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CYP17 polymorphism and risk for colorectal adenomas
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CYP17 polymorphism and risk for colorectal adenomas
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INFORMATION TO USERS
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CYP17 POLYMORPHISM AND RISK FOR
COLORECTAL ADENOMAS
by
Elizabeth Osth
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(MOLECULAR EPIDEMIOLOGY)
December 1999
Copyright 1999 Elizabeth Osth
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UMI Number: 1409653
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UNIVERSITY O F S O U T H E R N CALIFORNIA
THE GRADUATE SCHOOL.
UNIVERSITY PARK
LOS AMOELES. C A LIFO R N IA 1 0 0 0 7
This thesis, written by
e u s A e f r - r l J M _____________________
under the direction of h J L C . Thesis Committee,
and approved by all its members, has been pre
sented to and accepted by the Dean of The
Graduate School, in partial fulfillment of the
requirements for the degree of
W f & c e z . o f s & te^ C E .
THESIS COMMITTEE
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NOTE TO USERS
Page not included in the original manuscript is
unavailable from the author or university. The
manuscript was microfilmed as received.
• ■
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This reproduction is the best copy available.
UMI'
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ACKNOWLEDGEMENTS
Dr. Sue Ingles has been an inspiring mentor. I greatly appreciate her kindness, her
patience, and her presence in the lab to answer all of my silly questions. I feel
honored to be her first student to complete the Master’s in Molecular Epidemiology.
I would like to take this opportunity to express my gratitude to my committee
members. Dr. Heinz Lenz and Dr. Robert Haile.
Last, but not least, my classmates, friends, and labmates: Rowena, Wendy, Jun, and
Katie. Thanks to you all.
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TABLE OF CONTENTS
DEDICATION ii
ACKNOWLEDGEMENTS iii
LIST OF TABLES v
ABSTRACT vi
BACKGROUND I
MATERIALS AND METHODS 4
RESULTS 7
DISCUSSION 16
REFERENCES 18
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LIST OF TABLES
Table 1 Genotype Frequency (%), controls only 10
Table 2 Odds ratios adjusted for matching variables 1 1
Table 3 Analysis stratified by HRT and BMI 12
Table 4 Stratification of not current HRT users by BMI
and adjusted for possible confounders 13
Table 5 Odds ratios stratified by ethnicity 14
Table 6 Analysis stratified by BMI and adjusted for
possible confounders. Whites only 15
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ABSTRACT
Recent findings on hormone replacement therapy (HRT), genetic control of estrogen
levels, and age and sex differences in the incidence of colorectal cancer have
motivated the hypothesis that genetically controlled variation in endogenous estrogen
levels might influence risk for colorectal cancer in women. We conducted a case-
control study of 327 colorectal adenoma cases and 361 controls of age 50 to 75. All
subjects were members of a prepaid health plan in Los Angeles who underwent
sigmoidoscopy in 1991-1993. We found that subjects carrying at least one copy of
the CYP17 A2 allele were at increased risk of colorectal adenomas. Compared to
subjects with the A l/A l genotype, the odds ratios were 1.2(CI: 0.9,1.7) for subjects
with genotype A1/A2 and 1.7(CI: 1.1.2.6) for subjects with genotype A2/A2.
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VI
BACKGROUND
Several studies have reported protective effects of hormone replacement therapy (HRT)
against colon cancer (1,2,3,4). Results from these studies raise the question of whether
there is an association between endogenous estrogen levels and risk for colon cancer.
CYP17 is an estrogen metabolism gene. The gene CYP17 encodes the cytochrome
P450cl7a (5). P450cl7a has two enzymatic activities, both under ACTH regulation via
cAMP in the steroidogenic pathway of the adrenal cortex, thecal cells of the ovary and
the testis. 17a-hydroxylase activity converts pregnenolone to 17-OH pregnenolone. 17,
20 lyase activity converts 17-OH pregnenolone to DHEA, the precursor to
androstenedione. Androstenedione and DHEA are precursors of estradiol and
testosterone. The enzymatic actions of P450cl7 are critical to the metabolism of
estradiol, thus, polymorphism in CYP17 is the subject of much curiosity.
A single nucleotide polymorphism in the 5’ region of CYPI7 has been documented (7).
34 basepairs upstream from the initiation of translation a T is replaced by a C to create an
SPl-type (CCACC box) promoter site along with a recognition site for the digestive
enzyme MspA 1. The allele that contains the basepair change is the less common allele,
and will be referred to as the A2 allele. The published sequence will be referred to as the
A1 allele.
