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American Cancer Society, National Home Office, Atlanta, Georgia 30329-4251 [H. S. F.]; Departments of Preventive Medicine [H. S. F., R. M-C., G. A. C., D. O. S., B. E. H.] and Urology [G. A. C.], University of Southern California Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California 90033-0800; and Cancer Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813 [L. N. K.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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One such gene, CYP17, encodes the cytochrome p450c17
enzyme, which mediates both steroid 17-hydroxylase and 17,20-lyase
activities, and functions at key branch points in human steroidogenesis
(3)
. A single-bp polymorphism (T27C) in the 5'
untranslated region of CYP17 (34 bp upstream from the
initiation of translation and 27 bp downstream from the transcription
start site) creates a recognition site for the MspAI
restriction enzyme and has been used to designate two alleles,
A1 (the published sequence) and A2. We and others
have found that endogenous hormone levels are associated with this
polymorphism (4
, 5)
. Furthermore, several studies have
examined the association with CYP17 and breast cancer with
mixed results (5, 6, 7, 8, 9, 10, 11, 12)
. Most recently, we have shown that
women who carry the CYP17 A2/A2 genotype were about half as
likely as women with the A1/A1 genotype to be current
HRT3
users (13)
.
We have now examined the importance of a second candidate gene in this polygenic model: the 17ß-hydroxysteroid dehydrogenase 1 (HSD17B1) gene. HSD17B1 encodes the 17HSD type 1 enzyme that catalyzes the final step of estradiol biosynthesis, i.e., the conversion of estrone to the more biologically active estradiol. 17HSD type 1 is expressed in both normal and malignant breast epithelium (14) . Several polymorphisms have been identified in HSD17B1 including a common polymorphism in exon 6 that results in an amino acid change from serine (allele A) to glycine (allele G) at position 312 (14 , 15) . Although current evidence indicates that this amino acid change may not affect the catalytic or immunological properties of the enzyme (16) , an early report suggested that individuals who were homozygous for serine were at marginally significantly increased risk for breast cancer (14) .
We evaluated whether polymorphisms in these two steroid biosynthesis genes were useful in developing a breast cancer risk model that could help discriminate women who are at higher risk of breast cancer. If polymorphisms in these genes affect the level of circulating estrogens, they may directly influence breast cancer risk. We hypothesized that the effect of these polymorphisms would be most pronounced in women without other sources of estrogen, i.e., lean women in whom peripheral conversion of androgens in the adipose tissue would be minimal and women who are not currently receiving HRT. We further evaluated whether these genetic components showed evidence of increased penetrance by stage at diagnosis, age at onset, or family history of breast cancer.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We identified incident cancer cases through the population-based tumor registries in Los Angeles and Hawaii (both of which are members of the National Cancer Institute’s Surveillance, Epidemiology, and End Results program) and the California State Tumor Registry. As of July 1, 1999, 1320 cases of incident breast cancer among the four larger ethnic groups (i.e., excluding Native Hawaiians) have been identified from the cohort of whom 80% (n = 1056) agreed to provide a blood specimen. For this analysis, we included 850 women who were diagnosed with incident breast cancer of stage 1 or greater. Of these, 235 cases had stage 2 or higher tumors (regional and metastatic disease) and are classified here as "advanced" disease. We excluded 200 cases of breast carcinoma in situ and 6 cases of unknown stage. Cohort members who did not give a blood sample were similar with respect to age, ethnicity, and education level to those who did provide a sample, and participation rates were similar for stage 1 and advanced stage cases.
A random sample of men and women was generated to provide potential cohort controls. Controls were contacted by phone and asked to provide a blood specimen. As of July 1, 1999, 1984 female cohort members had been asked to donate a blood specimen. This study includes 1508 (76%) cohort controls who agreed to provide a blood specimen and reported no history of breast cancer. At the time of the blood draw, informed consent forms were completed by all participants. Controls who reported a personal history of breast cancer on the baseline questionnaire were excluded from this analysis.
Statistical Analysis.
