Effect of family history of cancers and environmental factors on risk of

nasopharyngeal carcinoma in Guangdong, China

Ze-Fang Ren
a,c,1
, Wen-Sheng Liu
a,b,1
, Hai-De Qin
a,b
, Ya-Fei Xu
a,b
, Dan-Dan Yu
a,c
,
Qi-Sheng Feng
a,b
, Li-Zhen Chen
a,b
, Xiao-Ou Shu
d
, Yi-Xin Zeng
a,b
, Wei-Hua Jia
a,b,c,
*
a
State Key Laboratory of Oncology in South China, China
b
Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
c
School of Public Health, Sun Yat-Sen University, Guangzhou 510080, China
d
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine,
Nashville, TN 37203-1738, USA
1. Introduction
Although nasopharyngeal carcinoma (NPC) is a rare malignancy
throughout most of the world, it is endemic in a few well-dened
populations. One of these distinct populations are persons of
Cantonese origin [1,2]. While the incidence rates of NPC for both
males and females are <1/100,000 person-years in most regions of
the world, incidence rates in males and females reach 31/100,000
and 13/100,000 person-years, respectively among Cantonese living
in Guangdong province [1,2]. The incidences of NPC in regions near
Guangdong province vary by the degree of racial and cultural
Cantonese admixture. In Hong Kong, a region with a native
Cantonese population, NPC incidence in males has been reported
to be >20/100,000 [3]. Intermediate levels of NPC incidence are
associated with Thai, Maconese, and Malay indigenous populations
with a history of intermarrying with the Cantonese population [4].
This distinctive racial/ethnic and geographic distributionof NPC
suggests that both environmental factors and genetic traits
contribute to its development. Epstein-Barr virus (EBV) infection
has been consistently accepted as an important factor in the
etiology of NPC [5,6]. However, infection of EBV is widespread
around the world, while the unique geographical distribution of
NPC suggests that factors other than EBV also play an role in the
etiology of NPC. One well-established, non-viral, environmental
contributor to the development of NPC is the southern Chinese
tradition of consuming salted sh containing volatile nitrosamines
[2,7,8]. Cigarette smoking and consumption of alcohol are other
non-viral environmental factors associated with the development
of NPC [2,4]. There is also substantial evidence for a hereditable
component in the risk of NPC based on segregation studies, linkage
analysis, and candidate gene/genome-wide association studies in
the context of epidemiological studies [912].
Cancer Epidemiology 34 (2010) 419424
A R T I C L E I N F O
Article history:
Accepted 14 April 2010
Available online 12 May 2010
Keywords:
Nasopharyngeal carcinoma
Risk
Family history
Environmental factors
A B S T R A C T
Background: Family history of nasopharyngeal carcinoma (NPC) is an established risk factor for this
cancer, but the contributions of family history of other types of cancer and its interaction with
environmental factors have not been well characterized. Methods: A total of 1845 incident cases of NPC
and 2275 matched controls from Guangdong, China were included in this study. Odds ratios (OR) and
95% condence intervals (CI) were calculated from logistic regression models adjusted for smoking,
consumption of alcohol, salted sh consumption, and demographic factors. Results: A signicant
association between the risk of NPC and family history of any cancers in rst degree relatives was
observed, and higher number of affected family member was related to a higher risk (P
trend
< 0.01).
Family history of NPC was the strongest predictor for NPC (OR: 3.35, 95% CI: 2.464.55 for all rst degree
relatives). The risk of NPC was also positively associated with history of head and neck cancer among
parents and lung and breast cancers among siblings. The combination of family history of cancer,
especially NPC, and the consumption of salt-preserved sh signicantly increased the risk for NPC.
Conclusions: These results conrmthat the risk for NPC increases with family history of NPC and suggest
that lung and breast cancer contribute to risk for NPC. A possible interaction between family history of
cancer, especially NPC, and consumption of salt-preserved sh in the development of NPC was also
identied.
2010 Elsevier Ltd. All rights reserved.
* Corresponding author at: Sun Yat-Sen University Cancer Center, 651 Dongfeng
Road East, Guangzhou 510060, China. Tel.: +86 20 87343195; fax: +86 20 87343392.
