Cancer Causes Control
DOI 10.1007/s10552-015-0572-x
ORIGINAL PAPER
Tobacco smoking, family history, and the risk of nasopharyngeal
carcinoma: a casereferent study in Hong Kong Chinese
Shao-Hua Xie1 Ignatius Tak-sun Yu1 Lap Ah Tse1
Joseph Siu Kie Au2 June Sze Man Lau3
Received: 21 July 2014 / Accepted: 24 March 2015
Springer International Publishing Switzerland 2015
Abstract
Purpose This study aimed to investigate the associations
of tobacco smoking and family history of nasopharyngeal
carcinoma (NPC) with the risk of NPC in Hong Kong
Chinese.
Methods Between June 2010 and December 2012, we
conducted a casereferent study with 352 incident cases
and 410 referents in Hong Kong. We collected information
on tobacco smoking and family history of NPC via face-to-
face interviews.
Results There were 174 (49.4 %) and 131 (32.0 %) ever-
smokers among cases and referents, respectively. The ad-
justed odds ratio (OR) for NPC related to current smoking
was 1.67 [95 % confidence interval (CI) 1.06, 2.61]. Ex-
posureresponse relationships were observed between
years and total pack-years of smoking, and NPC risk
(p = 0.001 and p = 0.018, respectively). History of NPC
in first-degree relatives was associated with an increased
Electronic supplementary material The online version of this
article (doi:10.1007/s10552-015-0572-x) contains supplementary
material, which is available to authorized users.
& Ignatius Tak-sun Yu
iyu@cuhk.edu.hk
Shao-Hua Xie
shaohua1983-man@163.com
1
The Jockey Club School of Public Health and Primary Care,
The Chinese University of Hong Kong, 4/F, School of Public
Health Building, Prince of Wales Hospital, Shatin,
New Territories, Hong Kong SAR, China
2
Department of Clinical Oncology, Queen Elizabeth Hospital,
Kowloon, Hong Kong SAR, China
3
Department of Medicine, Queen Elizabeth Hospital,
Kowloon, Hong Kong SAR, China
NPC risk (adjusted OR = 4.52, 95 % CI 2.39, 8.55). The
increased NPC risk associated with sibling history (ad-
justed OR = 6.80, 95 % CI 2.63, 17.56) was higher than
that for parental history (adjusted OR = 3.04, 95 % CI
1.27, 7.25). The adjusted OR for ever-smokers with family
history using never-smokers without family history as the
reference was 4.54 (95 % CI 1.67, 12.34).
Conclusions This study verified the important roles of
tobacco smoking and family history on NPC risk among
Hong Kong Chinese. The provided evidence supported the
knowledge that both environmental exposures and in-
herited susceptibility contributed to the risk of NPC.
Keywords Tobacco smoking  Nasopharyngeal
carcinoma  Family history  Etiology  Epidemiology 
Risk factor
Introduction
Nasopharyngeal carcinoma (NPC) is a malignancy which
has fascinated generations of epidemiologists for its pe-
culiar geographical and racial variations in incidence. NPC
is rare in most parts of the world with age-adjusted inci-
dence rates less than one per 100,000 persons per year
irrespective of sex [13]. However, high incidence rates of
NPC are noted in certain areas, including Hong Kong. The
crude incidence rates in Hong Kong in 2010 were 19.5 and
5.8 per 100,000 for males and females, respectively.
Although the etiology of NPC has not been completely
understood, it has become increasingly clear that NPC is a
multifactorial disease resulting from the joint effects of
EpsteinBarr virus (EBV) infection, environmental expo-
sures, and genetic susceptibility [2, 4]. Among those pre-
viously investigated, tobacco smoking and family history
123

