Carcinogenesis vol.31 no.5 pp.827–833, 2010
Advance Access publication January 6, 2010
Common genetic variation in the sex hormone metabolic pathway and endometrial
cancer risk: pathway-based evaluation of candidate genes
Hannah P.Yang1,2,?, Jesus Gonzalez Bosquet1, Qizhai Li1,7,
Elizabeth A.Platz2, Louise A.Brinton1, Mark E.Sherman1,
James V.Lacey Jr1, Mia M.Gaudet3, Laurie A.Burdette1,4,
Jonine D.Figueroa1,8, Julia G.Ciampa1, Jolanta
Lissowska5, Beata Peplonska6, Stephen J.Chanock1,4and
1Division of Cancer Epidemiology and Genetics, National Cancer Institute,
National Institutes of Health, Department of Health and Human Services,
Bethesda, MD 20852, USA,2Department of Epidemiology, Johns Hopkins
Bloomberg School of Public Health, Baltimore, MD 21205, USA,
3Department of Epidemiology and Population Health, Albert Einstein College
of Medicine, New York, NY 10461, USA,4Core Genotype Facility at the
Advanced TechnologyCenter, NationalCancer Institute, National Institutesof
Health, Department of Health and Human Services, Bethesda, MD 20892,
USA,5Department of Cancer Epidemiology and Prevention, M. Sklodowska-
Curie MemorialCancer Centerand Institute of Oncology, Warsaw, Poland and
6Department of Occupational and Environmental Epidemiology, Nofer
Institute of Occupational Medicine, Lodz, Poland
7Present address: Key Laboratory of Systems and Control, Academy of
Mathematics and Systems Science, Chinese Academy of Science, Beijing,
8Present address: Division of Cancer Etiology, Department of Population
Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
?To whom correspondence should be addressed. National Cancer Institute,
6120 Executive Boulevard, EPS/5034a, Rockville, MD 20852, USA.
Tel: þ1 301 594 5640; Fax: þ1 301 402 0916;
Background. Estrogen plays a major role in endometrial carcino-
genesis, suggesting that common variants of genes in the sex hor-
mone metabolic pathway may be related to endometrial cancer
risk. In support of this view, variants in CYP19A1 [cytochrome
P450 (CYP), family 19, subfamily A, polypeptide 1] have been
associated with both circulating estrogen levels and endometrial
cancer risk. Associations with variants in other genes have been
suggested, but findings have been inconsistent. Methods. We ex-
amined 36 sex hormone-related genes using a tagging approach in
a population-based case–control study of 417 endometrial cancer
cases and 407 controls conducted in Poland. We evaluated com-
monvariation in these genes in relationto endometrial cancer risk
using sequential haplotype scan, variable-sized sliding window
and adaptive rank-truncated product (ARTP) methods. Results.
In our case–control study, the strongest association with endome-
trial cancer risk was for AR (androgen receptor; ARTP
P 5 0.006). Multilocus analyses also identified boundaries for
a region of interest in AR and in CYP19A1 around a previously
identified susceptibility loci. We did not find evidence for consis-
tent associations between previously reported candidate single-
nucleotide polymorphisms in this pathway and endometrial
cancer risk. Discussion. In summary, we identified regions in AR
and CYP19A1 that areofinterest for furtherevaluation in relation
to endometrial cancer risk in future haplotype and subsequent
fine mapping studies in larger study populations.
Endometrial cancer is the fourth most common cancer among women
and the most common gynecological cancer in the USA (1). Hor-
monal factors have been identified as major etiologic factors for en-
dometrial cancer (2). Data from cohort and case–control studies have
demonstrated consistent links between elevated circulating sexsteroid
hormones and endometrial cancer risk (3–5). Epidemiologic data
show that many exposures that are associated with endometrial cancer
may increase total estrogen exposure, including use of exogenous
unopposed estrogen or tamoxifen, early ages at menarche, late ages
at menopause, nulliparity and obesity (2). In addition, a 3-fold in-
creased endometrial risk has been associated with a family history
of endometrial cancer (6), suggesting the contribution of genetic
predisposition of endometrial cancer.