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Previous studies by Feigelson et al. (8,9) and Haiman et al. (10) have examined
associations between polymorphism in CYP17, hormone levels, and breast cancer risk.
The study by Feigelson et al. (9) examined a group of premenopausal women. Among
women carrying one or two copies of the CYP17 A2 allele compared to A l/A l women,
serum estradiol levels measured on day 1 1 of the menstrual cycle were 11% and 57%
higher (P=0.04). On cycle day 22 serum estradiol were 7% and 28% higher (/*=0.06),
and progesterone levels were 24% and 30% higher (f*=0.04). The mean age of menarche
among the A l/A l women was statistically significantly later than in women carrying the
A2 allele (13.4 versus 13.0, P=0.047) (Feigelson et al., 1997). The study by Haiman et
al. examined a group of 297 postmenopausal women. They found that A2 homozygotes
compared to Al homozygotes had elevated levels of estrone (+14.3%, P=0.01), estradiol
(+13.8%, P=0.08), testosterone (+8.6%, P=0.34), androstenedione (+17.1%, P=0.06),
DHEA (+14.4%, P=0.02) and DHEAS (+7.2%, P -0.26). Results associating CYP17
with breast cancer risk remain controversial. Two studies show an association between
the CYPI7 A2 allele and breast cancer, a disease related to estrogen exposure. Feigelson
et al. (8) conducted a case-control study showing an increased risk in women carrying the
A2 allele (OR=2.5; 95% Cl, 1.02-5.94). Bergman-Jungestrom et al. ( 11) also showed an
increased risk in carriers of the A2 allele (OR=2.0; 95% Cl, 1.1-3.5), but this study was
restricted to women less than 36 years of age. Four other studies showed no significant
associations (10,12,13,14). A third study by Feigelson et al. (15) found that the CYPI7
polymorphism is not only associated with hormone levels, but also predicts use of HRT.
Women who were A2 homozygotes were less likely than A l homozygotes to be current
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users of HRT than never users after adjusting for age, ethnicity, and weight (OR=0.54;
95% Cl, 0.31-0.92).
Genetic control of estrogens and the association of HRT with colon cancer have
motivated our hypothesis that genetically controlled variation in endogenous estrogen
levels might influence risk for colorectal adenoma in postmenopausal women. And, that
the CYPI7 A2 allele, being associated with higher levels of endogenous estrogens, would
be protective against the development of colorectal adenomas. The effects in men will
also be analyzed.
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3
MATERIALS AND METHODS
Study Population
Blood samples were obtained and DNA extracted from subjects who underwent
sigmoidoscopy at either of two Southern California Kaiser Permanente Medical
Centers(Bellflower and Sunset) from January 1, 1991 through August 25, 1993. Eligible
subjects were ages 50-75: were free of invasive cancer, inflammatory bowel disease, and
familial polyposis; were fluent in English; had no previous bowel surgery; were residents
of the metropolitan Los Angeles area; and had no physical or mental disability precluding
an interview. Subjects were excluded if they had symptoms that suggested any organic
intestinal disease. Cases were subjects diagnosed for the first time with one or more
histologically confirmed adenomatous polyp. Controls had no polyps of any type at
sigmoidoscopy, had no history of polyps, and were individually matched to cases by
gender, age (within 5-year categories), date of sigmoidoscopy (within 3-month
categories), and Kaiser Center.
Laboratory Methods
The CYP17 assay has been previously described (Carey et al., 1994). Briefly, a PCR
fragment containing the polymorphism was generated using the following primers: CYP-
1, 5-CATTCGCACTCTGGAGTC-3, and CYP-2, 5-AGGCTCTTGGGGTACTTG-3.
PCR reactions were carried out in 13-p.l aliquots containing 25 ng of genomic DNA, 2.5
pmol of each primer, IX reaction buffer[50 mM KCL, 1.5 mM MgCla, and 10 mM Tris
(pH 9.0 at room temperature)], 0.25 mM deoxynucleotide triphosphates, and 1.5 units of
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Taq polymerase. The amplification was for 33 cycles with denaturation at 94°C for 1
min, annealing at 57°C for 1 min, and extension at 72°C for 5 min were used. The PCR
products were digested for 3 h at 37°C using MspM, separated by gel electrophoresis,
and stained with ethidium bromide. Homozygotes with the polymorphism (A2/A2
individuals) generated one 335 bp fragment. Heterozygotes (A1/A2 individuals)
generated two fragments of 335 and 459 bp. Homozygotes (A l/A l individuals)
demonstrated an uncut product at 459 bp.