are two largely documented major risk factors for NPC.
Tobacco smoking has long recognized as an important
cause of cancers in the respiratory system; however, pre-
vious epidemiological findings on smoking and NPC risk
remain inconsistent. Most previous studies reported an in-
creased risk of NPC associated with tobacco smoking [5
8], while some others found no association [911]. Familiar
clustering of NPC cases has been noted in high-risk
populations. Individuals with a first-degree relative with
NPC have been reported to have four to over tenfold in-
creased risk of NPC [1214].
The incidence rate of NPC in Hong Kong is among the
highest in the world. Nevertheless, epidemiological evi-
dence from this unique population remains largely lacking
except for two casereferent studies in late 1970s and early
1980s. One study only reported similar distribution of to-
bacco smoking in cases and referents [11], while the other
one used cancer patients as referents [15] and thus might
have produced biased results since tobacco smoking is an
important risk factor for almost all types of cancers. Nei-
ther of them reported the association between family his-
tory and NPC risk.
In view of lack of epidemiological evidence from this
unique population, we performed a casereferent study to
identify the underlying risk factors for NPC in the Hong
Kong Chinese population. In this study, we examined the
independent effects of tobacco smoking and family history
on NPC risk. The joint effects of tobacco smoking and
family history on NPC risk were further assessed.
Subjects and methods
Subjects and data collection
All participants were recruited during the period of June
2010 to December 2012, from Queen Elizabeth Hospital
which houses the largest oncology center in Hong Kong.
All subjects were required to be Chinese residents of Hong
Kong aged 2075 years. All consecutive new incident pa-
tients with histologically confirmed diagnosis of primary
NPC who were diagnosed during the study period in the
Department of Clinical Oncology were recruited. Referents
were outpatients attending the same hospital during the
same period who did not have any history of cancer and
were frequency-matched by age (in 5-year groups), gender,
and residence district with cases. To reduce the risk of
introducing bias when referents were patients with a par-
ticular disease (or group of diseases), we recruited referents
from multiple clinical units.
All eligible subjects were invited to attend face-to-face
interviews conducted by trained interviewers. We used a
standardized structured questionnaire to collect information
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Cancer Causes Control
mainly on basic sociodemographic characteristics, dietary
habits, active smoking, lifelong workplace and domestic
passive smoking exposures, alcohol use, use of herbal
medicine, complete occupational history, living condition
and ventilation, source of indoor air pollution at home (use
of mosquito coils, incense burning, and cooking habits),
prior otolaryngology diseases or injuries, and history of any
cancer in first-degree relatives. Participants who had ever
smoked over 100 cigarettes or equivalent use of pipes were
defined as ever-smokers. Those who had quitted smok-
ing for at least 2 years were defined as ex-smokers [16].
Exposure assessment of smoking included duration, in-
tensity, and quantity, which are typically used in epi-
demiological studies. The duration of smoking was derived
from the starting and stopping age (if any) of regular
smoking. The intensity of smoking was measured by the
number of cigarettes smoked per day. The quantity of
smoking was estimated by the amount of any type of to-
bacco consumed over lifetime with the indicator of pack-
years. To assess passive smoking exposure, participants
were asked about their lifelong exposures to environmental
tobacco smoke generated from family members, co-
habitants, and co-workers [17]. A reduced version of the
Diet History Questionnaire (DHQ 2007) designed by the
US National Cancer Institute [18] was used to collect in-
formation on participants usual diet during the past year
prior to the interviews. Subjects were asked about the
frequencies of intake of major groups of foods, and the
amount they ate on average each time for dark green
vegetables, yellow/orange vegetables, and meats. The in-
takes of these three food items were quantified as numbers
of servings daily, where a serving equaled 80 g. Subjects
were also asked to report their frequency of salted fish
intake at the age of 10 years as an indicator for salted fish
consumption during childhood. A full occupational history
of each subject was recorded for each full-time occupation
held for 1 year or longer. Subjects were asked to identify
their self-estimation of exposures in each workplace to
common hazardous agents.
Cases were interviewed on the day of their admission to
the hospital for diagnostic workup or treatment. This study
was approved by the ethics committees of the medical
school and the hospital, and informed consent was obtained
from each participant at enrollment.
Statistical analyses
We performed data analyses with the statistical software
package SAS 9.3 for Windows (SAS Institute Inc., Cary,
NC, USA). We used Chi-square tests and analysis of
variance (ANOVA) for the similarity of sociodemographic
factors and exposures of interest between cases and refer-
ents. Unconditional logistic regressions were used to
Cancer Causes Control
estimate the odds ratios (ORs) and their confidence inter-
vals (CIs) of NPC risk associated with individual exposure
indicators. Multivariate logistic regressions were per-
formed to adjust for potential confounders. Inclusion of
covariates was based on both biological and statistical
considerations. Domestic exposure to cooking fumes, in-
take of vitamins and supplements, habit of drinking herbal
tea, and occupational exposures were included in the
models as dichotomous (yes/no) variables. The following
variables were coded as dummy variables which were
categorized as shown in Table 1: age, education, housing
type, family history of NPC, environmental tobacco smoke
exposures, intake of dark green vegetables, and fruits.
p values for trends were calculated by treating the exposure
levels as an ordinal categorical variable coded with integer
values to examine any exposureresponse relationship.
Possible interactions were formally assessed under both
additive and multiplicative models [19]. Multiplicative-s-
cale interactions were assessed by including a product term
between one factor and the other factor into logistic re-
gression models. Addictive-scale interactions were asses-
sed with the index of the relative excess risk due to
interaction (RERI) [19, 20], which was calculated as
follows:
RERI ORAB  ORAB  ORAB 1; p = 0.018, respectively). The risk of NPC in those who
where ORA?B? is the OR if both factors A and B were
present, ORA?B-is the OR if factor A was present, but
factor B was absent, and ORA-B? is the OR if factor A was
absent but factor B was present. RERI equaling zero means
no interaction, RERI over zero means positive interaction,
and RERI less than zero means negative interaction. The
95 % CIs of RERI were calculated with the delta method,
which is a straightforward Taylor expansion of the vari-
ances and covariances [21].
Results
A total of 373 NPC cases and 437 referents were identified
and invited to participate, among which 352 (94.4 %) and
410 (93.8 %) completed face-to-face interviews, respec-
tively. Interviews with 339 (96.3 %) subjects were con-
ducted before diagnosis or within 1 month after diagnosis,
8 (2.3 %) of the remaining cases were interviewed within
2 months after diagnosis, and only five subjects were in-
terviewed between 2 and 6 months after diagnosis. Refer-
ents were admitted for a wide range of conditions.
Considerable proportions of referents were diagnosed with
diseases of the circulatory system (27 %), diseases of the
nervous system (13 %), endocrine, nutritional, and
metabolic diseases (10.0 %), and under investigation for
isolated symptoms, signs, or abnormal laboratory findings
(12.7 %). None of other disease groups accounted for a
proportion of 10 % or more.
The distributions of sociodemographics, clinical char-
acteristics, and major risk factors for NPC among cases and
referents are shown in Table 1. No significant difference
was observed between the two groups in the distributions
of age and sex. The mean age was 51.6(10.2) years and
50.4(10.6) years among cases and referents, respectively.
Referents were better educated than cases. The recruited
NPC cases included 328 (93.2 %) non-keratinizing carci-
nomas, 17 (4.8 %) squamous cell carcinomas, and 7
(2.0 %) carcinomas with unspecified histological classifi-
cation. Distributions of major potential confounders in
cases and referents by smoking status are displayed in
Supplementary Material 1.
Table 2 presents the association between tobacco
smoking and NPC risk. There were 174 (49.4 %) and 131
(32.0 %) ever-smokers among cases and referents, re-
spectively. The adjusted ORs for NPC related to current
smoking and ex-smoking were 1.67 (95 % CI 1.06, 2.61)
and 1.51 (95 % CI 0.94, 2.41), respectively. Exposure
response relationships were observed between two indica-
tors of cumulative active smoking, years and total pack-
years of active smoking and NPC risk (p = 0.001 and
smoked for 30 years or more was as high as 2.48 times that
in never-smokers. Smoking for over 300 pack-years was
associated with 1.7-fold increased risk of NPC with never-
smoking as reference. Smokers who started smoking before
the age of 18 years were at higher risk of NPC than those
who started later and never-smokers. Ex-smokers who had
quitted smoking for over 10 years were at a decreased,
though not statistically significant, risk of NPC compared
with current smokers (adjusted OR = 0.79, 95 % CI 0.43,
1.45).The exposureresponse relationship between inten-
sity of tobacco smoking and NPC risk was nonlinear that
smoking less than ten cigarettes per day was associated
with a higher risk of NPC (adjusted OR = 2.75, 95 % CI
1.49, 5.07) than smoking with heavier intensity.
Associations between history of cancers in first-degree
relatives and NPC risk are shown in Table 3. Having any
first-degree family member with a diagnosis of NPC was
associated with an increased risk of NPC (adjusted
OR = 4.52, 95 % CI 2.39, 8.55). The adjusted OR for NPC
associated with sibling history (adjusted OR = 6.80, 95 %
CI 2.63, 17.56) was higher than that for parental history
(adjusted OR = 3.04, 95 % CI 1.27, 7.25). No significant
association was observed between NPC risk and family
history of cancers other than NPC.
The joint effects of tobacco smoking and family history
on NPC risk are presented in Table 4. The adjusted ORs for
NPC associated with current tobacco smoking and family
history of NPC alone were 1.67 (95 % CI 1.06, 2.65) and
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Table 1 Distributions of Variables Cases n = 352 Referents n = 410 p valuea

