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Risk factors of testicular germ cell tumor
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Risk factors of testicular germ cell tumor

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Content


RISK FACTORS OF TESTICULAR GERM CELL TUMOR  

by



No Kang Myung






A Thesis Presented to the  
FACULTY OF THE USC GRADUATE SCHOOL  
UNIVERSITY OF SOUTHERN CALIFORNIA  
In Partial Fulfillment of the  
Requirements for the Degree  
MASTER OF SCIENCE  
(BIOSTATISTICS)







May 2014









Copyright, 2014                                                                                      No Kang Myung
ii

DEDICATION

I have been able to finish my degree with the supports of my parents, friends, and
professors at University of Southern California. I thank them again because this thesis is
dedicated to all who have helped me. I thank God that has allowed me to study at the
wonderful university.  
 
iii

TABLE OF CONTENTS

Dedication ii
List of Tables  iv
List of Figures v
Abstract  vi
Introduction 1
Methods of Systematic Review 3
Marijuana use 6
Tobacco Smoking 8
             Tobacco Smoking by TGCT cases 8
             Maternal Smoking  12

Androgen Receptor 16
Results   21
             Meta-Analysis   21
             Supplementary Results    22

Discussion   23

Conclusion   26

References   48


 
iv

LIST OF TABLES  

Table 1: Studies addressing marijuana use 28
Table 2: Studies addressing subject smoking 30
Table 3: Studies addressing maternal smoking 32
Table 4: Studies addressing androgen receptor (CAG)n polymorphism  34
Table 5: Studies addressing miscellaneous androgen receptor polymorphisms 35
Table 6: Statistical interactions between marijuana use and cigarette smoking 37
Table 7: Smoking effects on TGCT after or before adjusting for marijuana use   38













v

LIST OF FIGURES  

Figure 1: Trends in cigarette smoking among persons 18+ years old, by gender – United                  
              States, 1955-1997. 27

Figure 2: Forest plot of marijuana use for all TGCT          38
Figure 3: Forest plot of subject smoking for all TGCT                  39
Figure 4: Forest plot of maternal smoking for all TGCT         40
Figure 5: Funnel plot of marijuana use for all TGCT          41
Figure 6: Funnel plot of subject smoking for all TGCT          41
Figure 7: Funnel plot of maternal smoking for all TGCT 41
Figure 8: Forest plot of marijuana use for seminoma 42
Figure 9: Forest plot of marijuana use for nonseminoma/mixed GCT 42
Figure 10: Forest plot of subject smoking for seminoma 43
Figure 11: Forest plot of subject smoking for nonseminoma 43
Figure 12: Funnel plot of maternal smoking for seminoma 44
Figure 13: Funnel plot of maternal smoking for nonseminoma 45
Figure 14: Forest plot of sensitivity analysis of subject smoking for all TGCT 46
Figure 15: Forest plot of sensitivity analysis of maternal smoking for all TGCT 47




vi

ABSTRACT

Testicular germ cell tumors (TGCTs) are a group of neoplasms derived from germ
cells and TGCTs occur most frequently in adolescent and adult men ages 15 to 45 years.
The incidence rates of TGCTs among young men have almost doubled in the US in
recent decades; the incidence of TGCT in whites is higher than other races. Many studies
have been conducted in an effect to reveal etiology of TGCTs, thereby establishing
personal history of undescended testis and family history of TGCT as risk factors.
However, neither of these factors appears to account for the temporal pattern of the
increasing incidence of TGCT. More recently, marijuana use, cigarette smoking of young
men and their mothers, and mutations in the androgen receptor (AR) gene have been
investigated as risk factors of TGCT. In the present work, a systematic review of
published studies on these factors was conducted. After reviewing the literature, meta-
analyses were performed summarizing associates of TGCT occurrence with each of
marijuana use, subject smoking, and maternal smoking during pregnancy. Ever marijuana
use or maternal smoking during pregnancy was not associated with TGCT risk (random-
effects summary-OR = 1.19, 95% CI = 0.72-1.95; Q

= 6.80, df =2, p = 0.033, and
random-effects summary-OR = 0.99, 95% CI = 0.87-1.13; Q = 3.06, df = 10, p = 0.98,
respectively). However, ever subject smoking was statistically significantly associated
with TGCT risk (random-effects summary-OR = 1.19, 95% CI = 1.03-1.38; Q = 21.02, df
= 9, p = 0.013). We found no evidence that an association between ever marijuana use
and TGCT risk differed by never vs. ever subject smoking (OR = 0.21, 95% CI = 0.03-
vii

1.60). Based on the author’s knowledge, this is the first study of performing meta-
analysis of marijuana use and subject smoking, and testing the interaction effect between
marijuana use and subject smoking.  

1

INTRODUCTION

Testicular germ cell tumors (TGCTs) are a group of neoplasms derived from germ
cells that occur most frequently in adolescent and adult men ages 15 to 45 years
1
. The
National Cancer Institute reports that TGCTs comprise 1% of all malignant neoplasm in
men and that 7920 newly diagnosed cases of TGCT were identified in 2013
2
. Incidence
rates of TGCT among young men have almost doubled in the US in recent decades; the
age adjusted incidence rates of TGCT among U.S. males aged 15-49 years increased
from 2.9 to 5.1 per 100.000 between 1975 and 2004
3
. White men have had the highest
incidence rate of TGCT in the United States

from 1975 to 2004 and in the United
Kingdom from 1975 to 2008
3,4
. The incidence of TGCT is influenced by geography;
incidence in northern European countries are approximately twice as high as the US and
the UK
5
. Established risk factors of TGCT are adolescent and young adult age, non-
Hispanic white race/ethnicity, personal history of an undescended testicle
(cryptorchidism), abnormal development of testicles, and family history of TGCT, which  
in utero hormonal exposures are a commonly postulated cause
6–8
. In addition, cigarette
smoking, marijuana use, maternal cigarette smoking, and mutations in the androgen
receptor (AR) gene have been individually considered as risk factors of TGCT. Three
studies found that marijuana use was positively associated with TGCT risk. However, the
effects of cigarette smoking, maternal cigarette smoking, and mutations in the androgen
receptor (AR) gene on TGCT still remains poorly understood. In the review, we
evaluated roles of cigarette smoking, maternal cigarette smoking, and mutations in the
2

androgen receptor (AR) gene on occurrence of TGCT in study participants or offspring.
Specifically, we hypothesize that each of these risk factors is individually associated with
TGCT risk. We also consider biological plausibility that the association between
marijuana use and TGCT risk varies by cigarette smoking because both cigarette smoking
and marijuana use contain harmful products of incomplete combustion. The study
reviewed by Pagotto et al demonstrated that cannabinoids decreased testosterone
production and secretion of males
9
. We postulate that the association of mutation in the
AR gene with TGCT risk differs by marijuana use. By summarizing these interactions, it
can be postulated that the environmental interaction between cigarette smoking and
marijuana use differs by polymorphisms in the AR gene.  


















3

METHODS OF SYSTEMATIC REVIEW


Both PubMed and Web of Knowledge were used to complete a review of  
literature published through January 2013 by using as search terms: ‘testicular’, ‘tumor’,
‘TGCT’, ‘smoking’, ‘cigarette’, ‘tobacco’, ‘cancer’, ‘neoplasm’, ‘mother’, ‘prenatal’,
‘maternal’, ‘AR’, ‘androgen receptor’, ‘CGA’, ‘polymorphism’, and ‘marijuana’. Also
we checked references in the published articles and review papers. Thus we found 3
studies of marijuana use, 11 studies of subject smoking, 11 studies of maternal smoking,
and 12 studies of androgen receptor (CAG)n polymorphism through the literature review.
In order to contribute data to the meta-analysis, published studies were required to have
the following properties: (1) outcome was occurrence of testicular cancer in the study
participants or offspring, (2) exposure was marijuana use, subject smoking, or maternal
smoking during pregnancy, (3) estimated associations between exposure and outcome
had to be presented risk ratio or odds ratio with accompanying confidence interval, or
data from which such associations could be calculated has to be provided.  
In histology-specific analyses of marijuana use, Trabert et al did not report odds
ratios of nonseminoma/mixed GCT risk, but reported separate odds ratios of
nonseminoma or mixed GCT risk, while Daling et al and Lacson et al reported odds
ratios of nonseminoma/mixed GCT risk. We therefore used meta-analysis assuming
random-effects to estimate summary-ORs and 95% CIs of nonseminoma/mixed GCT
associations combining ORs for exposure-nonseminoma and exposure-mixed GCT
associations. Henderson et al did not provide 95% CIs of subject smoking and maternal
4