E-mail address: jiaweih@mail.sysu.edu.cn (W.-H. Jia).
1
These authors contributed equally to this work.
Contents lists available at ScienceDirect
Cancer Epidemiology
The International Journal of Cancer Epidemiology, Detection, and Prevention
j our nal homepage: www. cancer epi demi ol ogy. net
1877-7821/$ see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.canep.2010.04.011
While family history of NPC has consistently been associated
with an increased risk of NPC [1317], only a few studies have
examined the role of family history of other types of cancer in
relation to NPC risk. Two cancer registry-based studies had
compared the risk of cancer in NPC relatives and non-relatives
versus a whole population and yielded conicting results [16,17],
One of these studies, conducted in Greenland, suggested that
increased risk of cancer in NPC families was not restricted to NPC,
but actually extended to other cancers such as that of the salivary
glands and cervical uteri [17]. No previous studies have considered
potential interaction of family history with known environmental
risk factors. Using data from a large-scale, casecontrol study, we
evaluated the association between rst-degree family history of
cancer and the risk of NPC, and their interaction with known
environmental risk factors.
2. Patients and methods
2.1. Study population
This casecontrol study included Cantonese individuals
newly diagnosed with NPC between October 2005 and October
2007 from Sun Yat-sen University Cancer Center (SYSUCC), the
largest center for cancer prevention and treatment in Guangz-
hou, China. To be eligible for this study, patients had to have
lived in the Guangdong province for at least 5 years, have no
prior history of cancer, and be able to complete an in-person
interview. A total of 1948 eligible NPC cases were identied and
1845 (94.7%) interviews were completed. Reasons for non-
participation in the study were refusal (77 cases, 4.0%) and
inability to provide information about the history of malignancy
in rst degree relatives, including parents, siblings, and offspring
prior to the interview (26 cases, 1.3%). The majority of cases
(1767 cases, 95.8%) were interviewed less than 6 months after
diagnosis of NPC.
Controls were selected to match the frequency of NPC cases in
relation to geographic area, age (5-year interval), and gender. A
municipality is an administrative subunit, and the Guangdong
province contains 21 municipalities. In each municipality, poten-
tial participants were randomly selected from people who
attended general hospitals for health examinations. All of the
controls were native residents without any history of malignancy
or immunologically mediated disease. In-person interviews were
completed for 2275 (95.5%) of the 2381 eligible controls. The main
reason for non-participation was refusal. All study participants
were of Han origin. This study protocol was approved by the
Human Research Ethics Committee of SYSUCC and each participant
provided informed consent prior to participation.
2.2. Data collection
A structured questionnaire was administered to study parti-
cipants by trained interviewers. Collected information included
demographic characteristics (age, sex, ethnicity, marriage, educa-
tion, and income), residential history, occupational history, history
of chronic ear, nose, and respiratory tract conditions, family history
of NPC, dietary habits, cigarette smoking, alcohol consumption, tea
consumption, and use of Chinese herbal medicine. Information on
probands themselves, along with family history of cancer for rst
degree relatives, or cancer in other relatives, was obtained. Cancers
of the lung, liver, stomach, colon and rectum, esophagus, breast,
and other head and neck cancers other than NPC (i.e. oral cavity,
oropharynx, hypopharynx, and larynx) were reported. Whenever
probands were unsure of their answers, additional family
members were interviewed to ensure the accuracy of the
information collected. Additionally, approximately 5 ml of venous
blood was collected from each consented participant for detection
of Epstein-Barr virus antibodies.
Participants dened as smokers who had smoked at least 100
cigarettes in their lifetime. Information regarding the number of
cigarettes smoked per day in certain phases of life was also
collected. Pack years of smoking was calculated for an assessment
of cumulative exposure as follows: the average number of
cigarettes smoked per day was divided by 20 and multiplied by
the total number of years of reported smoking. Consumption of
alcohol was recorded for participants who reported drinking beer,
yellow wine, grape wine, fruit wine, or distilled rice liquor at least
once a week for six months. Similarly, participants who consumed
salt-preserved sh at least once a week for six months were
recorded as regular consumer of salted sh.
