability if fewer than 30% of the repeats were unstable and
at least 6 of the 10 repeats were typed. To simplify analyses, we
combined these primer sets into a panel of 12 and scored a tumor as
unstable if it was unstable with the panel of 10 tetranucleotides (as
defined above), or BAT-26 or TGFßRII. Any associations detected in
this way were then further defined by considering MSI results with each
of these three measures separately. The evaluation of MSI was begun
before the development of the Bethesda consensus panel; however, we
have evaluated the markers used in this study with the Bethesda
consensus panel. We observed that instability in the panel of 10
tetranucleotide markers (
30% unstable markers) showed 98.4%
concordance in classifying instability in a sample of 427 people; the
BAT-26 marker showed 98.6% concordance with the Bethesda consensus
panel in a sample of 442 people.
Statistical Analyses.
The distribution of MSI by population characteristics was determined.
Logistic regression models were fit with the dichotomous-dependent
variables as either "no disease" or "MSI+" or "no disease"
or "MSI-." The case-control comparison was conducted to estimate
the relative risk for developing the disease given the exposure with
specific genetic mutations. Logistic regression models also were fit
with a dichotomous-dependent variable (MSI+ or MSI-). The purpose of
the case-case comparison was to evaluate etiological heterogeneity with
respect to the risk factor under study. Logistic regression models were
used to adjust for other potential confounding variables; these models
varied slightly by the test being done. In evaluating age and gender
differences in MSI, we adjusted for age, cigarette smoking, and alcohol
intake because these factors are associated with gender as well as MSI
(17)
. Models evaluating reproductive effects were
adjusted for age and energy intake because these variables were thought
to be potentially important confounding variables for these
associations. In evaluating the interaction between physical activity
and BMI in men and women we adjusted for factors that may influence
these variables, such as age, dietary intake, and cigarette smoking.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. For men, the effect of age was of borderline statistical significance
(P = 0.07); for women the difference in MSI
by age was statistically significant (P < 0.01). Men <50 years of age were more likely to have MSI+ colon tumors
than younger women (Table 1)
. However, older women had more MSI+ tumors
relative to younger men whereas older men were less likely to have
unstable tumors than younger men. We observed a statistically
significant interaction between gender and age and MSI tumors status
(P 
0.01). Although the panel of 12 MSI
markers was used in these analyses, results were similar for individual
marks (i.e., panel of 10 tetranucleotide repeats, BAT-26,
and TGFßRII).
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). However, women were at no greater risk of having MSI- tumors than
men. The differences in association were confined to proximal tumors.
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. Mean age at first and last pregnancy, age at menarche, and age at
menopause were not different between those with MSI+ tumors and those
with MSI- tumors or controls. Means of total months pregnant and total
ovulatory months were greater in those with MSI+ tumors than either
MSI- tumors or controls. Those who had used oral contraceptives or
were recent users of HRT were less likely to have MSI+ tumors. Results
for BAT-26 and TGFßRII were similar to those presented in Table 3
for
the panel of 12 markers, although TGFßRII showed slightly stronger
associations.
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although no linear trend was observed in that increasing number of
pregnancies was not associated with a greater risk reduction than
having been pregnant. A halving of risk of having MSI+ tumors was
observed, regardless of the number of pregnancies, the age at first or
last pregnancy, or the number of total months pregnant (data not
shown). In complementary fashion, total ovulatory months increased the
risk of having a MSI+ tumor. All indicators of MSI showed similar
results, with the strongest associations being detected for TGFßRII.
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. Former users of HRT were at a greater risk of MSI+ tumors, although
not of MSI- tumors, than women who never used HRT. Further evaluation
of these data by age showed that the increase in risk of MSI+ tumors
was confined to women <60 years of age who had taken HRT for <5
years. All indicators of MSI showed similar results, with the strongest
associations being detected for TGFßRII.
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. However, for women, high BMI was associated with a reduced risk of
having an MSI+ tumor. Among women, the combined effects of low physical
activity and high BMI increased risk only of MSI- colon cancer.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It has been previously hypothesized that estrogens could inhibit the pathway to colon cancer involving mismatch repair deficiency and MSI (8) . This hypothesis was based on the observation that younger women had a low prevalence of MSI in colon tumors whereas, among older women, the prevalence of MSI in colon tumors was high (8) . As pointed out by Breivik et al. (8) , hereditary nonpolyposis colon cancer, an inherited colon cancer syndrome in which MSI is seen in nearly all colon cancers, women with hereditary nonpolyposis colon cancer have half the risk of developing colorectal adenomas as their male relatives (18) .