Data were analyzed using logistic regression methods to estimate RRs
and 95% CIs. Age and ethnicity were included in the statistical models
to adjust for possible differences in allele distribution. Weight was
also included in the models based on the a priori assumption
that small differences in serum hormone levels that can be attributed
to genetic polymorphisms may be masked by the peripheral production of
estrogens in the adipose tissue of postmenopausal women. The
CYP17 A2 allele and the HSD17B1 A allele were
considered the "high-risk" alleles. Subjects were then classified
according to number of high-risk alleles. For example, a woman whose
genotype was A1/A1 for CYP17 and G/G
for HSD17B1 would be scored as zero high-risk alleles, a
women with A1/A2 and A/G would be scored as 2,
and so on to the highest risk category: A2/A2 and
A/A, which would be scored as 4. This method of
classification allows the computation of a test for trend. Although the
high-risk alleles for CYP17 (A2) and HSD17B1 (A)
may not equally affect risk of breast cancer, they were considered
exchangeable in the allele counting based statistical model. Dummy
variables were also created for each number of high-risk alleles and
were entered into the logistic regression model to obtain risk
estimates for each number of high-risk alleles.
Because our hypothesis is that these polymorphisms act by influencing lifetime levels of endogenous estrogens (from ovarian synthesis), we were interested in statistically testing whether these high-risk alleles could predict circulating estrogen levels (where estrogen is estrone + estradiol). Using plasma estrogen measurements from postmenopausal control women (who were not taking estrogen or progestogen in the 2 weeks prior to blood draw), we estimated the relationship between log estrogen and CYP17 and HSD17B1 as: log estrogen = constant + ß1 · (number of high-risk CYP17 alleles) + ß2 · (number of high risk HSD17B1 alleles). This is equivalent to log estrogen = constant + (number of high-risk CYP17 alleles) + (ß2/ß1) · (number of HSD17B1 high-risk alleles). Our fitted results gave an estimated ß2/ß1 = 1.41. We then used this fitted equation in a logistic regression model to estimate the risk of breast cancer per unit change in log estrogen as predicted by the genotypes of these two genes. Finally, we compared the likelihoods of the two models (allele counting versus predicted hormone equations) to determine whether the two models fit the data equivalently. If the likelihoods are similar, this suggests that the allele counting model is consistent with the apparent effect of the alleles on plasma estrogens.
We used the results of earlier studies (13
, 18)
to guide
our stratified and subset analyses. Because a significant amount of
circulating estrogen results from aromatization of androstenedione to
estrone in peripheral tissues, we stratified the data by weight. An
a priori cutpoint of 170 pounds (
80 kg) was chosen to
reflect the nonlinearity of the body weight-endogenous hormone
relationship (18)
. It has been shown that <170 pounds,
there is no statistically significant association with body weight and
endogenous hormone levels. Above 170 pounds, levels of endogenous
estrogens rise in response to aromatase activity in adipose
tissue.4
This 170 pound cutpoint also corresponds with the 75th percentile of
the weight distribution among our control women. We have reported that
women with CYP17 A2 alleles were less likely to use HRT
(13)
, thus we stratified on HRT use. We also used
stratified analysis to examine genotype by stage, age of onset, and
family history, because these are often factors that can reflect gene
expression. We examined the effect of CYP17 and
HSD17B1 among women <55 years of age; 324 controls and 40
advanced cases were <55 years at the time of diagnosis (or time of
blood draw among controls). Women were considered to have a positive
family history of breast cancer if they reported having a mother or
sister(s) with breast cancer on the baseline questionnaire. Thirty-nine
women with advanced breast cancer and 162 controls reported a positive
family history. Finally, to help assess the consistency of the
association, the data were stratified by ethnicity.
Genotyping.
DNA was purified from buffy coats of peripheral blood samples. The
CYP17 assay has been described previously (19)
.
A PCR fragment containing the bp change was generated using the
following primers: CYP-1, 5-CATTCGCACTCTGGAGTC-3; and CYP-2,
5-AGGCTCTTGGGGTACTTG-3. PCR reactions were carried out in 25-µl
aliquots containing about 50 ng of genomic DNA, 50 pmol of each primer,
1x reaction buffer, 100 µM deoxynucleotide
triphosphates, and 1 unit of Taq polymerase (Pharmacia). The
amplification was for 30 cycles with denaturation at 94°C for 1 min,
annealing at 57°C for 1 min, and extension at 72°C for 1 min. An
initial denaturation step of 5 min at 94°C and a final extension at
72°C for 5 min were used. The PCR products were digested for 3 h
at 37°C using MspAI, separated by agarose gel
electrophoresis, and stained with ethidium bromide to identify the bp
change.