2.3. Data analysis
Chi-square statistics were used to evaluate casecontrol
differences in the distribution of demographic factors and potential
riskfactorsof NPC. Odds ratios(OR) and95%condenceintervals (CI)
were used to estimate the strength of the association of the risk of
NPC with family history of NPC or other malignant tumors among
rst degree relatives with adjustment for gender, age, education,
number of siblings and children, and other potential confounding
factors in logistic regression models. The effect of family history of
cancer was evaluated separately by parents, siblings, and all rst
degree relatives. Stratied analyses based on age (45 and >45 y)
and gender were performed to examine whether the association of
NPC was stronger within a specic group. Since NPC patients
consistently have high levels of viral capsid antigen IgA (VCAIgA) of
EBV (87.1%), this parameter was not included in the analyses.
The possible synergistic effect of family history of cancer and
environmental factors was evaluated using an additive model
Table 1
Comparison of cases and controls by selected demographic characteristics and
major risk factors for NPC, The Guangdong NPC Etiological Study, 20052007.
Factors Cases (%) Controls (%) P-value
Gender
Male 1349 (73.1) 1610 (70.8) 0.096
Female 496 (26.9) 665 (29.2)
Age (years)
<30 102 (5.5) 130 (5.7) 0.072
30 425 (23.0) 542 (23.8)
40 607 (32.9) 693 (30.5)
50 493 (26.7) 579 (25.5)
60 218 (11.8) 331 (14.5)
Education
Primary school or less 436 (23.7) 326 (14.3) <0.001
Middle school 630 (34.3) 503 (22.2)
High school 492 (26.8) 725 (32.0)
College or above 280 (15.2) 714 (31.5)
Cumulative amount of cigarette use (pack-years)
None 845 (46.8) 1189 (52.6) <0.001
<15 287 (15.9) 463 (20.5)
15 327 (18.1) 296 (13.1)
30 348 (19.3) 312 (13.8)
Alcohol consumption
Never or rarely 1495 (81.8) 1933 (85.0) 0.006
Ever 333 (18.2) 341 (15.0)
Salt-preserved sh consumption
Never or rarely 990 (54.0) 1680 (74.6) <0.001
1/month 313 (17.1) 198 (8.8)
4/week 531 (28.9) 373 (16.6)
VCA IgA (EBV)
Positive (>1:40) 1584 (87.1) 21 (0.9) <0.001
Negative (1:40) 234 (12.9) 2254 (99.1)
Z.-F. Ren et al. / Cancer Epidemiology 34 (2010) 419424 420
proposed by Rothman [18]. Multivariate logistic regression models
were used to estimate the departure from additivity. By crossing
the two main factors, dummy variables of four categories were
obtained: 2 for the presence of each factor in the absence of the
other, 1 indicating the presence of joint factors, and 1 for the
absence of exposure to each factor. The latter was used as the
reference category in the models. To assess deviation from the
additive model of no interaction, the synergism index (S) and its
95% CI was calculated: S = (OR
11
-1)/(OR
01
+ OR
10
-2). Data were
analyzed using SAS software (Version 9.1, SAS Institute, Cary, NC,
USA) and all statistical tests were two-sided.
3. Results
Presented in Table 1 is a comparison of cases and controls with
regard to demographic factors and potential NPC risk factors. The
median age at diagnosis was 46, (ranged from 13 y to 80 y). The
male-to-female ratio was 2.72. The majority of NPC cases (1599,
87.5%) were pathologically classied as WHO type III (undifferen-
tiated non-keratinizing squamous carcinoma), 6.8% as type II
(differentiated non-keratinizing squamous carcinoma), and 5.6%as
type I (non-keratinizing squamous carcinoma). NPC patients and
controls were comparable in gender and age. NPC patients were
more likely to have smoked cigarettes, consumed alcohol,
consumed salt-preserved sh, relative to controls. Presence of
Epstein-Barr VCA IgA was signicantly associated with risk of NPC.