smoking during pregnancy, but provided ORs and numbers of cases and controls.
Because the study of Henderson et al used an individually matched case-control study,
we estimated 95% CIs of subject smoking and maternal smoking during pregnancy. We
excluded 1 study (Coldman et al) because 95% CIs were not available and could not be
calculated. Since Gallagher et al, Garner et al, Srivastava et al, and Dusek et al did not
report odds ratios of never vs. ever cigarette smoking, but reported odds ratios of
smoking exposures, we combined all effect sizes over smoking exposures and estimated
random-effects summary-ORs for never vs. ever smoking that were used in meta-analysis.
Similarly, Brown et al and Weir et al did not report ORs of never vs. ever maternal
smoking during pregnancy. So we estimated summary-ORs of associations of ever versus
never smoking during pregnancy and occurrence of testicular cancer in the son produced
by the pregnancy. Although two studies of Thune et al and Mongraw-Chaffin et al did not
report ORs of never vs. ever smoking or maternal smoking during pregnancy, we decided
to include them by using estimates they provided. Meta-analyses were performed using
information from 3 publications reporting on marijuana use (Table 1), 10 publications
reporting on subject smoking (Table 2) and 11 publications reporting on maternal
smoking during pregnancy (Table 3). Using a random-effects model, we separately
estimated summary associations for cohort studies, population-based case-control studies,
and hospital-based case-control studies; thereafter we estimated summary associations for
studies of all types combined. Furthermore, we conducted sensitivity analyses of subject
smoking and maternal smoking during pregnancy in which we estimated summary
associations while systematically excluding each individual study from the analysis.  
5

None of the published reports addressed statistical interactions between marijuana
use and tobacco smoking. However, we asked Lacson et al about access to the data used
in their published manuscript. After deriving dichotomous variables for marijuana use
(ever marijuana use/non-marijuana use) and cigarette smoking (ever smokers/non-
smokers), we performed analyses investigating whether the association of marijuana use
with TGCT risk varied with subject smoking. ORs and 95% CIs were estimated by
unconditional and conditional logistic regressions. Since Lacson et al did not provide
histology-specific ORs of subject smoking, we estimated ORs and 95% CIs using
conditional logistic regression with the same matching variables.  
Meta-analysis and logistic regression were performed with STATA statistical
software version 11.0 (StataCorp, College Station, TX, USA) for ORs and 95% CI. Two
sided p-value ≤ 0.05 was considered to be statistically significant.  














6

MARIJUANA USE

The US Food and Drug Administration (FDA) has approved medical marijuana
use for relief of pain, nausea, spasticity, glaucoma, and movement disorder
10
. According
to the report of National Institute on Drug Abuse, marijuana use gradually increased from
5.8% (14.4 million) of people aged 12 years or older in 2007 to 7.3% (18.9 million) in
2012
11
. One concern with the increasing use of marijuana use for clinical care and
increasing frequency of recreational use is that marijuana use may be positively
associated with many cancers. Recently, three studies reported that marijuana use was
positively associated with TGCT risk
12–14
.  
Daling et al assessed the role of marijuana use of the TGCT development using a
population-based case-control study published in 2009. The study reported that a current
marijuana smoker was positively associated with TGCT risk (OR = 1.7, 95% CI = 1.1-
2.5)
12
. Among current marijuana users, the first use at age < 18 years and daily or weekly
use were related with TGCT risk (OR = 1.8, 95% CI = 1.2-2.8, and OR = 2.0, 95% CI =
1.3-3.2, respectively)
12
. In the analyses of histologic subtypes, marijuana use was not
associated with pure seminoma, but was associated with nonseminoma/mixed GCT.
Patients with nonseminoma/mixed GCT were more likely to be current marijuana users
(OR = 2.3, 95% CI = 1.3-4.0)
12
. Among current marijuana users, nonseminoma/mixed
GCT risk was associated with first marijuana use at age < 18 years, length of use (> 10
years), and frequency of use (daily or ≥1 day per week) (OR = 2.8, 95% CI = 1.6-5.1, OR
= 2.7, 95% CI = 1.5-5.0, and OR = 3.0, 95% CI = 1.5-5.6, respectively)
12
.  
7

Trabert et al, in a hospital-based case-control study with 187 cases and 148
controls published in 2010, reported associations between marijuana use and TGCT risk
13
.
Frequent marijuana users (daily or more frequent) had a greater than 2-fold risk of TGCT
compared to never marijuana users (OR = 2.2, 95% CI = 1.0-5.1)
13
. When histology-
specific analyses were conducted, frequent users and long-term (≥10 years) users were
significantly associated with nonseminoma risk (OR = 3.1, 95% CI = 1.2-8.2, and OR =
2.4, 95% CI=1.0-6.1, respectively)
13
.
Lacson et al conducted a population-based case-control study with 163 TC
patients and 292 controls published in 2012. The study reported that former marijuana
users had an increased overall TGCT risk (OR = 2.3, 95% CI = 1.2-4.4), while the study
found that that ever use of cocaine was inversely associated with TGCT risk (OR = 0.54,
95% CI = 0.32-0.91)
14
. According to histology-specific analyses of TGCT, former
marijuana use was not associated with seminoma risk, but was significantly associated
with nonseminoma/mixed GCT risk (OR = 2.42, 95% CI = 1.08-5.42)
14
.  
Thus, all three studies observed consistent results in the association between
marijuana use and overall TGCT risk. Histology-specific analyses showed that current or
ever use of marijuana was positively associated with risk of nonseminoma/mixed GCT,
alone.  



8

TOBACCO SMOKING

A report by the Centers for Disease Control and Prevention (CDC) found that the
smoking population gradually deceased from 1955 to 1997 and that 43.8 million US
adults were current cigarette smokers in 2011
15,16
. Cigarette smoking has been an
important risk factor of many cancers because cigarette smoking contains about 7,000
chemicals among which 250 are revealed as harmful chemicals
17
. Along with cigarette
smoking related cancer studies such as lung, larynx, pharynx, bladder and stomach
cancers, some studies assessed the relation between cigarette smoking and TGCT risk.
Since the effect of cigarette smoking on TGCT is uncertain, we will complete a
systematic review and meta-analysis of the literature from 1979 to 2013, and evaluate the
hypothesis that chronic exposure of cigarette smoking is positively associated with TGCT
risk.

Tobacco Smoking by TGCT Cases  
The first study of reporting the association between cigarette smoking and TGCT
was an individual-matched case-control study of Henderson et al published in 1979
18
.
The study found no evidence that ever cigarette smoking was positively associated with
TGCT risk (OR = 1.1, 95% CI = 0.67-1.80)
18
.  
           The study reviewed by Coldman et al in Vancouver, British Columbia published
in 1982 observed no relation between TGCT and smoking related questions: smoking
behavior, number smoked per day, number of years smoked or tobacco product used
19
.  
9

UK testicular Cancer Study Group examined the hypothesis that cigarette
smoking was positively associated with TGCT risk using a population-based case-control
study published in 1994
20
. The study reported that ever smoking was not positively
associated with TGCT risk (OR = 1.18, 95% CI = 0.96-1.46) and observed no trend in
TGCT risk by increasing smoking intensity (


= 2.58, p for trend = 0.11)
20
.  
Thune et al conducted a population-based cohort study of 53,242 men in Norway
published in 1994 to test association between cigarette smoking and TGCT risk
21
. The
study reported no association between smoking per 10 cigarettes and TGCT risk (RR =
1.2, 95% CI = 0.85-1.7)
21
.  
A population-based case-control study of 510 TGCT cases and 996 controls was
conducted by Gallagher et al in Canada published in 1995
22
. The study found no evidence
that ex-smokers were not significantly associated with TGCT risk (OR = 1.2, 95% CI =
0.9-1.6). An elevated association between current smokers who had ≥11 pack-year
history and TGCT risk was found (OR = 1.4, 95% CI = 1.0-1.8), but the association did
not achieve statistical significance
22
.  
Møller et al conducted a population-based case-control study in Denmark to
examine tobacco smoking effect of cases on TGCTs published in 1996
23
. The study
found that ever cigarette smoking was not significantly associated with TGCT risk (OR =
0.92, 95% CI = 0.71-1.18)  and observed no trend in TGCT risk by increasing average
amount smoked (p for trend = 0.76)
23
.  
Garner et al conducted a population-based case-control study with 601 Canadian
cases and 744 controls published in 2003 to assess the role of dietary risk factors for
10