Our data provide further support for the involvement of estrogens in reducing the risk of colon cancer via a MSI-related pathway. We observed a reduction in risk of MSI in tumors with ever having been pregnant and the reverse with total ovulatory months. Having taken oral contraceptives and being a recent user of HRT also were associated with a lower likelihood of having an unstable tumor. Consistent with our previous observations of the association between HRT and colon cancer risk (7) , former users of HRT were, if anything, at an elevated risk of MSI+ tumors. Pregnancy, a state of steady elevated estrogen levels, was associated with reduced risk of MSI+ tumors. During pregnancy different forms of estrogen are present than in the nonpregnant state (19) . However, variation in other factors, such as growth hormones and prostaglandins, also exist during pregnancy and could contribute to observed associations (19 , 20) . Given that neither numbers of pregnancies nor age at first or last pregnancy altered the observed association, it is likely that a mechanism involving homeostasis is involved.
It seems possible that both long-term and short-term fluctuations in estrogen exposure may determine risk and that this results in either or both of the following: variation in lifetime cumulative estrogen exposure (above a certain level is sufficient to prevent MSI+ tumors, irrespective of source) or a homeostasis maintained by the mean lifetime level of estrogen (higher peaks and deeper troughs are associated with elevated risk of MSI+ tumors). The fact that there is an excess of MSI+ tumors in women compared with men, but that this excess is explained wholly by the excess at older ages (indeed, there are fewer MSI+ tumors in young women than young men) and the elevated risk after cessation of HRT use, add weight to the homeostasis argument.
The model we propose to explain these observations is shown in Fig. 1
. Issa et al. (21)
have shown that
hypermethylation, and, thus, reduced expression, of the ER in the colon
is a concomitant of aging. Furthermore, they have shown that colon
tumors almost universally arise from cells that have lost ER expression
(21)
. On the basis of our findings, one could hypothesize
that HRT may reduce the risk of colon cancer in women by reducing the
likelihood of ER methylation and, thus, the pool of cells that give
rise to colon tumors (22)
.
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What we have shown here is that this yin/yang pattern of risk in women (but not men) is confined to MSI+ tumors. It is the absence of this group of tumors that accounts for male/female differences that we have previously shown to exist in relation to obesity/physical activity and colon cancer (9) and colorectal polyps.5
What remains to be determined is why estrogen levels are associated with MSI+ tumors. It is not likely to be due just to the already established association between MSI and hypermethylation of specific genes (e.g., hMLH1) because the primary issue here is the role of endogenous (reproductive status), exogenous (HRT), and metabolic (obesity-associated) estrogens and their plausible association with preventing ER methylation specifically, not with the methylation process per se. It seems reasonable to hypothesize that at least one of the major DNA mismatch repair genes is estrogen responsive and that loss of estrogen results in loss of DNA mismatch repair capacity. Our data do not exclude, however, an effect of estrogens on hypermethylation, in general, or on the specific hypermethylation on hMLH1.
In summary, these data provide support for the hypothesis that estrogens prevent MSI+ tumors, whether endogenous, exogenous, or obesity associated. These findings increase the likelihood that the colon neoplasia/HRT association is causal and that HRT use is protective against colon cancer—not just a marker for a low-risk lifestyle. Furthermore, they provide additional details on the long-standing observation that hormones are important in the etiology of colon cancer. Finally, they raise some questions about mechanisms, including the possibility that one or more mismatch repair genes are estrogen responsive.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Funded by National Cancer Institute Grants
CA48998 and CA61757 (to M. L. S.). This research was supported by the
Utah Cancer Registry, which is funded by Contract N01-PC-67000 from the
National Cancer Institute, with additional support from the State of
Utah Department of Health and the University of Utah, the Northern
California Cancer Registry, and the Sacramento Tumor Registry. The
contents of this manuscript are solely the responsibility of the
authors and do not necessarily represent the official view of the
National Cancer Institute. 
2 To whom requests for reprints should be
addressed (M. L. S.), at Health Research Center, Department of Family
and Preventive Medicine, 391 Chipeta Way, Suite G, University of Utah,
Salt Lake City, UT 84108; Phone: 801-585-6955; E-mail: mslatter{at}dfpm.utah.edu; or (J. D. P.), at Fred Hutchinson Cancer
3 The abbreviations used are: MSI, microsatellite
instability; HRT, hormone replacement therapy; BMI, body mass index;
ER, estrogen receptor; TGFßRII, transforming growth factor ß
receptor type II.
4 W. S. Samowitz, K. Curtin, D. Schaffer, L.
Ballard, M. Leppert, and M. L. Slattery. Microsatellite instability in
sporadic colon cancer is associated with an improved prognosis at the
population level, submitted for publication.
5 J. D. Potter, L. Fosdick, R. Bostick, M. L.
Slattery, T. A. Louis, and P. Grambsch. Energy balance and adenomatous
polyps: beyond physical activity, submitted for publication.
Received 6/21/00. Accepted 10/25/00.
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REFERENCES |
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