Associations of NPC risk with family history of NPC or other
malignant tumors are presented in Table 2. For all cancer types
except breast cancer in rst degree relatives, the ORs were
essentially unchanged after adjusting for the environmental risk
factors listed in the footnotes of Table 2. Compared to participants
without a family history of any type of cancer, patients with family
histories of any cancer among parents, siblings, and all rst degree
relatives had signicantly elevated risk of NPC (ORs: 1.37, 2.54, and
1.72; 95% CI: 1.141.64, 1.963.30, and 1.472.03, respectively).
Those witha family history of onlyNPC among parents, siblings, and
all rst degree relatives had higher risk of NPC (ORs: 2.42, 5.29, and
3.35; 95% CI: 1.623.60, 3.328.45, and 2.464.55, respectively).
These signicant associations were seen in both age groups (45
and>45y) andbothgender groups. The ORs and95%CIs for patients
over 45 y with a family history of NPC among parents, siblings, and
all rst degree relatives were 3.21 (1.726.01), 5.89 (3.4110.15),
and 4.47 (2.936.81), respectively. The ORs and 95% CIs for male
patients witha family history of NPCamongparents, siblings, andall
rst degree relatives were 3.02 (1.914.77), 4.63 (2.807.67), and
3.48 (2.464.91), respectively. Compared with participants who did
not have family history of any type of cancer, those withone, two, or
three or greater rst degree relatives witha historyof anycancer had
higher riskof NPC(ORs: 1.64, 2.17, and2.61; 95%CI: 1.381.94, 1.44
3.27, 0.759.07, respectively). This trend for increased risk of NPC
was statistically signicant (P < 0.01). The same pattern was
observed for patients with a family history of only NPC.
Table 2
Frequency of family history of NPC and other cancers in rst degree relatives and odds ratios (95% CIs) for NPC risk, the Guangdong NPC Etiological Study, 20052007.
Cancer types in FDRs FDRs Cases (+/) Controls (+/) OR
a
(95% CI) OR
b
(95% CI)
Nasopharynx Parents 85/1760 43/2232 2.58 (1.763.79) 2.42 (1.623.60)
Siblings 113/1730 25/2250 5.70 (3.658.91) 5.29 (3.328.45)
All 184/1661 68/2207 3.58 (2.674.79) 3.35 (2.464.55)
1 159/1661 67/2207 3.17 (2.354.28) 3.04 (2.224.17)
2 25/1661 1/2207 30.34 (4.07226.14) 21.78 (2.89164.27)
Lung Parents 57/1788 87/2188 0.85 (0.601.22) 0.85 (0.581.24)
Siblings 22/1823 12/2263 2.55 (1.245.28) 2.73 (1.255.96)
All 79/1766 98/2177 1.08 (0.791.47) 1.09 (0.781.52)
Liver Parents 54/1791 54/2221 1.26 (0.851.88) 1.13 (0.751.71)
Siblings 19/1826 19/2256 1.58 (0.813.07) 1.42 (0.702.86)
All 71/1774 74/2201 1.26 (0.891.78) 1.12 (0.781.61)
Stomach Parents 27/1818 33/2242 0.98 (0.581.66) 1.18 (0.682.05)
Siblings 5/1840 14/2261 0.44 (0.151.25) 0.36 (0.131.22)
All 32/1813 48/2227 0.79 (0.501.26) 0.83 (0.511.35)
Colon or rectum Parents 26/1819 30/2245 1.17 (0.682.02) 1.10 (0.612.00)
Siblings 4/1841 8/2267 0.67 (0.202.31) 0.45 (0.111.92)
All 30/1815 37/2238 1.08 (0.661.80) 0.98 (0.561.70)
Head and neck except nasopharynx Parents 28/1817 20/2255 1.94 (1.073.53) 2.01 (1.083.75)
Siblings 19/1826 14/2261 1.88 (0.923.84) 1.49 (0.713.15)
All 47/1798 34/2241 1.88 (1.192.99) 1.74 (1.072.81)
Breast Parents 6/1839 11/2264 0.86 (0.312.39) 0.67 (0.231.91)
Siblings 16/1829 11/2264 2.02 (0.924.47) 2.50 (1.085.76)
All 23/1822 23/2252 1.44 (0.792.62) 1.36 (0.732.56)
Esophagus Parents 25/1820 29/2246 1.04 (0.601.82) 0.95 (0.531.70)
Siblings 7/1838 3/2272 3.60 (0.9014.31) 2.78 (0.7011.07)
All 32/1813 32/2243 1.27 (0.762.11) 1.14 (0.671.92)
Others Parents 48/1797 42/2233 1.42 (0.932.16) 1.66 (0.972.87)
