Prostate cancer in African-American men and polymorphism in the calcium-sensing receptor

Research paper
Cancer Biology & Therapy 9:12, 994-999; June 15, 2010; © 2010 Landes Bioscience
Prostate cancer in African-American men and
polymorphism in the calcium-sensing receptor
Gary G. Schwartz,1,* Esther M. John,2,3 Glovioell Rowland4 and Sue A. Ingles4
1
Wake Forest University Health Sciences; Departments of Cancer Biology, Urology, Epidemiology and Prevention; Winston-Salem, NC USA; 2Cancer Prevention Institute of
California (formerly the Northern California Cancer Center); Fremont, CA USA; 3Department of Health Research and Policy; Stanford School of Medicine and Stanford Cancer
Center; Stanford, CA USA; 4Department of Preventive Medicine; University of Southern California; Los Angeles, CA USA
Key words: prostate cancer, African-Americans, calcium-sensing receptor, genetics
Background: Prospective epidemiologic studies indicate that the risk for advanced prostate cancer is increased among men
with high levels of serum calcium. Because serum calcium levels are influenced by the calcium-sensing receptor (CaSR), we
examined prostate cancer in African‑American men in relation to three single nucleotide polymorphisms (SNPs) in the CaSR
gene, A986S, R990G and Q1011E. This is the first study of CaSR polymorphisms and risk of prostate cancer.
Results: The CaSR genotypes were not associated with prostate cancer overall. However, we observed significant heterogeneity by disease stage for the Q1011E polymorphism (p = 0.02). Advanced cases were significantly less likely than controls or
localized cases to be homozygous for the minor allele of the Q1011E polymorphism (1 vs. 5%). Cases with advanced disease were
six times less likely to carry two copies of the minor allele than were controls (OR = 0.16, p = 0.02) or localized cases (OR = 0.15, p
= 0.01) and were significantly older at diagnosis (68.8 ± 5.7 vs. 64.0 ± 9.0 y for the QQ and EE genotypes, p = 0.004).
Methods: We genotyped three CaSR SNPs for 458 African‑American prostate cancer cases and 248 controls from a population-based case-control study, the California Collaborative Prostate Cancer Study.
Conclusions: The CaSR Q1011E minor allele, which is common in populations with African ancestry, may be associated with
a less aggressive form of prostate cancer among African‑American men.
Introduction
Prostate cancer is the most commonly diagnosed and the most
prevalent non-skin cancer among men in the U.S. and the U.K.1,2
The geographic distribution of fatal prostate cancer, which shows
higher mortality rates in populations living at northern latitudes,
and the higher mortality rate among African‑Americans, has
stimulated interest in the etiologic role of vitamin D.3-6 Although
many studies have examined prostate cancer risk in relation to
genetic polymorphisms in the receptor for 1,25-Dihydroxyvitamin
D (reviewed in ref. 6), the role of polymorphisms in the receptor
for calcium has been little studied. However, in a large, prospective cohort (the first National Health and Nutrition Examination
Survey [NHANES I] Epidemiologic Follow-up Study), we
reported a 2.5-fold increased risk of fatal prostate cancer in
U.S. men with high serum levels of calcium.7 This finding was
confirmed in a second, independent cohort, NHANES III. In
NHANES III, we reported a greater than 3-fold increased risk of
fatal prostate cancer in men whose serum levels of ionized calcium
was at the high end of its normal reference range.8
Serum levels of calcium are under strong genetic control
mediated in part by the calcium-sensing receptor (CaSR), a
G protein-coupled receptor that is expressed on the chief cells
of the parathyroid glands. The CaSR regulates the secretion and
release of parathyroid hormone (PTH), which regulates calcium
absorption from the gut and bone.9 Several lines of evidence suggest that the CaSR plays a role in prostate cancer. For example,
the CaSR is expressed on prostate cancer cells and its activation
by calcium causes an increase in cell proliferation and an inhibition of apoptosis.10 Additionally, microarray data suggest that
CaSR expression is associated with prostate cancer metastasis.11
In addition to the CaSR, prostate cancer cells express receptors for PTH (PTH-type I receptors) and respond to PTH with
an increase in cell proliferation and metastasis.12,13 These findings suggest that factors that influence serum levels of calcium
and/or PTH may play roles in the pathogenesis of prostate cancer. Polymorphisms in the CaSR gene have been examined in
studies of colorectal cancer but have not previously been examined in prostate cancer.14 We examined prostate cancer risk in
African‑American men in relation to three single nucleotide
polymorphisms (SNPs) in the CaSR gene, A986S (rs1801725),
R990G (rs1042636) and Q1011E (rs1801726) that alter the
amino acid sequence of the CaSR protein.
