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Colorectal cancer risks in Singapore Chinese: Polymorphisms in the insulin-like growth factor-1 and the vitamin D receptor

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Colorectal cancer risks in Singapore Chinese: Polymorphisms in the insulin-like growth factor-1 and the vitamin D receptor

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Content COLORECTAL CANCER RISKS IN SINGAPORE CHINESE:
POLYMORPHISMS IN THE INSULIN-LIKE GROWTH FACTOR-1 AND THE
VITAMIN D RECEPTOR.
by
Hui-Lee Wong
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(MOLECULAR EPIDEMIOLOGY)
May 2002
Copyright 2002 Hui-Lee Wong
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U M I Number: 1414858
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UNIVERSITY OF SOUTHERN CALIFORNIA
The Graduate School
University Park
LOS ANGELES, CALIFORNIA 900894695
This thesis, w ritten b y
U nder th e d irectio n o f h Thesis
C om m ittee, a n d a p p ro ved b y a ll its m em bers,
has been p re sen te d to a n d accepted b y The
G raduate School, in p a rtia l fulfillm en t o f
requirem ents fo r th e degree o f
CAto » ^
Dean o f Graduate Studies
D ate | Z O 1 0 ( '________
THESIS C O M M ITTEE
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TABLES OF CONTENTS
LIST OF TABLES iv
ABSTRACT V
INTRODUCTION 1
Colorectal Cancer 2
Singapore Chinese Health Study 2
Insulin-like Growth Factors 2
Vitamin D Receptor 3
Interaction between Insulin-like Growth Factor-1 and Vitamin D Receptor 5
Goals of the Study 5
MATERIALS AND METHODS 6
Study Population 6
Laboratory Measurements 7
Statistical Analysis 7
RESULTS 8
Insulin-like Growth Factor-1 8
Vitamin D Receptor 10
DISCUSSION 12
Insulin-like Growth Factor-1 12
Vitamin D Receptor 14
CONCLUSION 16
REFERENCES 17
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LIST OF TABLES
Table 1. Distribution of the IGF-1 alleles in Singapore Chinese control
subjects
Table 2. Gene dose effect of the IGF-1 CA19 allele in colorectal cancer,
Singapore Chinese Health Study
Table 3. Association of the IGF-1 19/19 genotype with colorectal cancer,
Singapore Chinese Health Study
Table 4. Association of the VDR Fokl genotype with colorectal cancer,
Singapore Chinese Health Study
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Introduction
Colorectal cancer
Colorectal cancer (CRC) incidence is rapidly rising in Westernized Asian
populations. Geographic clustering of this cancer implicates Western dietary
influence in its etiology. Further, gene-environment interactions causally involved in
CRC (reviewed by Potter 1999) is believed to potentially complicate risks in Asian
populations exposed to the inevitable globalization. As an indication of future trends,
migrant studies reveal that Japanese Hawaiian males are now hit with incidence rates
twice as high as foreign-born Japanese and 60% higher than those of US-bom white
men (Flood 2000).
Colorectal cancer in the newly industrialized Singapore, as in developed
countries, ranks as the second most frequent in incidence. The age-standardized
incidence rates in the Singapore Chinese have recently increased towards United
States Whites incidence rates (Cancer Incidence in S’pore 2000). The increasing
CRC trend in Singapore however did not mirror the current anatomical shift
experienced by Westernized countries i.e. from distal to proximal.
Among the players in colorectal carcinogenesis are the Insulin-like Growth
Factors (IGF) axis and the Vitamin D receptor (VDR). The present study investigates
colorectal cancer risk in relation to genetic variations in loci of IGF-1 and VDR
within the framework of the Singapore Chinese Health Study.
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Singapore Chinese Health Study
The Singapore Chinese Health Study is a population-based prospective study
initiated in 1993 to investigate dietary effects on cancer risks. Information that
included dietary and cancer risk factors were compiled on the participants followed
by collection of blood samples from a random 3% of the cohort and all CRC cases.
The target population, the Republic of Singapore, is a Southeast Asian island nation
of 87% ethnic Chinese. In general, compared to US Whites and Blacks, this
Singapore cohort has lower intakes of dietary fats, calcium and alcohol (Hankins,
submitted). From the Singapore Chinese Health Study with available DNA, the
present study utilized 149 colorectal cases and 710 healthy cohort subjects.
Insulin-like Growth Factors
Insulin growth factor-1 (IGF-1) is a potent survival factor for colorectal cells:
a strong mitogen in colon epithelial cells (Lahm 1992) and apoptosis inhibitor (Wang
1994, Playford 2000). Indeed, IGF-1 circulating levels have been positively
associated with the occurrence of colorectal cancer (Ma 1999, Manousos 1999;
Kaaks 2000; Giovannucci 2000).
Circulating IGF-1 levels may be, in part, genetically determined. In two
studies, (Rosen1998; Jemstrom 2001), lower circulating IGF-1 levels were observed
among individuals homozygous for the 19-repeat allele of a (CA)n polymorphism
one kilobase upstream from the IGF-1 gene transcription start site. However,
association between an IGF-1 polymorphism and cancer has yet to be reported. To
determine whether homozygotes for the 19-repeat allele are at decreased risk for
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colorectal cancer, we genotyped this IGF-1 (CA)„ polymorphism in 149 colorectal
cancer cases and 710 non-diseased Singapore Chinese. This thesis summarizes the
association studies of colorectal cancer with the IGF-1 polymorphism.
Vitamin D Receptor
Vitamin D is anticarcinogenic against colon neoplasia; the evidence is from
epidemiologically, in vitro and animal studies. Lower mean levels of its serum
Vitamin D metabolite, 25(OH)D (Garland 1989; Braun 1995; Tangrea 1997 and Niv
1999) is associated with increased risk of colon carcinoma. Cell culture studies
demonstrated the antiproliferative(Liu 1996), proapoptotic (Mathiasen 1999) and
antioxidant (reviewed in Chatteqee 2001) actions of Vitamin D. Most convincingly,
ablation of the receptor for Vitamin D in mice predisposes to formation of the
colonic tumors (Kallay 2001).
The receptor for Vitamin D (VDR) mediates the protective actions of the
hormonally active Vitamin D, l,25(OH)aD3 (Narvaez 1996, reviewed in Narvez
2001). Upon activation by Vitamin D, the receptor (VDR) binds to the promoter of
target genes such as the gene encoding the cell- cycle regulator protein, p21 (Liu
1996), to result in decreased proliferation in colon cancer cells (Scaglione-Sewell,
2000). We hypothesize that dysregulation of the transactivation of VDR downstream
signaling in cell differentiation and apoptosis may predispose to colorectal cancer.
A polymorphism in exon 2 of the VDR gene changes the first of two initiation
codons from ATG to ACG, resulting in a receptor protein that is shorter by three
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amino acids (Gross 1996). The shorter allele, designated as F, was previously shown
(Arai 1997; Jurutka 2000) to be more efficient at transactivating vitamin D-regulated
target genes. This Fokl polymorphism singularly produces two structurally distinct
VDR isoforms. The product of the shorter allele, designated as F hVDR, was
previously shown to be more efficient at transactivating vitamin D-regulated target
genes (Arai 1997; Jurutka 2000). The mechanistic link was evidenced by the shorter
F hVDR demonstrating stronger interactions with basal transcription factor IIB, more
efficient transactivation in physiologically relevant cell lines {i.e. osteoblasts), and
higher endogenous F hVDR transcriptional activity in fibroblast cells (Jurutka 2000).
Accordingly, the subpopulation carrying the more active allele is
hypothesized to be at lower risk of CRC. By comparison with other cancers, a recent
malignant melanoma study did report lower risk associating with homozygozity for
the more active allele in small hospital based case-control study (Hutchinson 2000).
No associations with were demonstrated with breast cancer (Curran 1999; Ingles
2000) and prostate cancer risk (Correa-Cerro 1999).
The goal of this study is to determine whether risk of colorectal carcinoma in
a cohort of Singapore Chinese depends on the VDR start codon polymorphism.
Genotypes for this start site polymorphism were determined by a Fokl restriction
fragment length polymorphism (RFLP) in 149 colorectal cancer cases and 710 non
disease members of the Singapore Cohort Study. This report presents the relative
risks associated with the genotypes, stratified by site of the tumors and discussion on
the possible implications of the results.
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Interaction between IGF-1 and VDR
Evidence is accumulating for the involvement of the IGF axis in the VDR-
mediated l,25(OH)2D3 induced growth arrest. IGF-1 and 1,25(OH)2D3 mutually
upregulate their respective receptors (VDR and IGF1R) in growth plate
chondrocytes. In fact, IGF-1 stimulates VDR expression by fourfold (Klaus 1998).
To the author’s knowledge, only one reported epidemiologic study examined the