Because HSD17B1 has an adjacent pseudo-gene, the PCR
amplification was nested to insure that the pseudo-gene was not
coamplified (14)
. The first PCR fragment was generated
using the following primers: HSD1-F, 5'-CGGGAGCCGCTCTGGGGCGATCT-3'
(forward); and HSD1-R, 5'-GGTGCCACTGTGCTGATTTTTAAATTTTCT-3' (reverse).
The primers for the second PCR reaction were: HSD2-F,
5'-AAGCCGACCCTGCGCTACTTCAC-3' (forward); and HSD2-R,
5'-TCTATCTTAATTAGCCACCCACAGC-3' (reverse). The PCR reactions were
carried out in 25-µl aliquots containing 50 pmol of each primer, 1x
reaction buffer, 100 µM deoxynucleotide
triphosphates, and 1 unit of Taq polymerase (Pharmacia) + DMSO (5% final). In the first PCR, 50 ng of genomic DNA were used
as a template; in the second PCR, 1 µl of the first PCR reaction mix
was used as a template. The amplification was for 30 cycles for the
first PCR and 19 cycles for the second PCR with denaturation at 94°C
for 1 min, annealing at 60°C for 1 min, and extension at 72°C for
1.5 min for the first PCR and 1 min for the second PCR. An initial
denaturation step of 3 min at 94°C and a final extension at 72°C
for 5 min were used in both cases. The PCR products were digested for
3 h at 60°C using BstUI, separated by agarose gel
electrophoresis and stained with ethidium bromide to identify the bp
change.
All samples were run in batches that contained positive controls (of each genotype) and negative controls (samples with no DNA added). All batches included both breast cancer cases and non-cases. In addition, 5% of the samples were repeated (blind) in subsequent batches, and results of both batches were accepted only if the duplicates were identical. Gels were read blind to case/control status.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The data shown in Table 1
suggest that CYP17 and HSD17B1 both contribute to
a modest increased risk of advanced breast cancer after adjusting for
each other and for age, weight, and ethnicity, although the CIs do not
differ from 1.0. The test for linear trend is of borderline statistical
significance for the CYP17 A2 allele (P = 0.05) but not for the HSD17B1 A allele, although the
magnitude of risk for the high-risk alleles are similar. Neither gene
was associated with stage 1 breast cancer. In the logistic regression
model, the risk factors (including CYP17 and
HSD17B1) are assumed to act in a multiplicative manner, and
there was no statistical evidence that this assumption did not hold.
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shows that when the genes are considered together, there is evidence of
a linear trend of increasing risk for advanced breast cancer as the
number of high-risk alleles increases (P = 0.03). Women who carry four high-risk alleles (i.e., those
whose genotype is CYP17 A2/A2 and HSD17B1 A/A)
have a RR of 2.21 (95% CI, 0.98–5.00) for advanced breast cancer.
Regardless of the number of high-risk alleles, there is no elevation of
risk in women with stage 1 breast cancer.
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, the increasing
risk of advanced breast cancer associated with the CYP17 and
HSD17B1 high-risk alleles was largely limited to women who
reported that they had never used HRT or were former HRT users
(P for trend = 0.09).
The increase risk associated with CYP17 and
HSD17B1 high-risk alleles is most pronounced among women
weighing <170 lbs. (Table 3)
. Compared with having no high-risk alleles, women who are homozygous
for the high-risk alleles of both genes have a >3-fold increased risk
for developing advanced breast cancer (OR, 3.05; 95% CI, 1.29–7.25;
P for trend = 0.02). In heavier women, the
effect of genotype is still present but may be diluted by the
contribution of estrogen production in the adipose tissue (data not
shown). Using body mass index instead of weight did not affect the
results.
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Ethnic-specific relative risks for advanced breast cancer by number of
high-risk alleles are presented in Table 4
to illustrate that the genotype effects are consistent in each ethnic
group included in the study. For women carrying four high-risk alleles,
the RR for advanced breast cancer ranges from 1.70 among Japanese women
to 3.38 among Latina women.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The HSD17B1 gene originally received much attention as a promising candidate gene for BRCA1, given its function and chromosomal location (14 , 15) . However, after it was eliminated as a candidate for BRCA1, it has received little attention, despite a rather compelling body of biochemical evidence for its important role in the synthesis of estradiol. To our knowledge, only one other epidemiological study of breast cancer has evaluated the role of this HSD17B1 polymorphism (14) . Our results warrant further exploration of HSD17B1.