TGCT
24
. The study reported that any levels of smoking were not significantly associated
with TGCT risk and observed no trend in TGCT risk by increasing smoking pack-years
(p for trend = 0.95)
24
. The study preformed similar analyses according to histologic
subtypes; cigarette smoking was not significantly associated with either seminoma or
nonseminoma risk with no trend by increasing smoking pack-years (p for trend = 0.61,
and p for trend = 0.31, respectively)
24
.  
While two studies of Daling et al and Trabert et al assessed the effect of
marijuana use on TGCT, they did not report on analyses addressing associations between
cigarette smoking and TGCT risk. However, Lacson et al estimated associations between
smoking related questions and TGCT risk. The study found that ever cigarette smokers,
current cigarette smokers, men who smoked 20 cigarettes per day, or men who smoked
≥10 years were not associated with TGCT risk (OR = 0.98, 95% CI = 0.58-1.67, OR =
0.89, 95% CI = 0.46-1.69, OR = 0.91, 95% CI = 0.48-1.74, and OR = 1.26, 95% CI =
0.61-2.59, respectively)
14
.  
Few studies found significantly elevated ORs between cigarette smoking and
TGCT risk
25–27
. Brown et al evaluated an association between cigarette smoking and
TGCTs using a case-control study with cases from three hospitals (NIHCC, USUNH, and
WRAMC) in Washington, DC published in 1987
25
. The study reported that men who had
smoking experience at least 100 cigarette during their lifetime had a 1.5 fold increased
TGCT risk (OR=1.5, 95% CI=1.0-2.1), and the association achieved statistical
significance
25
. The relative risks of three hospitals were inconsistent; smoking was
significantly associated with TGCTs at NIHCC, but not at USUNH and WRAMC, and
11

observed a significant trend in TGCT risk by increasing number of packs of cigarettes
smoked at NIHCC (p for trend = 0.022), but not at USUNH and WRAMC
25
.
A national case-control study conducted by Srivastava et al in Ontario, Canada
published in 2004 found a significant association between cigarette smoking and TGCT
risk
26
. The study reported that men who smoked 12 and 24 pack-years, men who smoked
≥24 pack years and men who smoked ≥12 years were positively associated with TGCT
risk (OR = 1.96, 95% CI = 1.04-3.69, OR = 2.31, 95% CI = 1.12-4.77, and OR = 3.18, 95%
CI = 1.32-7.64, relatively)
26
.  
Dusek et al evaluated various risk factors for TGCT in a hospital-based case-
control study in the Czech Republic published in 2008. The study reported that former
and active smoking were positively associated with TGCT risk compared to non-smokers
(OR = 1.5, 95% CI = 1.02-2.03, and OR = 1.6, 95% CI = 1.10-2.33, respectively)
27
. It
reported that men who smoked 2.6-12 pack years and over 12.1 pack-years had the
increased risk of TGCT compared to non-smokers in the univariate model (OR = 3.3, 95%
CI = 1.69-6.42, and OR = 4.93, 95% CI = 1.63-12.58, respectively) with a significant
trend by increasing cigarette smoking pack-years (p for trend = 0.037)
27
.  
Three studies observed that TGCT risk was associated with men who had a
history of smoking, while 8 of 11 studies reported no association between cigarette
smoking and TGCT risk. Because of inconsistent associations between cigarette smoking
and TGCT risk, we need more studies to support whether cigarette smoking has an
adverse influence on TGCT risk.  

12

Maternal Smoking
It has been postulated that maternal cigarette smoking before or during conception
may be related with the development of TGCTs because of harmful products of
incomplete combustion. The rate of tobacco smoking among women aged 18 years or
older increased from 1995 to the mid-1960’s, and remained to plateau from the mid-
1960’s to the mid-1970’s, and gradually decreased from the mid-1970’s to 1997 (Figure
1)
15
. Also, the prevalence of maternal smoking during pregnancy in the United States
decreased from 18.4% in 1990 to 9.3% in 2007, while the age-adjusted new cases of
TGCT patients per 100,000 men per year increased from 3.7 in 1975 to 5.8 in 2010
2,28
.
We carefully postulated that the high prevalence of women smoking in the period from
the mid-1960’s to the mid-1970’s has been related with the increased incidence rate of
TGCT.  
A individual-matched case-control study was performed by Henderson et al to
investigate the effects of parental characteristics on TGCT risk in male offspring
published in 1979
18
. The study reported no significant association between maternal
smoking during conception and TGCT risk in their offspring (OR = 1.00, 95% CI = 0.52-
1.92)
18
.
Brown et al performed a population-based case-control study to examine the
effects of prenatal and perinatal risk factors on TGCTs in the US published in 1986
29
.
The study observed that mothers during pregnancy who smoked one pack or less a day or
smoked more than one pack a day were not associated with TGCT risk in their sons (OR
= 1.5, 95% CI = 0.8-2.9, and OR = 0.8, 95% CI = 0.4-1.5, respectively)
29
.  
13

Swerdlow et al examined the role of parental factors for TGCT risk in male
offspring using a stratum-matched case-control study in the UK published in 1987
30
. The
study found no association between maternal smoking at the time of the subject’s birth
and TGCT risk in their sons (OR = 1.0, 95% CI = 0.7-1.5) as well as no association
between maternal ever-smoking and TGCT risk in their sons
30
.  
Møller et al conducted a population-based case-control study using the Danish
cancer registry to examine associations between TGCT risk in their sons and maternal
smoking published in 1996
23
. The study found that maternal tobacco smoking before or
during pregnancy was not associated with TGCT risk in male offspring (OR = 1.00, 95%
CI = 0.72-1.39, and OR = 0.97, 95% CI = 0.69-1.37, respectively); regular paternal
smoking at time of conception was not associated with TGCT risk in male offspring (OR
= 0.95, 95% CI = 0.63-1.42)
23
.  
Weir and colleagues investigated the effect of maternal smoking on TGCT risk in
male offspring in a population-based case-control study published in 2000, in Canada
31
.
The study observed the significant association between maternal cigarette (12+
cigarettes/day) smoking during pregnancy and TGCT risk in their sons (OR = 0.6, 95%
CI = 0.4–1.0)
31
.
Coupland et al examined the role of maternal smoking for TGCT risk in male
offspring in a population-based case-control in the UK published in 2004
32
. The study
observed that maternal smoking before or during pregnancy was not associated with
TGCT risk in their offspring (OR = 0.99, 95% CI = 0.74-1.31, and OR = 1.16, 95% CI =
0.85-1.57, respectively)
32
.  
14

A population-based case-control was conducted by McGlynn and colleagues to
test the effects of passive, paternal, and maternal smoking exposures on TGCT risk in
male offspring published in 2006
33
. It found no evidence that mothers who ever smoked,
smoked during pregnancy, and smoked while breastfeeding were associated with TGCT
risk in their sons (OR = 1.0, 95% CI = 0.8-1.3, OR = 1.0, 95% CI, 0.8-1.4, and OR = 1.2,
95% CI = 0.7-2.0, respectively)
33
.  
Pettersson et al conducted a population-based case–control study with 192 cases
and 494 controls to examine the relation between maternal smoking and TGCT risk in
their sons in Sweden published in 2007
34
. The study found that maternal smoking during
pregnancy was not associated with TGCT risk in sons (OR = 0.91, 95% CI, 0.64-1.30),
and there was no trend over increasing maternal smoking
34
.  
A hospital-based case-control study reviewed by Sonke et al published in 2007
was used to examine an association between maternal smoking during pregnancy and
TGCT risk in the offspring
35
. The study found that maternal smoking during pregnancy
was not significantly associated with TGCT risk in their sons (OR = 1.1, 95% CI = 0.5-
2.2)
35
.  
Mongraw-Chaffin et al performed a nested case-control study in a 40-year follow-
up cohort study published in 2008 to examine maternal characteristics during pregnancy
and TGCT risk in the offspring
36
. The study observed no significant association between
maternal cigarette smoking (≥7/<7 cigarette/day) during pregnancy and TGCT risk in
their sons (OR = 1.06, 95% CI = 0.26-3.89)
36
.  
15

Tuomisto et al conducted a nested case-control study with Finnish, Swedish and
Icelandic mothers and a meta-analysis with seven published papers (total number of 2149
cases, 2762 controls) published in 2009
37
. They found that maternal cotinine level was
not significantly associated with TGCT risk in male offspring (OR = 0.68, 95% CI =
0.35-1.34)
37
. The meta-analysis reported no significant association between maternal
cigarette smoking during pregnancy and TGCT risk in their sons (OR = 1.0, 95% CI =
0.88-1.12)
37
.  
All studies found no association between maternal smoking during pregnancy and
TGCT risk in their sons except the study of Weir et al that reported the protective effect
on TGCT risk in their sons. Because of the inconsistent results of maternal smoking
during pregnancy, we need more studies to support that maternal smoking during
pregnancy has an adverse influence on TGCT risk in their sons.  