sociodemographics, clinical
characteristics, and major risk Sex
factors for NPC in cases and
Male 253 (71.9) 301 (73.4) 0.634
referents, n (%)
Female 99 (28.1) 109 (26.6)
Age (years)
\45 87 (24.7) 117 (28.5) 0.121
45* 125 (35.5) 159 (38.8)
55* 140 (39.8) 134 (32.7)
Education
Primary school and lower 96 (27.3) 71 (17.3) \0.001
High school 210 (59.7) 199 (48.5)
College and above 43 (12.2) 139 (33.9)
Housing type
Public rental housing estates 160 (45.5) 105 (25.6) \ 0.001
Home ownership scheme courts 44 (12.5) 46 (11.2)
Private mansion houses 104 (29.5) 203 (49.5)
Private tenement houses 30 (8.5) 31 (7.6)
Others 12 (3.4) 22 (5.4)
Employment
Unemployed 109 (31.0) 102 (24.9) 0.061
Employed 243 (69.0) 308 (75.1)
Smoking status
Never-smokers 178 (50.6) 279 (68.0) \0.001
Ex-smokers 73 (20.7) 62 (15.1)
Current smokers 101 (28.7) 69 (16.8)
ETS exposures
No 96 (27.3) 141 (34.4) 0.027
At home or at work 186 (52.8) 212 (51.7)
Both 70 (19.9) 57 (13.9)
History of NPC in first relatives
No 299 (84.9) 394 (96.1) \0.001
Yes 53 (15.1) 16 (3.9)
Intake of dark green vegetables
\1 serving per day 120 (34.1) 92 (22.4) \0.001
One serving per day 39 (11.1) 29 (7.1)
Two or more servings per day 192 (54.5) 289 (70.5)
Intake of fruits
\Monthly 7 (2.0) 1 (0.2) \0.001
Monthly 33 (9.4) 13 (3.2)
Weekly 153 (43.5) 174 (42.4)
daily 157 (44.6) 221 (53.9)
Salted fish intake during childhood
\Monthly 136 (38.6) 159 (38.8) 0.199
Monthly 102 (29.0) 137 (33.4)
Weekly 95 (27.0) 88 (21.5)
Daily 9 (2.6) 6 (1.5)
Habitual drinking of herbal tea# 84 (23.9) 68 (16.6) 0.012
Cooking experience at home 167 (47.4) 153 (37.3) 0.005