Although the ethnic-specific risk estimates are imprecise, the data in
Table 4
suggest that these findings are consistent across different
ethnic groups. Because these ethnic groups traditionally differ in
overall rates of breast cancer incidence, mortality, and factors such
as socioeconomic status, access to medical care, parity, and HRT use,
the similarities of these risk estimates are compelling. These loci, as
well as others involved in the synthesis and metabolism of steroid
hormones, may help explain the increasing risk of breast cancer in
countries such as Japan, who are generally leaner than United States
and European women.
The primary limitation of this study is its size. Although it includes over 850 cases of incident breast cancer, only 28% (235) of them are advanced cases. Further stratification by either weight or HRT use creates strata with small numbers, especially among advanced cases who are homozygous for both CYP17 and HSD17B1. However, when we used this model to also estimate risk of breast cancer per unit change of log estrogen, the risk estimates are remarkably similar, adding confidence to the validity of the model.
Beyond the apparent internal consistency of these data, there is evidence that stage at diagnosis is dependent on the same combination of low- or high-risk alleles. Only 22% of cases who are double homozygotes for the low-risk alleles present with advanced disease, versus 39% of those homozygous for the high-risk alleles. The fact that increased risk from the high-risk alleles in limited to advanced cases of breast cancer may be explained at least two ways: (a) these advanced cases may have a different etiology; (b) these tumors may be more aggressive and progress to an advanced stage more rapidly. We are currently investigating whether survival or histopathology differ by (germ-line) CYP17 and HSD17B1 status. Although these genes do not appear to play an important role in localized disease, it is perhaps more relevant to look for characteristics to discriminate women who are at risk for advanced breast cancer, because these are the women who may most benefit from early interventions or be candidates for chemopreventive therapies.
It is yet to be determined whether these polymorphisms are in
themselves functional or are linked to a variation elsewhere in the
gene or other nearby locus. It was shown recently (11)
that the T27C polymorphism in CYP17 (converting the sequence
CACT into CACC) does not influence Sp-1 binding in in vitro
assays, as had been suggested based on its similarity to other known
Sp-1 binding sequences. Additional functional studies are needed to
determine whether the A2 allele confers specifically a
higher expression level of CYP17 (11)
. Early
work (16)
on site-directed mutagenesis of
HSD17B1 failed to demonstrate changes in the catalytic or
immunological properties of the enzyme resulting from this Ser
Gly
change. However, one would not expect standard assays to necessarily
detect the relatively small differences in activity predicted from the
epidemiological data. For example, the model of breast tissue age by
Pike et al. (20)
demonstrates that a relative
risk of 2.0 reflects only a 20% difference in levels of circulating
estrogen. This 20% difference is generally consistent with what has
been reported in the studies that have looked at the association
between endogenous hormone levels and CYP17 genotype
(4
, 5)
.
There is compelling evidence from this work and others that breast cancer risk has a strong genetic component. Some lifestyle factors, such as exercise or severe dietary change, may influence risk, either directly or by interrupting ovulatory function, and thus diminish the expression of this underlying genetic determination. In the same way, the use of exogenous hormones, or obesity, may add additional sources of estrogen, which would tend to augment this underlying susceptibility. Nevertheless, the further characterization of germ-line and somatic sequence variants in relevant genes holds promise for individualizing diagnosis, screening, and therapeutic intervention. We present this two-gene model as an example of how a multigene model can contribute to our understanding of, and ultimately the prevention of, diseases such as breast cancer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Grants 2FB-0212 and 4KB-0147 from
the California Breast Cancer Research Program of the University of
California and by National Cancer Institute Grants CA63464 and
CA54281. 
2 To whom requests for reprints should be
addressed, at American Cancer Society, National Home Office, 1599
Clifton Road, NE, Atlanta, GA 30329-4251. Phone: (404) 929-6815; Fax:
(404) 327-6450; E-mail: hfeigels{at}cancer.org
3 The abbreviations used are: HRT, hormone
replacement therapy; RR, relative risk; CI, confidence interval; lbs.,
pounds.
4 N. Probst-Hensch, personal communication.
Received 5/15/00. Accepted 11/ 7/00.
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gene (CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res., 58: 585-587, 1998. gene (CYP17) polymorphism predicts use of hormone replacement therapy. Cancer Res., 59: 3908-3910, 1999.This article has been cited by other articles:
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