16

ANDROGEN RECEPTOR

Mutations in androgen receptor (AR) gene regulate normal male sexual
differentiation and development and controls male reproductive functions by mediating
androgen actions
38
. The AR gene located on X chromosome has two polymorphic
trinucleotide repeat regions: a (CAG)n CAA stretch encoding for glutamine and (GGT)3
GGG (GGT)2 (GGC)n encoding for glycine, generally referred to the CAG and GGN
repeats
39
. Functional variants in the AR gene, which disrupts AR function, lead androgen
insensitivity syndrome, spinal and bulbar muscular atrophy, androgenetic alopecia, breast
cancer, and prostate cancer
39
. In an extensive meta-analysis, Davis-Dao et al found that
men with increased AR CAG length were more likely experience male infertility
compared to men with AR CAG length
40
. This result is relevant to TGCT, because of
reported associations between primary infertility and TGCT risk
41,42
. Recent studies have
postulated that variations of CAG and GGC repeat lengths in the AR gene were related
with TGCT risk.      
King et al observed expanded (CAG)n tract size among patient with testicular
tumor cell lines and sporadic testicular tumors and among most family members of
testicular cancer families in the study published in 1997 using the method of a repeat
expansion detection (RED) assay
43
. The study suggested a possibility that an increased
(CAG)n tract size may be associated with occurrence of TGCT
43
.  
17

Teh et al conducted RED method to effects of changes of CAG/CTG tract size on
TGCT risk with eight white families published in 1999
44
. The study did not find that an
increase of CAG/CTG tract size was related with risk of familial testicular cancer
44
.  
A study, reviewed by One et al published in 2001, evaluated the association
between CAG/CTG tract size in the AR gene and sporadic TGCTs
45
. It did not find that
expansions of CAG/CTG tract size in the AR gene were not associated with sporadic
TGCT risk
45
.  
Rajpert-De Meyts et al conducted a case-control study with 102 cases and 110
controls to examine an association between TGCT risk and polymorphisms in CAG
repeat length in the AR gene for Danish people published in 2002
46
. The study found no
evidence that the distribution of (CAG)n was significantly different from between TGCT
cases and controls (p = 0.85)
46
. Furthermore, the study observed that CAG repeat length
in the AR gene was not associated with increased risk of the tumor type and severity of
the disease
46
.  
Casella et al examined associations between AR gene polyglutamine length
variations and TGCT in the case-control study including 12 seminoma cases and 55
controls published in 2003
47
. It reproted that the median length of CAG repeat length of
seminoma patients was statistically significantly longer than controls (p = 0.043)
47
.  
The case-control study including 83 TGCT patients and 220 controls was
conducted by Giwercman and colleagues published in 2004 to assess a linkage between
CAG repeat length in the AR gene and TGCT histological subgroup as well as presence
of metastases
48
. The study found no evidence that the mean of CAG or GGN repeat
18

lengths was different between overall TGCT cases and controls. However, it reported that
the percentages of seminomas and all TGCT patients with CAG ≥ 25 were statistically
lower than that of controls (p = 0.05, and p = 0.007, respectively) and the higher median
CAG length was significantly associated with presence of metastases at the time of
diagnosis (Stage II-IV), but median GGN length was not different in the tumor stages
48
.  
Garolla et al evaluated effects of CAG and GGC repeat lengths on TGCT in the
case-control study with 123 cases and 115 controls published in 2005. The study reported
that the combination of CAG repeat length = 20 and GGC repeat length = 17 was
associated with TGCT risk because proportion of the joint distribution of CAG and GGC
was significantly different between TGCT patients (8.1%) and controls (1.7%) (p-value <
0.05)
49
.  
Three single nucleotide polymorphisms (SNPs) in the AR gene were examined by
Figueroa and colleagues in a case-control study using U.S. military servicemen of 577
cases and 707 controls published in 2008
50
. The study found no association between
TGCT risk and mutations in the AR gene whose SNPs were rs6152, rs1204038, and
rs1337080
50
.
Biggs and colleagues performed a population-based case-control study with cases
(n = 246) and controls (n =630) to examine whether TGCT risk associated with p,p’-DDE
was modified by CAG or GGN repeat length in the AR gene published in 2008
51
. The
study found no evidence that the association between TGCT risk and p,p ’-DDE was
varied by CAG (<23 versus ≥23 repeats) or GGN (<17 versus ≥17 repeats) genotype (p
for interaction = 0.8, and p for interaction = 0.3, respectively)
51
.  
19

Davis-Dao et al performed a case-control study to examine whether TGCT risk
was associated with variation in the functional (CAG)n polymorphism in the AR gene
published in 2011
52
. It found no evidence that AR CAG repeat length was significantly
associated with overall TGCT risk. However, the study reported that men with CAG ≤  
20, CAG 20-21, CAG 22-23, and CAG ≥ 24 were less likely to develop seminomas
compared to men with CAG ≤ 19 (OR = 0.54, 95% CI = 0.31-0.93, OR = 0.82, 95% CI =
0.43-1.58, OR = 0.39, 95% CI = 0.19-0.83, and OR = 0.42, 95% CI = 0.20-0.86,
respectively) with a significant trend over decreasing CAG repeat length categories (p for
trend = 0.003)
52
.  
Västermark et al evaluated whether AR CAG and GGN repeat lengths were
associated with risk of TGCT or metastatic disease using a case-control study with 367
cases and 214 controls published in 2011
53
. It found a significant association between the
rare genotype of G of SNP rs12014709 and TGCT risk (OR = 2.07, 95% CI = 1.03-
4.15)
53
. While CAG or GGN repeat length was not associated with overall TGCT or
nonseminoma risk, GGN < 23 was positively associated with risk of metastatic disease
(OR = 2.15, 95% CI = 1.04-4.45)
53
.  
A population-based case-control study was conducted by Kristiansen et al for
Norwegian men published in 2012 to investigate associations of variations in the
testosterone pathway genes with TGCT risk
54
. Whereas the study found no evidence that
an increase in AR CAG repeat length was associated with overall and histology-specific
TGCT risk, it reported that men with AR GGN > 23 were more likely to develop overall
TGCT compared to men with AR GGN = 23 (OR = 1.73, 95% CI = 1.01-2.97)
54
. In
20

histology-specific analyses, subjects with GGN < 23 or GGN > 23 were more likely to
develop seminomas than subjects with GGN = 23 (OR = 1.73, 95% CI = 1.01-2.97, and
OR = 1.45, 95% CI = 1.03-2.05, respectively)
54
.  
Effects of CAG and GGN repeat lengths in the AR gene on the development of
TGCTs were inconsistent. Some studies have reported that CAG and/or GGN repeat
lengths were associated with TGCT risk, whereas others did found no significant
association between variants in the AR gene and TGCT risk. The more studies are needed
to reveal an association between CAG and/or GGN repeat lengths in the AR gene and
TGCT risk.  















21

RESULTS

Systemic Review  
The meta-analysis of studies of all designs found no statistically significant
association of marijuana use with TGCT risk (Figure 2, random-effects summary-OR =
1.19, 95% CI = 0.72-1.95; Q