Siblings 29/1816 23/2252 1.56 (0.902.71) 2.34 (1.065.16)
All 77/1768 65/2210 1.48 (1.062.07) 1.82 (1.152.86)
All sites Parents 344/1501 337/1938 1.39 (1.181.65) 1.37 (1.141.64)
Siblings 219/1624 121/2154 2.71 (2.123.45) 2.54 (1.963.30)
All 521/1322 437/1838 1.81 (1.562.11) 1.72 (1.472.03)
1 442/1322 382/1838 1.72 (1.462.01) 1.64 (1.381.94)
2 67/1322 51/1838 2.14 (1.433.12) 2.17 (1.443.27)
3 12/1322 4/1838 4.10 (1.3112.89) 2.61 (0.759.07)
a
OR adjusted for age, gender, and education.
b
OR adjusted for age, gender, education, smoking, consumption of alcohol, salted-sh consumption, number of siblings, and number of children.
Z.-F. Ren et al. / Cancer Epidemiology 34 (2010) 419424 421
Those withfamily historyof cancers inthe headandneck(except
the nasopharynx) among parents and family history of lung and
breast cancer among siblings, were found to have a signicantly
increased risk of NPC. These increases were limited mainly to male
and older participants. The adjusted OR for NPC increased 4-fold for
male participants with a family history of breast cancer among
siblings (OR: 3.95, 95% CI: 1.3811.33). In contrast, no elevated risk
of NPC was associated with family histories of liver, stomach,
colorectal, and esophageal cancers among any of the rst degree
relative groups. Associations between the risk of NPC and the
presence of other types of cancers including kidney, lymphomas,
bladder, prostate, pancreas, cervical, corpus uterine, and leukemia
were evaluated; however, the sample sizes were too small to assess
the strengthof the associations (datanot shown). The associations of
NPC risk with family history of any cancer and most individual
cancers (except for cancers of the stomach, colon and rectum, head
and neck other than NPC) appeared to be greater among siblings
than among parents, although some associations did not reach
signicant levels.
To assess potential joint effects of family history of cancer
among rst degree relatives and environmental risk factors in the
development of NPC, participants were classied based on the joint
distribution of family history of any cancer and known environ-
mental risk factors. The risk of NPC associated with either family
history of any cancer or history of NPC among rst degree relatives
was elevated in virtually all categories of environmental factors
considered, particularly with regard to patient history of smoking,
consumption of alcohol, and consumption of salt-preserved sh
(Table 3). The co-existence of family history of any cancer and
consumption of salted sh particularly increased the risk (OR) of
NPC to 4.25 (95% CI: 3.325.43), higher than the individual risks
associated with consumption of salted sh alone (OR: 2.62, 95% CI:
2.243.07) or having only positive family history of cancer (OR:
1.84, 95% CI: 1.512.24). A similar pattern and a stronger
association was detected between the risk for NPC and family
history of NPC among rst degree relatives. Furthermore, the co-
existence of family history of NPC and consumption of salted sh
raised the risk (OR) of NPC to 9.38 (95% CI: 5.3716.38), much
higher than the individual risk associated with a positive family
history of NPC (OR: 3.21, 95% CI: 2.224.62) alone or consumption
of salted sh alone (OR: 2.54, 95% CI: 2.202.94). The interaction
between salt-preserved sh and family history was more than
additive according to the synergism S index and its 95% CI [1.27
(0.891.82), 2.20 (1.114.36)] for family history of any cancer and
family history of NPC, respectively.