Results
Socio-demographic data for cases and controls are shown in Table 1.
Men from Northern and Southern California were similar with
*Correspondence to: Gary G. Schwartz; Email: [email protected]
Submitted: 02/10/10; Revised: 03/04/10; Accepted: 03/04/10
Previously published online: www.landesbioscience.com/journals/cbt/article/11689
DOI: 10.4161/cbt.9.12.11689
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Cancer Biology & Therapy
Volume 9 Issue 12
Research Paper
Research paper
Table 1. Characteristics of African‑American cases and controls, by study site
Controls
Advanced cases
Localized cases
LA
SF
LA
SF
LA
N = 163
N = 85
N = 140
N = 107
N = 211
Age (yrs)
≤49
14
9%
4
5%
12
9%
3
3%
8
4%
50–59
42
26%
21
25%
44
31%
34
31%
44
21%
60–69
68
42%
35
41%
56
40%
43
41%
89
42%
70–79
34
21%
25
29%
25
18%
27
25%
54
26%
≥80
5
3%
0
0%
3
2%
0
0%
16
8%
Median
63
65
62
63
66
SES score*
1 (low)
42
26%
9
11%
53
38%
12
11%
88
42%
2
51
31%
19
22%
32
23%
21
19%
56
27%
3
38
23%
19
22%
29
21%
35
33%
37
18%
4
25
15%
22
26%
22
16%
21
19%
22
10%
5 (high)
7
4%
16
19%
4
3%
18
17%
8
4%
High school or less
62
38%
37
44%
66
47%
50
46%
85
40%
Some college
64
39%
31
37%
40
29%
34
32%
94
45%
College graduate
34
21%
16
19%
34
24%
22
20%
31
15%
Unknown
3
2%
1
1%
0
0%
1
1%
1
<1%
Education
Family history of prostate cancer
*
No
147
90%
72
85%
108
77%
80
75%
166
79%
Yes
16
10%
13
15%
32
23%
27
25%
45
21%
SES based on census tract of residence.
respect to age and education. Northern Californians were less
likely to reside in census tracts with a low SES score. Cases with
advanced disease were diagnosed at a younger age than those
with localized disease (median age 62 and 66 y, respectively).
Among advanced cases, 20% had distant metastasis at diagnosis,
and 38% were of high histological grade (Gleason grade ≥8) vs.
15% among localized cases. Both localized and advanced cases
were significantly more likely than controls to have a family history of prostate cancer (p = 0.001 and p < 0.001, respectively).
Genotype frequencies for cases and controls are shown in
Table 2. Among controls, the minor allele frequencies were
3, 4 and 18%, for A896S, R990G and Q1011E, respectively.
Genotype frequencies among controls did not deviate from
Hardy-Weinberg equilibrium for any of the polymorphisms.
Only four haplotypes had estimated frequencies higher than 1%
among controls: ARQ (77%), ARE (16%), AGQ (4%) and SRQ
(3%). Thus few, if any, of the men carried a minor allele at more
than one locus.