= 6.80, df = 2, p = 0.033), and no association of maternal
smoking during pregnancy with TGCT risk in their sons (Figure 4, and random-effects
summary-OR = 0.99, 95% CI = 0.87-1.13; Q = 3.06, df = 10, p = 0.98). Because no
outlier was found in the funnel plots (Figure 7), no single study affected on extreme
changes of random-effects summary-ORs in the sensitivity analysis of maternal smoking
during pregnancy (Figure 15). However, subject smoking was positively associated with
TGCT risk (Figure 3, random-effects summary-OR = 1.19, 95% CI = 1.03-1.38; Q =
21.02, df = 9, p = 0.013). Although some outliers were found in the funnel plot (Figure 6),
the sensitivity analysis of subject smoking showed that no single study extremely
changed random-effects summary-ORs (Figure 14).    
Histology-specific meta-analyses with 3 studies found that marijuana use was not
associated with occurrence of either seminoma (Figure 8, random-effects summary-OR =
0.88, 95% CI = 0.48-1.61; Q = 5.45, df = 2, p = 0.066) or nonseminoma/mixed GCT risk
(Figure 9, random-effects summary-OR = 1.34, 95% CI = 0.74-2.43; Q = 6.32, df = 2, p
= 0.042). Garner et al, Dusek et al, and Lacson et al provided data on associations
between subject smoking and occurrence of TGCT of specific histologic types. In
histology-specific meta-analyses, subject smoking was not associated with seminoma or
22

nonseminoma risk (Figure 10 & 11, random-effects summary-OR = 0.98, 95% CI = 0.67-
1.43; Q = 5.19, df = 2, p = 0.074, and random-effects summary-OR = 1.22, 95% CI =
0.92-1.63; Q = 2.97, df = 2, p = 0.226, respectively). Data on associations between
maternal smoking and occurrence of TGCT of specific histologic types were provided in
only the 4 studies of Weir et al, McGlynn et al, Pettersson et al, and Tuomisto et al.
Histology-specific meta-analyses showed that maternal smoking during pregnancy was
not associated with occurrence of either seminoma (Figure 12, random-effects summary-
OR = 0.76, 95% CI = 0.50-1.17; Q = 5.84, df = 3, p = 0.119) or nonseminoma risk in
their sons (Figure 13, random-effects summary-OR = 0.95, 95% CI = 0.77-1.18; Q = 1.35,
df = 3, p = 0.718).  

Supplementary Results  
We found no evidence that the association of ever marijuana use with overall
TGCT or nonseminoma/mixed GCT risk varied with subject tobacco smoking (Table 6,
OR = 0.21, 95% CI = 0.03-1.60, and OR = 0.18, 95% CI = 0.01-3.34, respectively). We
found evidence that ever marijuana use was positively associated with overall TGCT or
nonseminoma/mixed GCT risk among non-smokers (Table 6, OR = 2.26, 95% CI = 1.13-
4.53, and OR = 2.71, 95% CI = 1.03-7.09, respectively). However, we could not find the
interaction effect among subjects who had seminomas because of small sample size. In
histology-specific analyses of subject smoking, we found no significant association of
subject smoking with seminoma risk as well as nonseminoma/mixed GCT (Table 7).      

23

DISCUSSION

We can come up with two hypotheses through the literature review. The first
hypothesis is that harmful products of incomplete combustion by smoking cigarette and
marijuana may be a risk factor of TGCT. Cigarette smoking has been tested as risk
factors of TGCT because of nicotine to cause cancer. However, cigarette smoking doesn’t
have active chemical  

- tetrahydrocannabinol (THC) in smoking marijuana that is the
risk factor of nonseminoma/mixed GCT. Furthermore, both cigarette smoking and
marijuana use contain many harmful products of incomplete combustion such as PAHs
and benzo alpha pyrene, we suggest that these products of incomplete combustion are
also speculated as possible risk factors of TGCT.  
The second possible hypothesis is that an association of marijuana use with TGCT
risk varied with tobacco smoking. This hypothesis is supported by reasonable evidence
because we observed increased risk of TGCT among marijuana users and decreased risk
of TGCT among subjects who used marijuana and smoked tobacco (Table 6). Therefore,
the result suggests that there may be a possibility to find the interaction effect between
marijuana use and cigarette smoking in future studies. However, because of small sample
size, specifically among subjects who smoked regularly but did not use marijuana, we
observed a wild 95% CI of the interaction effect.
Among selected 11 publications for meta-analysis of maternal smoking, Weir et
al only reported a protective effect of maternal smoking on TGCT in their sons; mother
smoked more than 12 cigarettes per day during pregnancy had the protective effect on
24

TGCT risk in their sons (OR = 0.6, 95% CI = 0.4-1.0)
31
. Similarly, Barrington-Trimis et
al also found a protective effect of maternal smoking during pregnancy on childhood
brain tumor in 2013;  mothers smoked 1-10 cigarettes per day during pregnancy had the
decreased risk of childhood brain tumor relative to non-smoking mother during
pregnancy (OR = 0.23, 95% CI = 0.08-0.65)
55
. We consider some problems in measuring
effects of cigarette smoking on TGCT risk in their sons. The first problem is information
bias caused by miscategorizing tobacco smoking variables as the dichotomous variable
(ever smokers vs. non-smokers); ever smoking is too broad to measure correct smoking
effects on TGCT risk. Therefore, nondifferential misclassification could have reduced
magnitudes of associations between tobacco smoking and TGCT risk. Reporting bias is
seriously considered in some studies. If case mothers underreported their smoking history,
differential misclassification could have biased associations of occurrence of TGCT so
that it may have underestimated associations of maternal smoking during pregnancy with
TGCT risk in their sons.  
It seems possible that the observed association between personal smoking and
TGCT may have arisen, at least in part, from confounding of the association by marijuana
use, because marijuana use appears to be a risk factor for TGCT, and marijuana use is
reportedly associated with smoking in the general population. However, apart from the
study of Lacson et al, analyses of the personal smoking-TGCT association do not appear
to have accounted for potential effects of marijuana. Indeed, this association appeared to
be null in the report of Lacson et al. Because we had access to these data, we repeated the
analysis without accounting for marijuana use, and found still no significant associations
25

that were larger point estimates than point estimates in the study of Lacson et al (Table 7).
Therefore, when estimating effects of subject smoking on TGCT, associations between
subject smoking and TGCT risk may have been overestimated because many studies did
not adjust for marijuana use.  





















26

CONCLUSION

In this study, we performed a comprehensive literature review followed by meta-
analyses addresses associations between occurrence of TGCT and each of 3 risk factors.
We found inconsistent effects of marijuana use on TGCT. Although the meta-analysis did
not identify a significant association between marijuana use and all TGCT, there were
notable subgroup patterns: positive associations in both population-based case-control
studies, and an apparent pattern of association with subset of tumors with nonseminoma
histology. Meta-analyses of tobacco smoking found the significant association between
subject smoking and TGCT risk, but this association may reflect confounding by
marijuana use, which was not addressed in many of the contributing studies. Meta-
analysis of maternal smoking during pregnancy provided no significant association that
was consistent finding like previous studies of maternal smoking. In addition, the relation
between change of CAG and GGN repeat lengths in the AR gene and TGCT risk has
been inconsistent. Thus, further studies are needed to understand clear associations
between TGCT risk and smoking, maternal smoking as well as change of CAG and GGN
repeat lengths in the AR gene. We hope that our study may be helpful to understand
associations between TGCT risk and addressed risk factors and to improve public health
implications.  



27


Figure 1: Trends in cigarette smoking among persons 18+ years old, by gender – United
States, 1995-1997. Adapted from Centers for Disease Control and Prevention, 1999
15
.












28

Table 1: Studies addressing marijuana use
Author
year
Source of
cases/controls
& smoking data
Source of
smoking data
Case
recruitment
period
Matching & adjusting  
factors
Cases/
controls
Daling
2009
Adult Testicular
Cancer Lifestyle and
Blood Specimen
Study/
Mitofsky-Waksberg
random digit dialing  

Interview,
questionnaire
1999-2006,
18-44 years of
age
Age & age, reference year,
alcohol use, current
smoking, history of
cryptorchidism  
369/979
Trabert
2010
University of Texas
M.D. Anderson
Cancer Center and
Tumor registry/
hospital based

Questionnaire 1990-1996, 18-
50 years of age
Age, race & age, race, prior
cryptorchidism, cigarette
smoking, alcohol intake  
187/148
Lacson  
2012
Los Angeles Cancer
Surveillance Program/
Neighborhood controls

Interview,
questionnaire
1986-1991, 18-
35 years of age  
Age, race, neighborhood &
Education, religiosity,
cryptorchidism, cocaine,
amyl nitrite.  
139/292









29


30

Table 2: Studies addressing subject smoking
Author
year

Source of cases/controls Source of
smoking data
Case
recruitment
period
Matching
factors
Adjusting factors Cases/
Controls
Henderson  
1979
Cancer Surveillance
Program/
neighborhood  
Questionnaire 1972-1974,
15-40 years
of age
Age (±5
years), sex,
social class
None 131/131
Brown  
1987
NIHCC, USUNH,
WRAMC/hospital
based
Interview 1976-1981,
18-42 years
of age
Age, race,
vital status,
year of
diagnosis
Age at diagnosis  271/259
UK study
1994