cross-talk between the two hormone systems i.e. a population based prostate case-
control in Shanghainese Chinese that found an interaction between plasma IGFBP3
and the ff genotypes, homozygotes for the postulated less active VDR allele on
cancer risk (Chokkalingam 2001).
Goals o f the study
Scarce data exist on the effects of the IGF-1 and VDR polymorphisms on
cancer susceptibility in Asian populations. The present study utilizes the resources
assembled by Yu and colleagues to examine the relations between colorectal cancer
and
1) the sole IGF-1 allele reported to associate with an IGF-1 related phenotype,
bone mineral density: the 19 (CA)n microsatellite, denoted in this study as
19CA.
2) the only demonstrably functional natural VDR polymorphism: Fokl C/T start
site polymorphism.
This study is powered to detect 94% of a two-fold risk effect of homozygotes
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for the postulated risk allele vs. all other genotypes (allele frequency = 0.5;
approximating the published Asian Fokl allele frequencies and Japanese IGF-1 19
(CA) repeat allele frequency).
Genetic variation in the IGF-1 and VDR pathways may contribute, in part,
towards attentuating colorectal cancer risk in Asian populations. This study was
designed to test the above hypothesis in hopes of working towards the etiology of
colorectal cancer and development of prevention strategies.
Material and Methods
Study population
Subjects were 859 participants in the Singapore Chinese Health Study. All
cohort enrollees provided detailed questionnaire information including validated
dietary intake frequency (Hankins submitted). Genomic DNA was available for 149
colorectal cancer subjects and 710 control subjects. The mean age for colorectal
cancer subjects was 66.4, and for healthy subjects was 59.3 years. Females comprise
53% of the controls and 42% of the colorectal subjects. Cases and controls do not
significantly differ in alcohol consumption, tobacco consumption, total dietary
calcium, total dietary fiber and total dietary fats. Only 85% of this study population
reported their weight. Thus, BMI and weight were not adjusted in the current
analyses but will be adjusted in future analyses once the imputed BMI values are
available. This study was conducted in compliance with the institutional review
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boards of the University of Southern California and the National University of
Singapore. All subjects signed informed consent.
Laboratory measurements
Genotypes. Two genes, IGF-1 and VDR, were examined. The genomic region in
IGF-1 containing the CA repeat was amplified with oligonucleotides as described by
Rosen (Rosen 1998). The 3 3 P-labeled PCR products were separated on 6%
denaturing polyacrylamide gels and visualised by autoradiography. The T/C
substitution polymorphism in the VDR start site was assayed by Fokl restriction
endonuclease digestion (Promega, Madison WI) of PCR amplified DNA as
previously described (Gross et al. 1996). All genotype batches included at least one
homogygote (ff) to ensure complete restriction enzyme reaction and one non
template control for contamination. Genotypes were scored by two independent by
two independent investigators and 5% of the genotypes were repeated with
laboratory staff blinded to repeat status.
Statistical Analysis
The observed allele frequencies among controls were used to calculate the
expected genotype frequencies under Hardy-Weinberg equilibrium. Departures from
t ■j
Hardy-Weinberg equilibrium were assessed with a x test where sample size
permitted.
Unconditional logistic regression models were fit using SAS software (SAS,
Cary NC) to obtain maximum likelihood estimates of the OR and 95% CL Gene dose
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effect was examined with tests for trend by assigning an ordinal value of 0,1 and 2 to
each of the categorical genotypes and treating the variable as continuous in the
logistic regression model. Age and sex were retained in every model. Risk factors
considered as potential confounders were estrogen use, physical activity, alcohol
intake, tobacco intake and caloric-adjusted dietary intake of protein, fat and fiber.
Covariates were included if they resulted in a 10% change in the regression
coefficients.
Power for this study was estimated using Power Ver.1.31 (Epicenter
Software, Pasadena). All Ps in this report are two-sided.
Results
Insulin Growth Factor-1
There were eleven IGF-1 alleles observed in the Singapore Chinese