Data Analysis
The distribution of the CYPI7 genotype stratified by sex and ethnicity was analyzed to
check for agreement with the Hardy-Weinberg equilibrium. Logistic regression models
were used to determine the association between the CYPI7 genotype and development of
colorectal adenomas. In order to observe the effects of increasing number of A2 alleles
on the odds ratio, trend tests were conducted. The models were adjusted for ethnicity
along with the matching variables: age. sex, exam date, and exam location. An
assessment of the potential confounders, BMI (<26 vs. >26), exercise (continuous
variable), and smoking (current vs. non), was conducted. Confounders were selected
based upon the confounders adjusted for in the study by Chen et al.(5) to enable
comparability of results. This study analyzed the association between HRT and
colorectal adenoma risk using the same data. In response to results of this study and
other previous studies showing an association between HRT and colorectal adenoma,
HRT was also examined as a possible confounder or effect modifier. The HRT variable
used was defined as HRT use (including estrogen only, progestin only, combined
5
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therapy) during the year prior to the sigmoidoscopy vs. no use of HRT during the year
prior to sigmoidoscopy. The data was further analyzed after stratification by adenoma
site, sex, and BMI to detect any differences in the odds ratios.
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RESULTS
The CYP17 genotype distribution of the controls stratified by sex and ethnicity is shown
in Table 1. The allele frequencies are similar to those previously observed (8). Allele
frequencies were similar for Non-Hispanic Whites, African-Americans, and Latinos.
Among Asians, the A2 allele was more common. Genotype frequencies were in Hardy-
Weinberg equilibrium (x2. 1 d.f. = 0.048) analyzing all ethnic groups combined.
However, when stratified by ethnicity the distribution of alleles for Asians were not in
Hardy-Weinberg equilibrium (x2, 1 d.f. = 4.15). The differences in the Asian population
could be due to small sample size. In order to maintain comparability to data of previous
studies (5), analyses were conducted with all ethnic groups combined.
Compared with subjects of the CYPI7 genotype A l/A l, carriers of the A2 allele had
increased risk of developing colorectal adenomas (Table 2). A1/A2 subjects showed an
odds ratio of 1.2 (95% Cl, 0.9-1.7) and A2/A2 subjects showed an odds ratio 1.7 (95%
Cl, 1.1-2.6). There was a significant trend in increased risk with increasing number of
copies of the A2 allele (p trend = 0.03). The model adjusted for possible confounding
variables yielded essentially the same results.
Stratification by adenoma site (rectal vs. left colon) revealed little evidence for
heterogeneity. Odds ratios were slightly higher for left colon than for rectum. The trend
of increased risk with increasing number of A2 alleles was statistically significant for
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colon (p trend = 0.03) but not for rectal adenomas (p trend = 0.30). The differences may
be due to the smaller number of rectal adenoma cases.
Both postmenopausal female and male carriers of the A2 allele showed increased risk for
colorectal adenomas, with similar trends for increasing relative risk with increasing
number of A2 alleles (Table 2). The odds ratios were slightly lower in females and were
not statistically significant which may be due, in part, to the smaller number of female
subjects. Female carriers of the A2 allele were only at increased risk for colon, but not
rectal adenoma. Among males, the A2 allele conferred increased risk for both colon and
rectal adenoma.
Both HRT use and BMI may influence estrogen levels. No confounding or effect
modification was observed between use of HRT and the CYP17 genotype; however, BMI
modified the effect of CYPI7 genotype in both male and female subjects. Analyses were
conducted with colon and rectal subsites combined. Analyses conducted on the colon
subset showed no evidence of heterogeneity compared to the combined analysis. Women
with high BMI (>26) showed increased risk associated with the A2 allele. Conversely,
low BMI women (<26) showed no increase in risk (table 3). Stratification of women who
do not use HRT by BMI revealed more significant differences by body mass (table 4).
Quite different results were observed among men. Men with high BMI (>26) showed a
modest, non-significant increase in risk associated with the A2 allele, whereas men with
normal BMI (<26) showed a much higher and statistically significant increase in risk.
The model adjusted for exercise and smoking showed no change in the odds ratios.