Cancer Registry/
List of the general
practitioner
Interview,
questionnaire
1984-1986,
15-49 years
of age
Age (±1
years)
Cryptorchidism,
inguinal hernia at
under 15 years of
age
794/794
Thune†  
1994
Cancer Registry of
Norway
Questionnaire 19-50 years
of age
None Age at entry,
geographic
regions, obesity  
47/
53,242
Gallagher
1995
Cancer Registry/
Medical service Plan
Questionnaire 1980-1985,
15-79 years
of age
Age (±5
years)
Age, ethnicity,
undescended
testis, inguinal
hernia requiring
surgery
506/992
Møller
1996
Cancer Registry/Central
Person Register  
Interview,
questionnaire
1986-1988 Year of
birth
None 505/720
Garner  
2003
National Enhanced
Cancer Surveillance
System/Provincial
cancer registries  
Questionnaire 1994-1997,
20-45 years
of age  
Age,
province
Age, providence,
BMI, smoking,
total energy
intake  
601/744
Srivastava
2004
Enhanced Cancer
Surveillance/Ontario
Ministry of Revenue
Property Assessment
databases
Questionnaire 1995-1996,
20-74 years
of age
Age (±5
years)
Education, age,
combined
moderate and
strenuous
recreational
physical activity
at adolescence,
BMI, for years
smoked, average
number of
cigarettes
smoked/day
198/244
Dusek  
2007
Czech cancer
centers/Blood donors,
hospital personnel  
Questionnaire 2000-2006
18-64 years
of age
Age, race None 356/317
Lacson  
2012
Los Angeles Cancer
Surveillance Program/
Neighborhood controls
Interview,
questionnaire
1986-1991,
18-35 years
of age  
Age, race,
neighbor-
hood  

Education,
religiosity,
cryptorchidism,
cocaine, amyl
nitrite.  
139/292
† Cohort study  

31

Red color is used to estimates ORs of Meta-Analysis.
a
Meta-Analysis ORs were calculated by the author.  
b
ORs were calculated by the author.
† Smoking per 10 cigarettes is a continuous variable.  





Table 2, Continued  
Author
year
Exposure of smoking Total TGCT
OR (95% CI)
Seminoma
OR (95% CI)
Nonseminoma
OR (95% CI)
Henderson  
1979
Nonsmoker 1.0    
Ever smoker 1.1 (0.67-1.80)  
Brown  
1987
< 100 cigarettes during their lifetime 1.0
≥ 100 cigarettes during their lifetime 1.5 (1.0-2.1)  
UK study
1994
Nonsmoker 1.0  
Ever smoker 1.18 (0.96-1.46)  
Thune

Nonsmoker 1.0  
1994 Smoking per 10 cigarettes  1.20 (0.85-1.70)†  
Gallagher
1995
Nonsmoker 1.0  
Ex-smoker  1.2 (0.9-1.6)  
Current smoker ≤ 10 pk yrs 1.1 (0.8-1.5)  
Current smoker 11 + pk yrs 1.4 (1.0-1.8)  
Ever smoker 1.23 (1.04-1.46)
a
 
Møller
1996
Nonsmoker 1.0  
Ever smoker 0.92 (0.71-1.18)  
Garner  
2003
Nonsmoker 1.0 1.0 1.0
1-5 pk yrs 0.86 (0.63-1.18) 0.82 (0.56-1.20) 0.82 (0.49-1.38)
5-12 pk yrs 0.89 (0.65-1.23) 0.92 (0.64-1.32) 0.92 (0.55-1.55)
12-24 pk yrs 1.01 (0.71-1.44) 0.89 (0.59-1.33) 1.42 (0.80-2.51)
24 + pk yrs 1.10 (0.67-1.80) 1.03 (0.59-1.80) 1.32 (0.54-3.25)
Ever smoker  0.93 (0.78-1.11)
a
0.89 (0.73-1.10)
a
1.03 (0.77-1.38)
a
Srivastava
2004
Nonsmoker 1.0    
> 0 to ≤ 5 pk yrs 1.56 (0.87-2.82)  
> 5 to ≤ 12 pk yrs 1.61 (0.89-2.92)  
> 12 to ≤ 24 pk yrs 1.96 (1.04-3.69)  
> 24 pk yrs 2.31 (1.12-4.77)  
Ever smoker  1.79 (1.31-2.45)
a
 
Dusek  
2007
Nonsmoker 1.0 1.0 1.0
Former smoker 1.50 (1.02-2.03) 1.08 (0.65-1.77) 1.42 (1.01-2.62)
Active smoker 1.60 (1.10-2.33) 1.57 (1.02-2.41) 1.75 (1.04-3.23)
Ever smoker 1.55 (1.20-1.99)
a
1.33 (0.93-1.92)
a
1.55 (1.08-2.23)
a
0.1-2.5 1.36 (0.65-2.82) 1.21 (0.48-2.99) 1.51 (0.63-3.65)
2.6-12.0 3.30 (1.69-6.42) 2.59 (1.21-5.56) 3.21 (1.96-9.02)
≥ 12.1 4.93 (1.63-12.6) 3.68 (1.75-8.78) 5.06 (2.56-18.2)
Lacson  
2012
Adjusting  
marijuana use  
Nonsmoker 1.0 1.0 1.0
Ever smoker 0.98 (0.58-1.67) 0.49 (0.17-1.40)
b
1.16 (0.56-2.38)
b
Current smoker 0.89 (0.46-1.69) 0.43 (0.12-1.50)
b
1.05 (0.45-2.48)
b
Former smoker 1.15 (0.58-2.26) 0.57 (0.16-2.02)
b
1.28 (0.52-3.17)
b
32

Table 3: Studies addressing maternal  smoking
Author
year
Source of
cases/controls
Source of
smoking data
Case
recruitment
period
Matching
factors
Adjusting factors Cases/
controls
Henderson  
1979
Cancer Surveillance
Program/
neighborhood  
controls
Questionnaire 1972-1974,
15-40 years
of age
Age (±5
years), sex,
social class
None 79/79
Brown  
1986
DC area medical
centers/hospital  
controls
Interview 1975-1981
18-42 years
of age
Age (±2
years)
Hospital and age at 202/206
diagnosis

Swerdlow
1987
Radiotherapy
centers/hospital
controls
Interview,
case notes
1977-1981 Age (the
same)
None 218/404
Møller
1996
Cancer
Registry/Central
Person Register
Interview,
questionnaire
1986-1988 Year of birth None 296/287
Weir
2000
Cancer
Registry/Ministry of
Revenue’s
Enumeration
Composite Records
Interview,
self-
administered
questionnaire  
1987-1989,
16-59 years
of age
Age (±5
years)
Age, exogenous
hormone use during
pregnancy,
bleeding/threaten
miscarriage,
pregnancy length,
treatment for
undescended testicle  
325/490
Coupland
2004
Cancer treatment
centers or regional
cancer
registries/hospital
controls
Interview,
questionnaire
1984-1987,
15-49 years
of age
Date of birth
(±1 year)
Age, place of
residence
446/420
McGlynn
2006
Military medical
databases/Defense
Serum Repository
Interview,
questionnaire
2002-2005,
0-46 years
of age
Age (±1
year), race,
date of serum
sample drawn
(within 30
days)
Son’s age, race,
family history of TC
514/560
Pettersson
2007
Cancer
Registry/hospital
controls
Birth registry 1973-2002,
≥15 years
of age
Date of birth
(first three
control
children born
after case
child)
Age, histology,
maternal age, birth
order, gestational
duration, birth
weight  
192/494
Snoke
2007
University of Texas
M.D. Anderson
Cancer Center
/friend controls  
Interview,
self-
administered
questionnaire
1990-1996,
18-50 years
of age
Race, age (±5
years), state
residence
Mother’s race,
education, BMI,
son’s birth weight,
age, history of
cryptorchidism,
nausea, length of
pregnancy
144/86
Mongraw-
Chaffin
2008
California Cancer
Registry/Neighbor-
hood controls  
Interview 1959-1967
17-38 years
of age
Birth year,
race
None 20/60
Tuomisto
2009
Cancer
Registry/hospital
controls
Serum Bank 1979-2006,  Date of birth
of the son (±1
month)
Date of birth of the
son (±1 month)
70/519
0-26 years
of age

33

Red color is used to estimates ORs of Meta-Analysis.

a
Meta-Analysis ORs were calculated by the author.