None of the CaSR SNP genotypes were associated with
prostate cancer risk overall. However, there was significant heterogeneity by stage of disease for the Q1011E polymorphism
(p = 0.02). Advanced cases were significantly less likely than controls or localized cases to be homozygous for the Q1011E minor
allele. Among controls and localized cases, 5% were homozygous
for the minor allele, compared to 1% of advanced cases. Cases
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with advanced disease were approximately six times less likely
to carry two copies of the minor allele than were controls [OR =
0.16 (0.03–0.74), Fisher’s exact p = 0.01].
When we evaluated age at diagnosis by genotype (Fig. 1), we
found that the Q1011E genotype was significantly associated
with age at diagnosis (p = 0.004). Men with the EE genotype
were diagnosed at a significantly older age compared to those
who carried at least one Q allele (68.8 ± 5.7 vs. 64.0 ± 9.0 y). The
A986S and R990G SNPs were not significantly associated with
age at diagnosis.
Discussion
The CaSR is a G protein-coupled receptor that was cloned from
bovine parathyroid glands in 1993.18 The CaSR functions as a
“thermostat” for ionized calcium, increasing PTH secretion in
response to low levels of calcium in serum and inhibiting secretion in response to increased serum calcium levels.19 However,
the CaSR likely plays other roles apart from its role in the regulation of serum calcium because it is expressed in tissues that
are not involved in mineral homeostasis, including the prostate
gland.20 Activation of the prostatic CaSR by extracellular calcium
promotes the proliferation and inhibits apoptosis in prostate cancer cells.10,21 Factors other than calcium are agonists for the CaSR,
including the polyamines spermine, spermidine and putrescine,
Cancer Biology & Therapy
995
Table 2. CaSR exon 7 genotypes and risk of prostate cancer in African‑Americans, by tumor stage
Controls
All cases
OR (95% CI)
all cases vs.
­controls
Advanced
cases
OR (95% CI)
advanced cases
vs. controls
Localized cases
OR (95% CI)
localized cases
vs. controls
rs1801725 (A986S)
AA
176
AS
SS
not AA
94%
397
12
6%
0
0%
12
6%
188
94%
1.0
198
24
6%
0.89 (0.43–1.81)
0
0%
*
24
6%
0.89 (0.43–1.81)
421
93%
1.0
199
15
7%
1.11 (0.51–2.44)
0
0%
*
15
7%
1.11 (0.51–2.44)
213
96%
1.0
9
4%
0.66 (0.27–1.61)
0
0%
*
9
4%
0.66 (0.27–1.61)
208
rs1042636 (R990G)
RR
182
92%
408
92%
1.0
217
91%
1.0
191
94%
1.0
RG
15
8%
33
7%
0.98 (0.52–1.85)
20
8%
1.12 (0.56–2.25)
13
6%
0.83 (0.38–1.78)
GG
1
1%
2
<1%
0.89 (0.08–9.90)
2
1%
1.68 (0.15–18.65)
0
0%
*
not RR
16
8%
35
8%
0.95 (0.51–1.96)
21
9%
1.19 (0.60–2.36)
13
6%
0.77 (0.36, 1.65)
1.0
198
443
239
204
rs1801726 (Q1011E)
QQ
135
69%
308
69%
QE
51
26%
125
EE
10
5%
13
61
31%
138
not QQ
196
1.0
170
70%
28%
1.07 (0.73–1.58)
70
3%
0.57 (0.24–1.33)
2
31%
0.99 (0.69–1.3)
72
446
1.0
138
68%
29%
1.09 (0.71–1.67)
55
27%
1.05 (0.67–1.65)
1%
0.16 (0.03–0.74)#
11
5%
1.08 (0.44–2.62)
30%
0.96 (0.63–1.44)
66
32%
1.03 (0.68–1.56)
242
204
*OR not estimable. #Fisher’s exact p = 0.01 for EE vs. QQ genotype.
which are found in especially high abundance in the prostate.22
The CaSR gene harbors three common nonsynonymous SNPs, all in
exon 7, arising in three different ethnic
populations: rs1801726 (Q1011E) in
Africans, rs1042636 (R990G) in Asians
and rs1801725 (A986S) in Europeans.