population (Table 1). The 19 CA repeat allele, at a frequency of 35.1%, was the most
frequent in healthy females and males. We detected two rare short alleles, CA
repeats of 12 and 15 not reported in previous studies.
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Table 1 Distribution of IGF-1 alleles in Singapore Chinese control subjects
Number of CA Allele frequency (%)
repeats Controls
(n=1420)
Colorectal Cancer
(n=308)
12 7 (0.5) 2 (0.7)
15 2 (0.2) 0 (0)
16 2 (0.2) 0 (0)
17 113(8.0) 31 (10.0)
18 236 (16.6) 65 (21.1)
19 499 (35.1) 101(32.8)
20 76 (5.4) 20 (6.5)
21 437 (30.7) 85 (27.6)
22 42 (2.9) 4 (1.3)
23 6 (0.4) 0 (0)
For the 19 CA-repeat allele, previously associated with lower levels of
plasma IGF-1 (Rosen et al. 1998; Jemstrom et al. 2001), we estimated ORs and
tested for a gene dose effect (zero vs. one vs. two copies) as summarized in Table 2.
Table 2 Gene dose effect of the IGF-1 CA19 allele in colorectal cancer,
Singapore Chinese Health Study
Genotype Cases (%) Controls (%) O Ra
other/other 65(42.2) 308(43.3) 1.0(referent)
19/other 77(50.0) 305(43.0) 1.2(0.8-1.8)
19/19 12(7.8) 97(13.7) 0.6(0.3-1.2)
Given that lower levels of serum (Rosen et al. 1998) and plasma (Jemstrom
et al. 2001) IGF-1 were reported only among homozygous carriers of the 192 allele
and no increased risk observed among heterozygotes (Table 2), we also compared
homozygous carriers of the 19CA allele (19/19 genotype) to the heterozygotes and
non-carriers combined (Table 3). Two copies of the 19CA allele (19/19 genotype)
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conferred a nearly 50% reduction in colorectal cancer risk, after adjusting for age
and sex (OR=0.51; 95% CI= 0.26, 0.99).
Table 3 Association of the IGF-1 19/19 genotype with colorectal cancer,
Singapore Chinese Health Study
Genotype Cases (%) Controls (%) ORa
Non-19/19 142(92.2) 613(86.3) 1.0(referent)
19/19 12(7.8) 97(13.7) 0.51(0.26-0.99)
a risk estimates from unconditional logistic regression after adjusting for age at blood specimen collection (continuous) and
gender.
The other two most common alleles, 18CA and 21CA allele were also
subjected to similar analyses. Neither was associated with colorectal cancer (data not
shown). We also explored other ways of categorizing genotypes such as analyzing
the three most common genotypes (19/21, 19/20 and 21/21 CA repeats) respectively
as compared to all other and by grouping the eleven alleles into either the
dichotomous or four largest categories. None of the analyses indicated any
significant association (data not shown).
Vitamin D Receptor
The frequency of the shorter VDR allele (F allele) among the cohort controls
(54.7%) is similar to previously reported Asian populations (Arai 1997; Minamitani
1998; Ingles 2001). In the gene dose analysis, risk ratios for the f allele
heterozygotes and homogygotes, compared to the FF homogygotes were similar
(Table 4). Thus, we compared the combined groups of heterozygotes and
homogygotes for this f allele to homozygotes for the more active F allele. The
presence of at least one of the longer alleles (genotype Ff or ff) increased age and
gender-adjusted risk of colorectal cancer (OR=1.6; 95%CI: 1.0,2.4). The effect is
to
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specific to colon cancer (OR=2.2; 95%CI: 1.2, 3.9) rather than rectal cancer
(OR=1.0; 95%CI: 0.5, 1.7). In the colon, the risk elevation is more pronounced in the
left/distal region (OR=2.5; 95%CI: 1.2, 5.1) than in the right/proximal region
(OR=T.6; 95%CI: 0.6, 4.0). The analyses were stratified on calcium and gender but
no effect modification was observed (data not shown).
Table 4 Association of the VDR Fokl genotype with colorectal cancer,
_________ Singapore Chinese Health Study_________________________
Site Genotype Controls (%) Cases (%) O Ra
Colorectal FF 207(29.3) 32(21.5) 1.0(referent)
Ff 356(50.4) 84(56.4) 1.6(1.0,2.5)
ff 143(20.3) 33(22.1) 1.5(0.9,2.7)
FF & ff 499(70.7) 117(78.2) 1.6(1.0,2.4)
( P t r e n d = 0 .1 2 j °
I. Colon FF 207(29.3) 15(16.1) 1.0(referent)
Ff & ff 499(70.7) 78(83.9) 2.2(1.2,3.9)
LA Proximal FF 207(29.3) 6(21.5) 1.0(referent)
Ff & ff 499(70.7) 22(78.5) 1.6 (0.6, 4.0)
I.B Distal FF 207(29.3) 9(13.9) 1.0(referent)
Ff & ff 499(70.7) 56(86.1) 2.5 (1.2, 5.2)
II. Rectal FF 207(29.3) 17(30.4) 1.0(referent)
Ff & ff 499(70.7) 39(69.6) 1.0(0.5,1.7)
“ risk estimates from unconditional logistic regression after adjusting for age at blood specimen collection (continuous) and
gender.
b test of trend for gene dose effect o f the three genotypes (zero vs one vs two copies o f the shorter VDR,f, allele), adjusted for