Table 3, Continued  
Author
year
Parental characteristic
(maternal smoking)
Total TGCT
OR (95% CI)
Seminoma
OR (95% CI)
Nonseminoma
OR (95% CI)
Henderson  
1979
Smoked during pregnancy    
No 1.0    
Yes 1.00 (0.52-1.92)  
Brown  
1986
Smoked during pregnancy    
No 1.0  
<1 1.5 (0.8-2.9)
≥1 0.8 (0.4-1.5)  
Yes 1.1 (0.59-2.04)
a
 
Swerdlow
1987
Smoking at time of subject’s
birth
 
No 1.0    
Yes 1.0 (0.7-1.5)  
Møller
1996
Smoked during pregnancy    
No 1.0  
Yes 0.97 (0.69-1.37)  
Weir
2000
Cigarettes/day during
pregnancy  
 
0 1.0  1.0 1.0
1-11 1.1 (0.8-1.6) 0.9 (0.5-1.5) 1.5 (0.9-2.4)
12 + 0.6 (0.4-1.0) 0.6 (0.3-1.1) 0.6 (0.3-1.2)
Yes 0.82 (0.46-1.50)
a
0.76 (0.50-1.16)
a
0.98 (0.4-2.4)
a
Coupland
2004
Smoked during pregnancy    
No 1.0  
Yes 1.16 (0.85-1.57)  
McGlynn
2006
Mother smoked    
No 1.0 1.0 1.0
Yes 1.0 (0.8-1.3) 1.2 (0.9-1.7) 0.9 (0.7-1.2)
  While pregnant 1.0 (0.8-1.4) 1.1 (0.8-1.7) 0.9 (0.7-1.3)
  While breast-feeding 1.2 (0.7-2.0) 1.0 (0.5-2.1) 1.3 (0.7-2.3)
Pettersson
2007
Maternal smoking
(cigarettes/day)
 
No 1.0 1.0 1.0
< 10 0.83 (0.52-1.3) 0.29 (0.09-0.99) 1.00 (0.6-1.66)
≥ 10 0.99 (0.65-1.52) 0.49 (0.17-1.43) 1.18 (0.73-1.91)
Yes 0.91 (0.64-1.30)

0.39 (0.17-0.86)
a
1.09 (0.77-1.55)
a
Snoke
2007
Cigarette smoking during
pregnancy
 
No 1.0  
Yes 1.1 (0.5-2.2)  
Mongraw-
Chaffin
2008
Cigarette smoking during
pregnancy
 
< 7 cigarette per day 1.0
≥ 7 cigarette per day 1.06 (0.29-3.89)  
Tuomisto
2009
Maternal smoking during
pregnancy
 
No 1.0 1.0 1.0
Yes 0.68 (0.35-1.34) 0.55 (0.09-3.13) 0.71 (0.35-1.47)
34

Table 4: Studies addressing androgen receptor (CAG)n polymorphism
Author
year
Cases/
controls
AR
genotype
Types of Tumor Controls Cases P value
(t-test)
Rajpert-De  
2002
102/110 CAG
mean
(SD)
Total 21.79 (3.36) 21.69 (3.11) 0.85
c

Seminoma  21.65 (3.38) 0.84
c

Nonseminoma  21.63 (3.05) 0.83
c

Mixed  22.55 (2.68) 0.48
c

Nonseminoma/mixed  21.85 (2.99) 0.90
c

Casella  
2003
12/55 CAG
Median
(Range)
Total  21.0 (8-27)  
Seminoma  22.0 (21-27) 0.043
Giwercman  
2004
83/220 CAG
Median
(Range)
Total 21.0 (12.0-30.0) 21.0 (13.0-28.0) > 0.05
d
Seminoma  21.0 (18.0-25.0) > 0.05
d

Nonseminoma  21.0 (13.0-28.0) > 0.05
d
Mixed non-seminoma-
seminoma
22.0 (19.0-25.0) > 0.05
d

GGN
Median
(Range)
Total 23.0 (10.0-25.0) 24.0 (16.0-24.0) > 0.05
d
Seminoma  23.0 (19.0-24.0) > 0.05
d

Nonseminoma  23.0 (16.0-24.0) > 0.05
d
Mixed non-seminoma-
seminoma
23.0 (17.0-24.0) > 0.05
d

CAG
Median
(Range)
Total  21.0 (13.0-28.0)
a
23.0 (19.0-27.0)
b
0.04
d

Pure seminoma 21.0 (18.0-24.0)
a
22.0 (20.0-25.0)
b
0.15
d

Pure nonseminoma 21.0 (13.0-28.0)
a
23.0 (19.0-27.0)
b
0.27
d

Mixed non-seminoma-
seminoma
21.0 (19.0-24.0)
a
23.0 (19.0-25.0)
b
0.57
d

Garolla  
2005
123/115 CAG
mean
(SD)
Total  21.6 (3.3) 22.3 (3.4) > 0.05
e

TC no cryptorchidism  22.2 (3.5) > 0.05
e

TC + cryptorchidism  23.0 (2.4) > 0.05
e

GGC
mean
(SD)
Total  17.0 (1.7) 17.2 (1.4) > 0.05
e

TC no cryptorchidism  17.3 (1.5) > 0.05
e

TC + cryptorchidism  16.9 (1.4) > 0.05
e

Davis-Dao
2011
273/273 CAG
mean
(SD)
Total 21.33 (3.30) 21.12 (3.01) 0.45
f
Seminoma 21.61 (3.19) 20.71 (2.92) 0.014
f

Nonseminoma 20.51 (3.15) 21.51 (3.00) 0.06
f

Mixed GCT 21.66 (3.66) 21.92 (3.00) 0.69
f

a
nonmetastatic TGCT
b
metastatic TGCT
c
Wilcoxon’s test
d
Mann-Whitney test
e
Wilcoxon’s rank sum test
f
p-value from paired t-test comparing mean length of case (transmitted) alleles and control (untransmitted) alleles






35


36

 
37


38

Table 7: Smoking effects on TGCT after or before adjusting for marijuana use  
Smoking Exposure

Total TGCT
OR
a
(95% CI)
Seminoma
OR
a
(95% CI)
Nonseminoma/
mixed GCT
OR
a
(95% CI)
Nonsmoker 1.0 1.0 1.0
Ever smoker 0.98 (0.58-1.67) 0.49 (0.17-1.40) 1.16 (0.56-2.38)
Current smoker 0.89 (0.46-1.69) 0.43 (0.12-1.50) 1.05 (0.45-2.48)
Former smoker 1.15 (0.58-2.26) 0.57 (0.16-2.02) 1.28 (0.52-3.17)
Smoking Exposure

Total TGCT
OR
b
(95% CI)
Seminoma
OR
b
(95% CI)
Nonseminoma/
mixed GCT
OR
b
(95% CI)
Nonsmoker 1.0 1.0 1.0
Ever smoker 1.12 (0.66-1.91) 0.54 (0.19-1.50) 1.33 (0.66-2.68)
Current smoker 0.97 (0.51-1.83) 0.47 (0.14-1.61) 1.13 (0.48-2.64)
Former smoker  1.36 (0.71-2.63) 0.63 (0.18-2.18) 1.49 (0.67-3.78)
a
adjusted for marijuana use, cocaine use, amyl nitrite use, cryptorchidism, education, and religion.
b
adjusted for cocaine use, amyl nitrite use, cryptorchidism, education, and religion.

 

Population-Based  
Case-Control Study

Daling 2009
OR=1.30, 95% CI=1.0-1.8
Lacson 2012
OR=1.94, 95% CI=1.02-3.68

Population-Based Case-
Control Study Combined  
OR=1.43, 95% CI=1.02-1.99

Hospital-Based  
Case-Control Study

Trabert 2010  
OR=0.7, 95% CI=0.4-1.1

All Studies Combined
OR=1.19, 95% CI=0.72-1.95  
 
0.422116                    OR=1                                                         3.6849  

Figure 2: Forest plot of marijuana use for all TGCT


39

Cohort Study




















Thune 1994
OR=1.20, 95% CI=0.85-1.70

Population-Based  
Case-Control Study
Henderson 1979
OR=1.10, 95% CI=0.67-1.80
UK Study 1994
OR=1.18, 95% CI=0.96-1.46
Gallagher 1995
OR=1.23, 95% CI=1.04-1.46
Møller 1996
OR=0.92, 95% CI=0.71-1.18
Garner 2003
OR=0.93, 95% CI=0.78-1.11
Srivastava 2004
OR=1.79, 95% CI=1.31-2.45
Dusek 2007
OR=1.55, 95% CI=1.20-1.99
Lacson 2012
OR=0.98, 95% CI=0.58-1.67