We found that African‑American men
who were homozygous carriers of the
CaSR Q1011E variant allele (EE genotype) were at significantly reduced risk
of advanced, but not localized prostate
cancer. Furthermore, cases with the EE
genotype were diagnosed at significantly
older ages compared to cases who carried
at least one Q allele. All 25 of the men in
this study who were homozygous carriers
of the E allele were also homozygous for
the “wild-type” alleles at the other two loci
and thus all carried two copies of the same
CaSR exon 7 haplotype.
Figure 1. Age at diagnosis of prostate cancer, by CASR Q1011E genotype.
Since advanced prostate cancer is likely
to become fatal, these results are consistent with our recent findings that high serum calcium levels
Population stratification is a potential concern in studies
predict fatal, but not incident prostate cancer.7,8 The data also when the frequency of both the outcome (e.g., advanced prostate
are consistent with a report that the CaSR haplotype containing cancer) and of the exposure (e.g., EE genotype of the CaSR) varies
the Q1011E variant (E) allele is associated with a significantly greatly by ethnicity.24 This is the case in our study, as both fatal
reduced risk of advanced colorectal adenomas.23
prostate cancer and the CaSR EE genotype are more common
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Volume 9 Issue 12
among African‑Americans. However, if the EE genotype were
simply a marker of African ancestry, we would expect positive
confounding, i.e., a bias in the odds ratio upwards away from the
null. In contrast, the EE genotype in our study is associated with
a reduced risk of advanced prostate cancer. Thus, to the extent
that there is confounding by ethnicity, the true odds ratio would
likely be lower.
To our knowledge, this is the first study of CaSR polymorphisms and prostate cancer. A limitation of this study is that our
findings for the Q1011E polymorphism are based on a relatively
small number of cases carrying two copies of the minor allele
(13/446). Thus, this novel finding should be considered hypothesis-generating. Conversely, this study has several strengths:
e.g., the sample size of African‑American patients is large and is
population-based. Additionally, the oversampling of cases with
advanced-stage disease allowed us to distinguish stage-specific
effects that would have been difficult to detect in a case series
that consisted mainly of early-stage disease.
The mechanism(s) underlying the association of a reduced risk
of advanced prostate cancer with a polymorphism in the CaSR is
unclear but may involve serum levels of calcium and/or PTH.
Gain-of-function mutations in the CaSR cause hypocalcemia and
loss-of-function mutations cause hypercalcemia.9 Polymorphisms
in the CaSR have been associated with modest changes in serum
calcium in some, but not all, studies.25-28 Recently, several investigators have reported that polymorphisms in the CaSR are associated with large differences in serum levels of PTH.29 Eren and
colleagues reported on CaSR codon 1011 polymorphisms in 192
Turkish patients with end-stage renal disease.30 They observed
significantly higher levels of PTH among patients with the
minor allele for the Q1011E polymorphism. Serum PTH levels
among patients with the CC, CG and GG genotypes (corresponding to QQ, QE and EE, respectively) were 1,015.2 ± 925.4,
523.8 ± 544.6 and 184.3 ± 107.1 pg/ml, respectively. Serum levels
of PTH are known to be positively correlated with serum levels of
PSA and to promote the progression of prostate cancer metastases
to bone.12,31 Thus, the association of the G allele of the CaSR with
lower levels of PTH could provide a mechanism for the lower
prevalence of advanced disease and the significantly older age at
diagnosis that we observed for men with the GG (EE) genotype.
Further studies of the association of CaSR polymorphisms with
prostate cancer risk are warranted.
Materials and Methods
Study population. African‑American prostate cancer patients
(cases) and men without a history of prostate cancer (controls)
participated in the California Collaborative Prostate Cancer
Study, a multiethnic population-based case-control study of
African‑Americans and non-Hispanic Whites from the San
Francisco Bay area (John et al. 2005)3 and African-Americans,
Hispanics and non-Hispanic Whites from Los Angeles county.