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Table 1 continued Variables
Histological type
Squamous cell carcinoma
Non-keratinizing carcinoma
Unspecified
ETS environmental tobacco smoke, NPC nasopharyngeal carcinoma
a
Chi-square tests
#
Defined as drinking at least one cup per week for at least 1 month
6.05 (95 % CI 2.69, 13.59), respectively. The OR for
current smoking and with family history of NPC using
never-smokers without family history as the reference was
8.94 (95 % CI 1.88, 42.57) after adjustment for potential
confounders. However, the interaction between tobacco
smoking and family history of NPC was not statistically
significant under either multiplicative (p = 0.207) or ad-
ditive assumptions (RERI = 1.01, 95 % CI -12.31, 14.33).
Discussion
As the first epidemiological study which specifically in-
vestigated the roles of tobacco smoking and family history
on NPC risk in the Hong Kong Chinese population, this
study confirmed significant associations of tobacco smok-
ing and family history with NPC risk. We further found
suggestive evidence for an additive interaction between
tobacco smoking and family history on NPC risk, although
there was no statistical significance.
The observed association between tobacco smoking and
NPC risk was similar to the pooled estimate reported in a
recent systematic review that the overall OR for NPC
among smokers versus nonsmokers combining 27 case
referents studies was 1.63 (95 % CI 1.38, 1.92) [22]. Since
tobacco smoking is an established risk factor for a wide
range of health conditions, use of hospital-based referents
might have produced diluted associations between tobacco
smoking and NPC. However, this speculation was not
supported by meta-analyses combining results from pre-
vious casereferent studies and the present study where
studies with different sources of referents resulted in
similar estimates (Supplemental Material 2).
The risk of NPC increased monotonically with the in-
creasing duration of smoking and total pack-years,
demonstrating exposureresponse relationships between
cumulative active exposures to tobacco smoke and NPC
risk. We also found suggestive evidence supporting the
benefits from quitting smoking, which would convey an
encouraging message for preventing NPC with tobacco
control. We observed the nonlinear pattern of the effects of
Cases n = 352 Referents n = 410 p valuea
17 (4.8)
328 (93.2)
7 (2.0)
smoking intensity on NPC risk: The excess risk was even
higher at lower intensity than that at higher intensity.
Similar results were also reported in previous epi-
demiological studies that the risks of lung cancer and
bladder cancer tended to level off with increased smoking
intensity [23, 24]. Such findings may be explained by the
changes in underlying biological processes in relation to
carcinogenesis induced by tobacco smoke, such as en-
hanced capacities in detoxification for carcinogenic com-
pounds and in DNA repair at higher intensities [2527]. It
might be alternatively explained by the variation in in-
halation practices such that lower-intensity smokers might
ingest relatively more deeply than higher-intensity smokers
[28]. Unfortunately, information on inhalation practices
when smoking was not collected in this study, and thus, we
were not able to examine this speculation. Furthermore, it
was possible, at least to some extent, to be explained by
misclassification on smoking intensity, particularly when
the degree of misclassification had increased with smoking
intensity, which might have resulted in more diluted as-
sociations at higher intensities. Nevertheless, the leveling
of risk of smokers at higher intensity only indicates the
magnitude of the increased risk but does not imply any
decrease in the risk of NPC.
Family history of NPC in first-degree relatives was ob-
served to be associated with an over four-time increased
risk of NPC, which is consistent with previous findings
[1214]. The association with family history would imply
the effect from both inherited predisposition and common
environmental exposures shared by family members. It was
notable that the magnitude of the effect associated with a
sibling history was much greater than that for a parental
history. The difference may be partially explained by the
effects from some common environmental exposures
shared within siblings, especially those at early ages, such
as consumption of salted fish and secondhand tobacco
smoke exposures. An alternative explanation is the inac-
curate self-reporting of family history that the reliability of
reporting sibling events might be greater than that for
parental events, because of the occurrence in siblings near
the time of interviews. Relatively more accurate reporting
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Table 2 Association between active tobacco smoking and NPC risk, n (%)
Exposure indicators Cases (n = 352) Referents (n = 410) Crude OR (95 % CI) Adjusted ORa (95 % CI)