These data suggest that interindividual variation in genes in-
volved in sex hormone metabolic pathway could be related to en-
dometrial cancer risk. Two variants in CYP19A1 [cytochrome P450
(CYP), family 19, subfamily A, polypeptide 1] (aromatase), which
have been shown to be related to circulating estrogen levels (7),
have been demonstrated to be associated with endometrial cancer
risk in a recent pooled analysis of 10 studies including nearly
5000 endometrial cancer cases (8). A large number of independent
studies have also assessed associations between other genes in
the sex hormone metabolic pathway and endometrial cancer risk
with inconsistent results. To date, single-nucleotide polymor-
phisms (SNPs) in AR (androgen receptor) (9,10), COMT (cate-
chol-O-methyltransferase) (11–15), CYP1A1 (CYP, family 1,
subfamily A, polypeptide 1) (11,14,16–23), CYP1A2 (CYP, family 1,
subfamily A, polypeptide 2) (11,14,19,21), CYP3A4 (CYP, family 3,
subfamily A, polypeptide 4) (14,24), CYP17A1 (CYP, family 17, sub-
family A, polypeptide 1) (19,25–33), CYP19A1 (CYP, family 19,
subfamily A, polypeptide 1) (6,8,21,26,31,32,34), CYP1B1 (CYP,
family 1, subfamily B, polypeptide 1) (11–15,19,35,36), ESR1 (estro-
gen receptor 1) (37–41), ESR2 (estrogen receptor 2) (37,42),
HSD17B1 [hydroxysteroid (17-beta) dehydrogenase 1] (43,44),
PGR (progesterone receptor) (14,45–48), SHBG (sex hormone-bind-
ing globulin) (14,49,50), SULT1A1 (sulfotransferase family, cyto-
solic, 1A, phenol-preferring, member 1) (14,19,21), SULT1E1
T1A1 (uridine diphosphate glucuronosyltransferase 1 family, poly-
glucuronosyltransferase 2 family, polypeptide B7) (53) have been
examined. Most of these studies, however, focused on candidate
SNPs, rather than a more comprehensive assessment of common ge-
netic variation on potentially important hormone-related genes in
a pathway-based analysis.
In the present population-based case–control study, we evaluated
36 sex hormone-related genes using a tagging approach. These in-
clude SNPs in genes involved in synthesis and bioactivation of es-
trogen and other sex hormones [AKR1C1 (aldo-keto reductase
family 1, member C1), AKRC2 (AKRC family 2, member C2),
AR, CYP17, CYP19A1, CYP11A1 (CYP, family 11, subfamily A,
polypeptide 1), CYP11B1 (CYP, family 11, subfamily B, polypep-
tide 1), CYP11B2 (CYP, family 11, subfamily B, polypeptide 2),
CYP21A2 (CYP, family 21, subfamily A, polypeptide 2), ESR1,
ESR2, HSDB17B1, HSDB17B2, HSDB17B3, HSDB17B4, HSD3B1
(hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-
isomerase 1), HSD3B2, HAO2 (hydroxyacid oxidase 2), PGR,
SHBG, SRD5A1 (steroid-5-alpha-reductase, alpha polypeptide 1),
SRD5A2, STAR (steroidogenic acute regulatory protein), SULT1A1,
SULT1A2, SULT1B1 and SULT1E1], synthesis of catecholestrogen
(CYP1A1, CYP1A2, CYP1B1 and CYP3A4) and inactivation of es-
trogen, catecholestrogen or its products (COMT, UGT1A8, UGT1A9,
UGT1A10, UGT2B11 and UGT2B17). We examined individual
SNPs and individual genes using sequential haplotype scan, vari-
able-sized sliding window and adaptive rank-truncated product
Abbreviations: ARTP, adaptive rank-truncated product; CYP, cytochrome
P450; SNP, single-nucleotide polymorphism.
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Received September 17, 2009; revised November 25, 2009;
accepted December 15, 2009
Pathway-based evaluation of sex hormone genes