age at blood specimen collection (continuous) and gender.
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Discussion
Insulin-Like Growth Factor-1
To our knowledge, this is the first report associating an IGF-1 polymorphism
with any neoplasm. In this Singapore Chinese cohort, homozygosity for the CA 19
allele was associated with decreased risk of colorectal cancer. This study supports
our hypothesis that the CA19 genotype, reported to associate with lower serum IGF-
1 levels (Rosen 1998, Jenstrom 2001) will confer lower colorectal cancer risk in
Singapore Chinese.
These data are consistent with previous studies linking IGF-1 to colonic
neoplasia. In two prospective case-control studies (Ma et al. 1999, Giovannucci et al.
2000), the authors concluded that elevated pre-diagnostic plasma levels of IGF-1
levels, after controlling for IGFBP-3 plasma levels, were associated with colorectal
risk. This was due to a significantly higher risk in the uppermost compared to the
lowest category of serum IGF-1 (OR=2.5, 95%CI: 1.15-5.46; OR=2.18, 95%CI:
0.94-5.08). Acromegalics, individuals with abnormally elevated levels of circulating
IGF-1, are also at increased risk for colorectal cancer (Jenkins et al. 2000). The
statistical power of this current study is insufficient to yield precise estimates of risk.
The observed association between IGF-1 and colonic neoplasm is not biologically
implausible and warrants a larger study of this IGF-1 polymorphism in colorectal
patients.
However, one limitation of this study is the lack of unestablished functional
relevance of the described polymorphism. One speculation was that the CA 19 allele
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induces conformational changes the IGF-1 promoter containing the estrogen
response elements, ERRE (Jemstrom et al. 2001). However, we believe that this
explanation is unlikely since this polymorphism does not lie in the ERRE region
(McCarthy et al 1997). We were unable to venture alternatives that argue for this
polymorphism as causal.
The argument that the CA 19 allele is not a causal polymorphism does not
necessarily negate the two reported associations between the CA19 allele and low
plasma IGF-1 levels. This CA repeat may instead be in linkage disequilibrium with
one nearer to the IGF-1 promoter. To test this hypothesis, De Lellis and colleagues
sequenced the one kilobase pair region between the CA microsatellite repeats and the
ATG translation site and identified two new single nucleotide polymorphisms
(DeLellis K, manuscript submitted). The two SNPs are in perfect linkage
disequilibrium with each other. One of the two new SNPs, an A/T polymorphism
that lies 424 bps from start site 2, lies within putative GATA elements of the highly
conserved IGF-1 promoter that potentially regulates the rat IGF-1 promoter activity
(Wang 2000). The IGF-1 gene is transcribed from two promoters that direct
synthesis of alternative first exons (exon 1 and exon 2) in the IGF-1 mRNAs (Tobin
1990). The SNPs lie in the region where the majority of the mRNA is transcribed
from the upstream TATA-less promoter in exon 1, namely start site 2 and 3 (out of a
total of four start sites). Preliminary data on 475 (55.4% of the study population)
subjects show that the T allele is in partial linkage with the CA19 allele. Genotyping
data to complete the study is being generated. Functional impact of the new SNP
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needs to be determined. Analyses will be performed to test if the new SNP can
explain the observed association between CA19/19 genotype with colorectal risk.
Vitamin D Receptor
This study, to the best of our knowledge, is the first to indicate an association
between a VDR variant and colon cancer. Homozygosity for the wild-type F allele
reduced colon cancer risk by 50%. The protective effect observed with the more
active VDR Fokl variant suggests that more efficient transactivation of VDR target
genes attentuates colon cancer risk. Our findings are consistent with knock-out
mouse data demonstrating that ablation of VDR predisposes mice to colonic
hyperproliferation, particularly in the distal colon (Kallay 2001). The observed VDR
Fokl effect is pronounced in distal colon cancer, indicating site-specificity in colonic
carcinogenesis.
The receptor (VDR) is thought to mediate most of the protective effects of
Vitamin D. In colon stem cells, the actions of l,25(OH)2D3 depend on local VDR
levels (Shao et al. 2001). This dependence argues for significant, if not exclusive,