8
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To determine whether BMI or HRT might be intermediate variables, we examined the
association between these two variables and CYP17 genotype. Mean and median BMI
did not vary by genotype. Consistent with previous studies ( 15), women with the A2/A2
genotype compared with Al/Al women were less likely to use HRT, however the
difference was not statistically significant (OR = 0.7; 95% CL 0.3-1.6). These results
may be due to small sample sizes. Only 71 women were current users of HRT, 13 were
A2 homozygotes and 28 were A 1 homozygotes.
After stratification by ethnicity, the CYPl 7 genotype showed association with increased
risk of development of colorectal adenomas only in the white population (Table 5). In
response to the paradoxical results in females and the puzzling significant results in
normal weight men the previous analyses were repeated on the white subset of the study
population. Table 6 illustrates the results of the analysis. Interestingly, the heterogeneity
by BMI was no longer observed in women or in men. No significant association between
CYPl 7 genotype and colorectal adenomas was observed in the female population. The
sample size of not current HRT users in the White population was too small to stratify by
BMI. However, there is a significant increase in risk in males carrying two copies of the
A2 allele.
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Table 1: Genotype Frequency (%), controls only
A l/A l A1/A2 A2/A2 Total
all 131(36.3) 171(47.4) 59(16.3) 361
females 53(36.8) 66(45.8) 25(17.4) 144
males 78(35.9) 105(48.4) 34(15.7) 217
Non-Hispanic Whites 76(36.0) 108(51.2) 27(12.8) 211
African-Americans 22(36.7) 29(48.3) 9(15.0) 60
Latinos 22(44.0) 23(41.8) 10(18.2) 55
Asians 11(31.4) 11(31.4) 13(37.1) 35
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Table 2: Odds ratios adjusted for matching variables*
A1/A2 A2/A2 p trend
Cases Controls OR Cl OR Cl
All 327 361 1.2 (0.9,1.7) 1.7 (1.1,2.6) 0.03
Colon 227 360 1.3 (0.9,1.9) 1.8 (1.1,2.9) 0.03
Rectal 99 360 1.2 (0.7,2.1) 1.4 (0.7,2.7) 0.3
Females 144 144 1.2 (0.7,2.1) 1.5 (0.8,3.0) 0.21
Colon 96 144 1.3 (0.7,2.4) 1.8 (0.8,3.8) 0.15
Rectal 47 144 1.1 (0.5,2.4) 1.0 (0.4,2.7) I
Males 183 217 1.3 (0.8,2.1) 2.0 (1.1,3.7) 0.03
Colon 131 216 1.3 (0.8,2.2) 2.1 (1.0,4.1) 0.04
Rectal 52 216 1.4 (0.7,2.9) 1.6 (0.6,4.2) 0.28
*data was controlled for ethnicity and matched on age, exam date, exam location, and sex
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11
Table 3: Analysis stratified by HRT and BMI*
A1/A2 A2/A2
Cases Controls O R C l O R C l
All
BMI <=26 121 180 1.1 (0.6,2.0) 1.8 (0.9,3.6)
BMI > 26 206 180 1.3 (0.8,2.1) 1.5 (0.8,2.7)
Females
BMI <=26 57 74 0.7 (0.3,1.7) 1.0 (0.3,2.8)
BMI > 26 87 70 1.7 (0.8,3.6) 1.8 (0.7,4.6)
no current HRT use 118 98 1.1 (0.6,2.0) 1.6 (0.7,3.5)
current HRT use 25 46 0.9 (0.3,3.5) 0.6 (0.1,3.5)
Males
BMI <=26 64 106 1.7 (0.8,3.8) 3.3 (1.2,9.0)
BMI > 26 119 110 1.2 (0.6,2.3) 1.4 (0.6,3.2)
*data was controlled for ethnicity and matched on age, exam date, exam location, and
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Table 4: Stratification of not current HRT users by BMI* and adjusted for possible
confounders**
A1/A2 A2/A2
Cases Controls OR Cl OR Cl
no current HRT use
BMI <=26 44 52 0.5 (0.16,1.4) 0.8 (0.2,3.2)
BMI > 26 74 46 2.1 (0.8,5.6) 2.3 (0.7,7.7)
*data was controlled for ethnicity and matched on age, exam date, exam location, and sex
**data was adjusted for exercise, and smoking
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13
Table 5: Odds ratios stratified by ethnicity4 1
A1/A2 A2/A2
Cases Controls OR Cl OR Cl
Non-Hispanic Whites 186 211 1.1 (0.7,1.7) 2.0 (1.1,3.7)
African-A mericans 64 60 1.1 (0.5,2.6) 1.0 (0.3,3.1)
Latinos 47 55 1.4 (0.5,3.7) 1.3 (0.4,4.7)
Asians 30 35 5.6 (0.9,34.4) 4.7 (0.7,30.1)
*data was matched on age, exam date, exam location, and sex
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Table 6: Analysis stratified by BMI* and adjusted for possible confounders**,
Whites only
A1/A2 A2/A2
Cases Controls OR Cl OR Cl
Females 74 84 1.0 (0.5,2.2) 0.9 (0.4,2.4)
BMI<=26 35 47 0.7 (0.2,2.3) 1.0 (0.2,4.4)
BMI>26 39 37 1.5 (0.4,5.0) 0.4 (0.1,2.2)
Males 112 126 1.2 (0.7,2.2) 3.5 (1.4,8.6)
BMI<=26 33 58 1.0 (0.3,3.2) 4.6 (1.0,20.6)
BMI>26 79 67 1.5 (0.7,3.3) 3.2 (1.0,10.1)