Smoking status
Never-smokers 178 (50.6) 279 (68.0) 1.00 1.00
Ex-smokers 73 (20.7) 62 (15.1) 1.85 (1.25, 2.72) 1.51 (0.94, 2.41)
Current smokers 101 (28.7) 69 (16.8) 2.29 (1.60, 3.29) 1.67 (1.06, 2.61)
p for trend \0.001 0.021
Ever-smokers 174 (49.4) 131 (32.0) 2.08 (1.55, 2.80) 1.59 (1.09, 2.33)
Age at start (years)
Never-smokers 178 (50.6) 279 (68.0) 1.00 1.00
C18 105 (29.8) 87 (21.2) 1.89 (1.35, 2.66) 1.40 (0.91, 2.15)
\18 69 (19.6) 44 (10.7) 2.46 (1.61, 3.75) 1.97 (1.19, 3.25)
p for trend \0.001 0.007
Cigarettes per day
Never-smokers 178 (50.6) 279 (68.0) 1.00 1.00
\10 45 (12.8) 23 (5.6) 3.07 (1.79, 5.24) 2.75 (1.49, 5.07)
10* 41 (11.6) 46 (11.2) 1.40 (0.88, 2.22) 1.26 (0.74, 2.16)
20* 88 (25.0) 62 (15.1) 2.23 (1.53, 3.24) 1.39 (0.86, 2.24)
p for trend \.001 0.206
Duration (years)
Never-smokers 178 (50.6) 279 (68.0) 1.00 1.00
\15 26 (7.4) 28 (6.8) 1.46 (1.87, 4.25) 1.00 (0.51, 1.93)
15* 67 (19.0) 58 (14.1) 1.81 (1.22, 2.70) 1.35 (0.83, 2.18)
30* 81 (23.0) 45 (11.0) 2.82 (1.87, 4.25) 2.48 (1.48, 4.16)
p for trend \.001 0.001
Pack-years
Never-smokers 178 (50.6) 279 (68.0) 1.00 1.00
\150 39 (11.1) 36 (8.8) 1.70 (1.04, 2.77) 1.42 (0.80, 2.50)
150* 30 (8.5) 25 (6.1) 1.88 (1.07, 3.30) 1.57 (0.82, 3.00)
300* 105 (29.8) 70 (17.1) 2.35 (1.65, 3.36) 1.70 (1.08, 2.68)
p for trend \.001 0.018
Years since quitting
Current smokers 101 (28.7) 69 (16.8) 1.00 1.00
\10 35 (9.9) 24 (5.9) 1.00 (0.55, 1.82) 1.09 (0.55, 2.13)
C10 38 (10.8) 38 (9.3) 0.68 (0.40, 1.18) 0.79 (0.43, 1.45)
Never-smokers 178 (50.6) 279 (68.0) 0.44 (0.30, 0.62) 0.60 (0.38, 0.94)
p for trend \.001 0.016
CI confidence interval, NPC nasopharyngeal carcinoma, OR odds ratio
a
Adjusted for sex, age, education, housing type, family history of NPC, environmental tobacco smoke exposures, intake of dark green
vegetables, fruits, vitamins and supplements, drinking herbal tea, occupational exposures (any of cotton dust, chemical fumes, welding fumes,
and disinfectants), and cooking experience at home