genomic induction of the antimitogenic effects of l,25(OH)2D3 for preventing
colonic carcinogenesis. The present study was motivated by evidence demonstrating
functional altered natural receptor variants. Thus, we postulated that differential
transactivation by allelic variants of VDR target genes in colorectal cells can alter
intestinal differentiation and thus, impact susceptibility to sporadic colorectal cancer.
This study supports our hypothesis by revealing that the presence of the predicted
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less active allele enhances risk for colorectal cancer (OR=l,6; 95%CI: 1.0, 2.4),
specifically in colon cancer (OR=2.2; 95%CI: 1.2, 3.9) and preferentially with distal
colon cancer (OR=2.6; 95%CI: 1.3, 5.3). This implies that intestinal epithelial cells
exposed to lower VDR transactivation abilities are susceptible to malignancy.
More interestingly, this finding of specific susceptibility to the left colon
supports prior suspected etiologic differences in proximal and distal colon
carcinogenesis. Two forms of genomic instability were observed in colorectal
carcinoma: sporadic microsatellite instability exclusively in the proximal site, and
chromosomal instability predominating in the distal (reviewed in Lindblom 2001).
Epidemiological data have indicated a shift of subsite CRC distribution in
westernized countries from the distal to the proximal (Levi 1998). On the contrary,
colon cancer incidence rates in Singapore Chinese revealed a higher risk for distal
lesions of the colon over the proximal (Huang 1999). Screening and preventive
policies may contribute to the differing anatomical distribution trend between
Singapore and westernized countries. Mechanisms of in the tumorigenesis colon are
believed to differ from rectum. Accordingly, no association was seen with rectal
cancer.
Since experimental evidence indicated interaction between the IGF system
and the VDR pathway, we further assessed the difference in plasma levels IGFs
among the three VDR genotypes in controls (levels of plasma IGF1 and its main
binding protein IGFBP3 were kindly available from Dr. Probst, University of Basel).
This study, not initially powered to detect interactions, did not find any significant
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differences. Future work can investigate how plasma IGFs influences the effect of
VDR f allele on the risk of colorectal cancer. A recently reported IGFBP3 functional
polymorphism (Deal 2001) and an ELISA for VDR measurements (Swami 2001)
may assist in examining how the combination of genetic variants and systemic levels
in both the IGFs and VDR pathways modulate colorectal cancer risk in Asian
populations.
Conclusion
In conclusion, to our knowledge, this is the first report of an association of a
VDR polymorphism with colorectal carcinoma. These findings support the site-
specific role of VDR in colon cancer susceptibility and perhaps, in distal
carcinogenesis. Confirmation in a larger series is warranted.
To our knowledge, this is also the first report of an IGF-1 polymorphism with
any neoplasm. Since the plasma IGF-1 levels do not correlate with the postulated
protective polymorphism, the undetermined functional relevance of this
polymorphism warrants restrained interpretations of this finding. Thus, we are
currently investigating two newly identified polymorphisms within 1 cM of the
described CA polymorphism in the IGF-1 promoter region as genetic predictors of
IGF-1 bioavailability and cancer risk.
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Asset Metadata

Creator Wong, Hui-Lee (author)

Core Title Colorectal cancer risks in Singapore Chinese: Polymorphisms in the insulin-like growth factor-1 and the vitamin D receptor

School Graduate School

Degree Master of Science

Degree Program Molecular Epidemiology

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag health sciences, oncology,health sciences, public health,OAI-PMH Harvest

Language English

Contributor Digitized by ProQuest (provenance)

Advisor [illegible] (committee chair), [illegible] (committee member)

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c16-299515

Unique identifier UC11341288

Identifier 1414858.pdf (filename),usctheses-c16-299515 (legacy record id)

Legacy Identifier 1414858.pdf

Dmrecord 299515

Document Type Thesis

Rights Wong, Hui-Lee

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the au...

Repository Name University of Southern California Digital Library

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