Newly diagnosed cases from both study sites were identified
through the regional cancer registries that ascertain all incident
cancers as part of the Surveillance, Epidemiology and End Result
(SEER) program and the California Cancer Registry.
www.landesbioscience.com
San Francisco Bay area. Eligible cases included men aged
40–79 y newly diagnosed with advanced prostate cancer,
including non-Hispanic Whites diagnosed between July 1,
1997–February 28, 2000 and African‑Americans diagnosed
between July 1, 1997–December 31, 2000. Of 1,015 advanced
prostate cancer cases identified by the Greater Bay Area Cancer
Registry, 768 met the eligibility criteria (alive, no physician
refusal, residing in the San Francisco Bay area, valid phone number, English speaking), and of these 533 (69%), including 107
African‑Americans, completed an in-person interview and provided a blood or mouthwash sample. Controls aged 40–79 y were
identified through random-digit dialing and random selections
from the rosters of beneficiaries of the Health Care Financing
Administration and frequency matched to cases on race/ethnicity and 5 y age group. Of 1,081 controls selected, 836 met the eligibility criteria and 525 (63%), including 85 African‑Americans,
provided the interview and a biospecimen sample.
Los Angeles county. Eligible cases included African‑Americans,
Hispanics and non-Hispanic Whites of any age diagnosed
with a first primary prostate cancer between January 1, 1999–
December 31, 2003, and identified by the Los Angeles County
Cancer Surveillance Program as having either (1) prostatectomy with documented tumor extension outside the prostate,
(2) metastatic prostate cancer in extra-prostatic sites, (3) needle
biopsy with a Gleason grade 8 or higher or (4) needle biopsy with
Gleason grade 7 and tumor in more than 2/3 of the biopsy cores.
Los Angeles County Cancer Registry records were obtained to
ascertain any advanced stage cases that were missed by the above
criteria. Of 3,114 cases identified, 1,870 met the eligibility criteria (alive, no physician refusal, residing in Los Angeles country, valid contact information, English speaking), and of these
1,234 (66%), including 351 African‑Americans, completed the
in-person interview and provided a blood sample. Controls were
frequency matched to cases on age (±5 y) and race/ethnicity, and
were identified using a standard neighborhood walk algorithm.15
Interviews and blood samples were obtained for 594 controls,
including 163 African‑Americans.
In both studies, advanced prostate cancer was defined
according to SEER 1995 pathologic and clinical extent of disease codes. Of participating cases, 1,164 (533 from Northern
California and 631 from Southern California) were diagnosed
with advanced stage, including 247 African‑Americans (107
from Northern California and 140 from Southern California).
Of participating cases from Southern California, 553 (including
211 African‑Americans) were diagnosed with localized disease.
The study was approved by the Institutional Review Boards
of the Northern California Cancer Center and the University of
Southern California. Written informed consent was obtained for
all subjects.
Genotyping. Two of the SNPs (rs1042636, and rs1801726)
were genotyped using an Illumina BeadLab System (San Diego,
CA) with GoldenGate® genotyping performed by the USC
Genomics Center. Samples were run in a 96-well format using
Illumina Sentrix Array technology, scanned on a BeadArray
Reader and analyzed using BeadStudio Software (v.3.0.9)
with Genotyping Module (v.3.0.27) (Illumina). In addition to
Cancer Biology & Therapy
997
duplicate samples, a set of 30 HapMap Trios were run for quality control purposes to compare genotype results with HapMap.
SNPs were automatically clustered using the BeadStudio software and clusters were manually edited to increase the call rate,
reduce replication errors, and reduce trio errors. Call rates were
95% for each of the two SNPs.
The rs1801725 SNP was genotyped on the TaqMan 7900HT
Sequence Detection System using the TaqMan Core Reagent Kit
(Applied Biosystems, Foster City, CA). PCR reactions were carried out using standard conditions recommended by the manufacturer. The following primer and probe sequences were used:
forward: 5'-CAC CTT CTC ACT GAG CTT TGA TGA,
reverse: 5'-AGG GAG TTC TGG TGC GTA GA, Vic-CCT
CAG AAG AAC GCC ATG, and FAM-CCT CAG AAG AAC
TCC ATG. Samples with known genotype were included as controls and clusters were manually called without knowledge of
case-control status. The call rate was 90%.