of sibling events might have led to underestimation (rela-
tive to sibling) of the association with parental events.
However, there is still possible underestimation of the ef-
fects from sibling history such that sibling events during
lifetime were not completely reported. By and large, the
magnitudes of effects from family history on NPC risk
need to be interpreted with caution and still warrant further
replication in studies with more accurate family history
ascertainment. In addition, three cases but no referents also
reported history of NPC in their spouses, which may to
some extent imply the effect from common environmental
exposures shared within couples.
In this study, we examined the interaction between to-
bacco smoking and family history on NPC risk and the
results revealed a possible synergistic effect between these
two factors. Among individuals without a family history of

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Table 3 Association between history of cancers in first-degree relatives and NPC risk, n (%)
Exposure indicators Cases (n = 352) Referents (n = 410) Crude OR (95 % CI) Adjusted ORa (95 % CI)

Family history of cancers

No 199 (56.5) 263 (64.1) 1.00 1.00
Yes 153 (43.5) 147 (35.9) 1.38 (1.03, 1.84) 1.43 (1.03, 1.99)
Family history of cancers other than NPC
No 236 (67.0) 274 (66.8) 1.00 1.00
Yes 116 (33.0) 136 (33.2) 0.99 (0.73, 1.34) 1.05 (0.74, 1.49)
History of NPC in first-degree relatives
No 299 (84.9) 394 (96.1) 1.00 1.00
Yes 53 (15.1) 16 (3.9) 4.37 (2.45, 7.79) 4.52 (2.39, 8.55)
History of NPC in parents
No 332 (94.3) 400 (97.6) 1.00 1.00
Yes 20 (5.7) 10 (2.4) 2.41 (1.11, 5.22) 3.04 (1.27, 7.25)
History of NPC in siblings
No 319 (90.6) 404 (98.5) 1.00 1.00
Yes 33 (9.4) 6 (1.5) 6.96 (2.88, 16.82) 6.80 (2.63, 17.56)
CI confidence interval, NPC nasopharyngeal carcinoma, OR odds ratio
a
Adjusted for sex, age, education, housing type, active tobacco smoking environmental tobacco smoke exposures, intake of dark green
vegetables, fruits, vitamins and supplements, drinking herbal tea, occupational exposures (any of cotton dust, chemical fumes, welding fumes,
and disinfectants), cooking experience at home, and, if appropriate, family history of NPC in siblings, in parents or in both

Table 4 Joint effects of tobacco smoking and family history on NPC risk, n (%)
Smoking No family history of NPC With family history of NPC
status a
Cases Referents Crude OR Adjusted OR Cases Referents Crude OR Adjusted ORa
(n = 178) (n = 279) (95 % CI) (95 % CI) (n = 174) (n = 131) (95 % CI) (95 % CI)