*data was controlled for ethnicity and matched on age, exam date, exam location, and
** data was adjusted for exercise, and smoking
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DISCUSSION
This is the first report that the CYPI7 genotype is associated with increased risk of
colorectal adenomas. Previous studies of CYP17 have shown that the A2 allele is
associated with increased estradiol levels in premenopausal women (9) and increased
levels of estrone, estradiol, testosterone, androstenedione, and DHEAS in
postmenopausal women (10). It may be this increase in estradiol levels that causes
increased risk for colorectal adenomas in subjects carrying the A2 allele. However, this
hypothesis is contradicted by five recent studies showing that estrogen treatment in the
form of HRT seems to protect against colonic cancer (1.2,3,4,5). The study by Chen et
al. (5) was conducted using the same case-control dataset of all ethnic groups combined.
Analyses were conducted to sort out this paradox. It could not be explained by the
influence of CYP17 genotype on HRT usage. No confounding or effect modification
between HRT and CYP17 was observed. Another explanation comes from results from
stratified analyses. After stratification by BMI and ethnicity the paradox is eliminated in
certain subsets of the population.
The effects of CYPI7 genotype appear to differ by BMI. Our results show that there is
no increase in colorectal adenoma risk for females of normal BMI that carry the A2
allele. However, women of high BMI (>26) who carry the A2 allele are at increased risk.
The CYP17 A2 allele may play a role in the increased levels of estradiol observed in
obese women. The production of estrone from androstenedione by the action of
16
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aromatase in peripheral body fat is associated with obesity. Obese subjects also have
higher estrogen bioavailability due to the association of decreased levels of serum
hormone binding globulin (SHBG) with obesity (16). Quite different results were
observed in men. Among men of normal BMI. the A2 allele substantially increases risk
for colorectal adenoma. Among men of high BMI, the increased risk was much smaller.
While the paradoxical results in women and the intriguing results in men after
stratification by BMI were generated after controlling for ethnicity, analysis of the white
subset of the study population showed different results. In white, post-menopausal
females, there is no association between the CYPI7 genotype and the development of
colorectal adenomas. However, in men there was a significant association among both
the normal weight men and men of BMI greater than 26.
Results of this study raise questions about the association of other hormones, such as
testosterone or DHEA, with risk of colorectal adenomas in men. Future studies are
needed to look at the association of CYPI7 with various serum hormone levels in normal
weight and overweight men in different ethnic groups. In women, larger studies are
needed to enable stratification by HRT and BMI among the various ethnic groups. The
differences in results between men and women in this study support the view that
endocrine factors play a role in the development of colorectal adenomas.
17
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15. Feigelson, H.S., McKean-Cowdin. R., Pike. M.C., Coetzee, G.A., Kolonel, L.N., Nomura. A.M.Y., Le
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Creator
Osth, Elizabeth Claire
(author)
Core Title
CYP17 polymorphism and risk for colorectal adenomas
School
Graduate School
Degree
Master of Science
Degree Program
Molecular Epidemiology
Publisher
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
biology, biostatistics,biology, genetics,health sciences, oncology,OAI-PMH Harvest
Language
English
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Ingles, Sue Ann (
committee chair
), Haile, Robert W. (
committee member
), Lenz, Heinz-Josef (
committee member
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289369
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Osth, Elizabeth Claire
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University of Southern California Dissertations and Theses
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biology, biostatistics
biology, genetics
health sciences, oncology