Of the 732 samples available for the study (107 cases and 85
controls from Northern California, 377 cases and 163 controls
from Southern California), 28 had insufficient DNA quantity to
be included on the Illumina panel and 25 were excluded due to
missing information on stage of disease. The number of subjects
with data on both CaSR genotype and stage of disease was 609
for rs1801725, 641 for rs1042636 and 642 for rs1801726.
Statistical analysis. Matching variables for conditional logistic regression were constructed by creating study site/socioeconomic status (SES) bins. An aggregate level SES variable was
derived from 2000 Census data on education, household income,
home value, proportion of blue collar workers, and proportion of
the population below poverty level in the census tract of residence
at the time of diagnosis (cases) or study selection (controls).16
Addresses that could not be geocoded to a census tract (n = 16)
were randomly allocated an SES quintile. The two lowest quintiles were collapsed at the Northern California site, and the two
highest quintiles were collapsed at each of the two sites, leaving
seven study site/SES groups (three from Northern California and
four from Southern California).
Allele frequencies were estimated by gene counting. Tests for
departures from Hardy Weinberg equilibrium among controls
were conducted by comparing observed and expected genotype
frequencies using a Chi Square test. Haplotype frequencies were
estimated using Haploview 4.1 (Cambridge, MA).17
Odds ratios (OR) and 95% confidence intervals (CI) were
estimated by fitting conditional logistic regression models, using
study site/SES as the matching variable and adjusting for age
998
(continuous variable) and family history of prostate cancer in
first-degree relatives (yes/no). To test for heterogeneity by stage of
disease, logistic models with stage (advanced vs. localized) as the
outcome variable were fit with and without a genotype term and
were compared using a likelihood ratio test. Average age at diagnosis was compared across genotypes using ANOVA (for three
genotype groups) and Student’s t test (for two genotype groups).
Satterthwaite’s approximation was used to allow unequal variances across genotype groups. Analyses were performed using
Stata/SE 10.0 (College Station, TX).
Acknowledgements
The Northern and Southern California studies were funded by
grants 99-00527V-10182 (to E.M.J.) and 99-00524V-10258
(to S.A.I.) from the Cancer Research Fund, under Interagency
Agreement #97-12013 (University of California contract
#98-00924V) with the Department of Health Services Cancer
Research Program and by grant R01CA84979 (to S.A.I.) from
the National Cancer Institute, National Institutes of Health.
Cancer incidence data used in this publication have been
collected by the Greater Bay Area Cancer Registry, of the Northern
California Cancer Center, under contract N01-PC-35136 with
the National Cancer Institute, National Institutes of Health,
and with support of the California Cancer Registry, a project
of the Cancer Surveillance Section, California Department of
Health Services, under subcontract 1006128 with the Public
Health Institute and the Los Angeles Cancer Surveillance
Program of the University of Southern California with Federal
funds from the National Cancer Institute, National Institutes
of Health, Department of Health and Human Services, under
Contract No. N01-PC-35139, and the California Department
of Health Services as part of the statewide cancer reporting
program mandated by California Health and Safety Code
Section 103885, and grant number 1U58DP000807-3 from the
Centers for Disease Control and Prevention. Mention of trade
names, commercial products, specific equipment or organizations does not constitute endorsement, guarantee or warranty
by the State of California Department of Health Services or
the U.S. Government, nor does it imply approval to the exclusion of other products. The views expressed in this publication
represent those of the authors and do not necessarily reflect the
position or policies of the Northern California Cancer Center,
the California Public Health Institute, the State of California
Department of Health Services, or the US Department of
Health and Human Services.
Cancer Biology & Therapy
Volume 9 Issue 12
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