Population-based Case-
Control Study: Combined  
OR=1.18, 95% CI=1.00-1.40

Hospital-Based
Case-Control Study
Brown 1987
OR=1.5, 95% CI=1.0-2.1

All Studies Combined
OR=1.19, 95% CI=1.03-1.38
 
0.57754                                    OR=1                                                                 2.44794

Table 3: Forest plot of subject smoking for all TGCT






 
40

Population-Based  
Case-Control Study
 
Henderson 1979
OR=1.00, 95% CI=0.52-1.92
Møller 1996
OR=0.97, 95% CI=0.69-1.37
Weir 2000
OR=0.82, 95% CI=0.46-1.50
Coupland 2004
OR=1.16, 95% CI=0.85-1.57
McGlynn 2006
OR=1.0, 95% CI=0.8-1.4
Mongraw-Chaffin 2008
OR=1.06, 95% CI=0.26-3.89

Population-based Case-
Control Study: Combined  
OR=1.02, 95% CI=0.87-1.20

Hospital-Based
Case-Control Study

Brown 1986
OR=1.10, 95% CI=0.59-2.04
Swerdlow 1987
OR=1.0, 95% CI=0.7-1.5
Pettersson 2007
OR=0.91, 95% CI=0.64-1.30
Snoke 2007
OR=1.1, 95% CI=0.5-2.2
Tuomisto 2009  
OR=0.68, 95% CI=0.35-1.34

Hospital-based Case-Control
Study: Combined  
OR=0.95, 95% CI=0.73-1.17

All Studies Combined
OR=0.99, 95% CI=0.87-1.13
 
0.274042                                             OR=1                                                         4.1001

Figure 4: Forest plot of maternal smoking of all TGCT





41

 
Figure 5: Funnel plot of marijuana use for            Figure 6: Funnel plot of subject smoking for  
all TGCT                                            all TGCT

  Blue point refers to a population-based  
  case-control study.
  Red point refers to a hospital-based  
  case-control study.  
  Green point refers to a cohort study.  




Figure 7: Funnel plot of maternal smoking for all TGCT






42

Population-Based  
Case-Control Study
 

Daling 2009
OR=1.2, 95% CI=0.9-1.8
Lacson 2012  
OR=1.07, 95% CI=0.37-3.07

Population-based Case-
Control Study: Combined  
OR=1.19, 95% CI=0.85-1.65


Hospital-Based
Case-Control Study

Trabert 2010
OR=0.5, 95% CI=0.3-1.1

All Studies Combined
OR=0.88, 95% CI=0.48-1.61

 
0.261116                                                     OR=1                                              3.08214

Figure 8: Forest plot of marijuana use of seminoma

Population-Based  
Case-Control Study
 

Daling 2009
OR=1.5, 95% CI=0.9-2.4
Lacson 2012  
OR=2.42, 95% CI=1.08-5.42

Population-based Case-
Control Study: Combined  
OR=1.71, 95% CI=1.12-2.60


Hospital-Based
Case-Control Study

Trabert 2010
OR=0.8, 95% CI=0.49-1.3

All Studies Combined
OR=1.34, 95% CI=0.74-2.43

 
0.491153                      OR=1                                                                               5.4213  

Figure 9: Forest plot of marijuana use of nonseminoma/mixed GCT
43


Population-Based  
Case-Control Study


Garner 2003
OR=0.89, 95% CI=0.73-1.10
Dusek 2008
OR=1.33, 95% CI=0.93-1.92
Lacson 2012
OR=0.49, 95% CI=0.17-1.40

Population-based Case-
Control Study: Combined  
OR=0.98, 95% CI=0.67-1.43

 
0.170748                                                                              OR=1                         1.911
Table 10: Forest plot of subject smoking of seminoma  



Population-Based  
Case-Control Study


Garner 2003
OR=1.03, 95% CI=0.77-1.38
Dusek 2008
OR=1.55, 95% CI=1.08-2.23
Lacson 2012
OR=1.16, 95% CI=0.56-2.38

Population-based Case-
Control Study: Combined  
OR=1.22, 95% CI=0.92-1.63

 
0.562683                                OR=1                                                                     2.3914
Table 11: Forest plot of subject smoking of nonseminoma  




44

Population-Based  
Case-Control Study
 

Weir 2000
OR=0.76, 95% CI=0.50-1.16
McGlynn 2006
OR=1.1, 95% CI=0.8-1.7

Population-based Case-
Control Study: Combined  
OR=0.97, 95% CI=0.62-1.51


Hospital-Based
Case-Control Study

Pettersson 2007
OR=0.39, 95% CI=0.17-0.86
Tuomisto 2009  
OR=0.55, 95% CI=0.09-3.13

Hospital-based Case-Control
Study: Combined  
OR=0.41, 95% CI=0.20-0.87

All Studies Combined
OR=0.76, 95% CI=0.50-1.17

 
0.090692                                                                            OR=1                        3.33546

Figure 12: Forest plot of maternal smoking of seminoma










45

Population-Based  
Case-Control Study
   

Weir 2000
OR=0.98, 95% CI=0.40-2.40
McGlynn 2006
OR=0.9, 95% CI=0.7-1.3

Population-based Case-
Control Study: Combined  
OR=0.91, 95% CI=0.68-1.22


Hospital-Based
Case-Control Study

Pettersson 2007
OR=1.09, 95% CI=0.77-1.55
Tuomisto 2009  
OR=0.71, 95% CI=0.35-1.47

Hospital-based Case-Control
Study: Combined  
OR=0.99, 95% CI=0.67-1.41

All Studies Combined
OR=0.95, 95% CI=0.77-1.18

 
0.346445                                                       OR=1                                                2.4005                                                              

Figure 13: Forest plot of maternal smoking of nonseminoma









46

Excluding addressed
the author  







Henderson 1979
OR=1.20, 95% CI=1.03-1.40
Brown 1987
OR=1.17, 95% CI=1.00-1.36
UK Study 1994
OR=1.20, 95% CI=1.01-1.42
Thune 1994
OR=1.19, 95% CI=1.01-1.40
Gallagher 1995
OR=1.23, 95% CI=1.06-1.44
Møller 1996
OR=1.24, 95% CI=1.08-1.43
Garner 2003
OR=1.12, 95% CI=0.99-1.27
Srivastava 2004
OR=1.16, 95% CI=1.00-1.35
Dusek 2007
OR=1.21, 95% CI=1.03-1.41
Lacson 2012
OR=0.98, 95% CI=0.58-1.67


 
OR=1
0.99272                                                                                                              1.43883

Figure 14: Forest plot of sensitivity analysis of subject smoking for all TGCT











47

Excluding addressed
the author  







Henderson 1979
OR=0.99, 95% CI=0.87-1.13
Brown 1986
OR=0.99, 95% CI=0.87-1.13
Swerdlow 1987
OR=0.99, 95% CI=0.86-1.14
Møller 1996
OR=1.00, 95% CI=0.87-1.15
Weir 2000
OR=1.00, 95% CI=0.88-1.15
Coupland 2004
OR=0.96, 95% CI=0.83-1.11
McGlynn 2006
OR=0.99, 95% CI=0.86-1.15
Pettersson 2007
OR=1.01, 95% CI=0.88-1.16
Snoke 2007
OR=0.99, 95% CI=0.87-1.13
Mongraw-Chaffin 2008
OR=0.99, 95% CI=0.87-1.13
Tuomisto 2009  
OR=1.01, 95% CI=0.88-1.15

 
0.831884                                                             OR=1                                     1.15729                                                      

Figure 15: Forest plot of sensitivity analysis of maternal smoking for all TGCT









48

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Abstract (if available)
Abstract Testicular germ cell tumors (TGCTs) are a group of neoplasms derived from germ cells and TGCTs occur most frequently in adolescent and adult men ages 15 to 45 years. The incidence rates of TGCTs among young men have almost doubled in the US in recent decades 
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Asset Metadata
Creator Myung, No Kang (author) 
Core Title Risk factors of testicular germ cell tumor 
School Keck School of Medicine 
Degree Master of Science 
Degree Program Biostatistics 
Publication Date 10/22/2014 
Defense Date 04/22/2014 
Publisher University of Southern California (original), University of Southern California. Libraries (digital) 
Tag androgen receptor,marijuana use,maternal smoking,OAI-PMH Harvest,subject smoking,testicular germ cell tumor 
Format application/pdf (imt) 
Language English
Contributor Electronically uploaded by the author (provenance) 
Advisor Azen, Stanley P. (committee chair), Cortessis, Victoria (committee chair), Mckean-Cowdin, Roberta (committee member) 
Creator Email nokangmy@hotmail.com,nokangmy@usc.edu 
Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-383202
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Tags
androgen receptor
marijuana use
maternal smoking
subject smoking
testicular germ cell tumor