Never- 148 (42.0) 269 (65.6) 1.00 1.00 30 (8.5) 10 (2.4) 5.45 (2.59, 11.47) 6.05 (2.69, 13.59)
smokers
Ex- 65 (18.5) 58 (14.1) 2.04 (1.36, 3.06) 1.66 (1.02, 2.69) 8 (2.3) 4 (1.0) 3.64 (1.08, 12.27) 2.32 (0.61, 8.80)
smokers
Current 86 (24.4) 67 (16.3) 2.33 (1.60, 3.40) 1.67 (1.06, 2.65) 15 (4.3) 2 (0.5) 13.63 (3.08, 60.42) 8.94 (1.88, 42.57)
smokers
Ever- 151 (42.9) 125 (30.4) 2.20 (1.61, 3.00) 1.67 (1.13, 2.47) 23 (6.6) 6 (1.5) 6.97 (2.78, 17.49) 4.54 (1.67, 12.34)
smokers

NPC, the risk of NPC was only around 1.7-times increased
in smokers compared with never-smokers, whereas the risk
was nearly nine-times increased in current smokers with
family history of NPC, despite that the observed interaction
was not statistically significant in either additive or mul-
tiplicative models due to limited sample size. Nevertheless,
from the perspectives of disease prevention, individuals
with family history of NPC should devote particular at-
tention to avoid hazardous environmental exposures, and
thus, to reduce their risk of developing NPC.
This study had several major limitations. First, all cases
were recruited from a single hospital and, thus, may not be
representative of all NPC patients in Hong Kong during the
study period. However, this hospital houses one of the
largest oncology departments in Hong Kong and serves
around a quarter of all NPC patients in Hong Kong. In
addition, the age and sex distributions of cases in this study
were quite similar to those of all NPC patients in Hong
Kong during the study period. Thus, the selection bias from
cases should not be a major problem in this study. Second,
we used hospital-based rather than population-based ref-
erents due to practical difficulties. However, efforts have
been made to reduce the risk of introducing bias when
referents are patients with a particular disease (or group of
diseases) by recruiting referents from multiple disease
units. Furthermore, tobacco smoking and family history of
cancers were less likely to be a preventive factor for the
health conditions of the referents. Thus, the selection bias

123

from using hospital referents when the selection was de-
pendent on the exposures, if any, would have led to weaker
or null estimates of the associations between exposures and
the disease instead of overestimated associations. Further-
more, results from sensitivity analyses excluding referents
in any of major disease groups suggested no substantial
risk of selection bias related to the diagnosis of referents.
Third, almost all known major environmental risk factors
have been taken into account, assessed and controlled for
their potential confounding effects on the observed asso-
ciations. Education level was probably an important con-
founder in the association between tobacco smoking and
NPC risk, since the OR estimates changed by around 10 %
after removing education level from multivariate models. It
was possible to be explained by the fact that the prevalence
of tobacco smoking was higher among less-educated peo-
ple who might be more vulnerable to cancers, possibly due
to lack of health knowledge, more exposures to carcino-
gens in both dwelling and workplace, as well as limited
access to medical resources. EBV infection-related markers
were not adjusted for in multivariate models because blood
samples were only collected and tested for EBV serological
markers in a small proportion (less than 30 %) of referents.
However, since individuals practice of tobacco smoking
and family history of cancers were less likely to be de-
pendent on the knowledge on their EBV infection status,
confounding effect from EBV infection status was not
plausible. Furthermore, sensitivity analyses restricted to
those with serological testing results suggested that the
point estimates of ORs remained not substantially changed
in spite of wider CIs (data not shown). Finally, again,
although this study had adequate power to observe sig-
nificant associations between individual factors and NPC
risk, the sample size was far from
enough to detect interactions. Exploring the interactions
between individual risk factors on the risk of NPC still
warrants additional large-scale investigations.
In summary, this study verified the important roles of
tobacco smoking and family history on NPC risk among
Hong Kong Chinese and provided valuable information for
developing strategies for preventing this disease in the
Hong Kong Chinese population. The evidence provided by
this study supports the knowledge that both environmental
exposures and inherited susceptibility contributed to the
risk of NPC. Clarifying the roles of individual risk factors
and their interactions on NPC risk still needs further in-
vestigation in more large-scale studies with refined expo-
sure assessment in the future.
Acknowledgments We thank the clinical and research staff in
Department of Clinical Oncology and Department of Medicine of
Queen Elizabeth Hospital, Hong Kong, for their help and supports in
the field work. This research was supported by Hong Kong Anti-
Cancer Society and Research Postgraduate Students Research/
123
Cancer Causes Control
Conference Grant of The Jockey Club School of Public Health and
Primary Care, The Chinese University of Hong Kong.
Conflict of interest The authors declare that they have no conflict
of interest.
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