4. Discussion
Our study is the largest casecontrol study to date on NPC and
provides clear evidence that the risk of NPC associated with family
history of cancer among rst degree relatives does not only apply
to family history of NPC alone, but may also extend to other cancers
such as cancers of the head and neck, lung, and breast in the
endemic area of Guangdong, China. Possible interactions between
family history of cancers and environmental factors were noted.
Consistent with previous studies, family history of NPC among
rst degree relatives was associated with higher risk for NPC,
although the ORs calculated in the current study were lower than
those reported by others (OR or RR 8) [7,17,19]. It is possible that
the lower ORs associated with this study are the result of the larger
number of participants included in the current study compared
with others. The results from this study also differed from results
reported by similar, yet limited, studies. For example, Yu et al.
compared the cancer rates of high risk families with two or more
NPC patients with the cancer rates of a population recorded in a
cancer registry in Taiwan [16]. They found the presence of
aggregation of NPC within the families, but did not provide
evidence for other cancers. Friborg et al. performed a comparison
of cancer incidences between rst degree relatives of NPC and non-
relatives in Greenland, and found that family history increased the
risk of NPC and cancers of the salivary glands and cervical uteri
[17]. Due to the small number of cases, we were not able to
evaluate the possible correlation between the risk of NPC and
family history of salivary gland and cervical uteri cancers in our
Table 3
Odds ratios (95% CIs) of NPC risk associated with joint distributions of family history of any cancer or NPC and known environmental risk factors related to NPC, the
Guangdong NPC Etiological Study, 20052007.
Family history
No Yes
Cases/controls OR (95% CI)
a
Cases/controls OR (95% CI)
a
Family history of any cancer
Smoking
No 614/985 1.00 (reference) 233/203 2.01 (1.602.51)
Yes 698/859 1.23 (1.021.49) 280/225 2.07 (1.622.65)
Alcohol consumption
Never or rarely 1066/1565 1.00 (reference) 429/367 1.87 (1.582.21)
Ever 248/280 1.23 (1.011.51) 85/61 1.99 (1.402.84)
Sal-preserved sh consumption
Never or rarely 722/1380 1.00 (reference) 268/299 1.84 (1.512.24)
Ever 597/446 2.62 (2.243.07) 247/125 4.25 (3.325.43)
Family history of NPC
Smoking
No 763/1156 1.00 (reference) 84/33 3.34 (2.165.16)
Yes 881/1049 1.13 (0.951.34) 97/35 3.70 (2.415.68)
Alcohol consumption
Never or rarely 1338/1873 1.00 (reference) 157/60 3.44 (2.504.72)
Ever 307/333 1.20 (1.001.45) 26/8 3.93 (1.729.00)
Salt-preserved sh consumption
Never or rarely 896/1628 1.00 (reference) 94/52 3.21 (2.224.62)
Ever 756/555 2.54 (2.202.94) 88/16 9.38 (5.3716.38)
a
Adjusted for age, gender, education, smoking, consumption of alcohol, salted sh consumption, number of siblings, and number of children.
Z.-F. Ren et al. / Cancer Epidemiology 34 (2010) 419424 422
study. Instead, we found that family history of NPC, lung cancer,
breast cancer, or head and neck cancer (excluding NPC) was
signicantly associated with risk of NPC. Given that the salivary
gland is one of the organs of the head and neck, our results are
generally consistent with the results of Friborg et al. We previously
observed a decreased risk of hepatic, lung, esophageal, gastric, and
breast carcinomas among rst degree relatives of probands with
NPC [15]. However, these results were obtained by a comparison of
population data from Shanghai and Hong Kong, the latter two
populations had a lower risk of NPC. The current study was based
solely on Guangdong population. Other possible reasons for the
differences between this study and others include the study
methods, the distinct geographic and ethnic populations analyzed,
and the adjustment for potential confounding factors.
In the current study, a stronger association of NPC risk and
family history of any cancer was observed among siblings than
parents, especially for cancers of the lung and breast. Previous
investigations revealed similar ndings [2022]. We hypothesized
that the consistency of these results may be due to recessive
genetic factors or the environment shared by a family during the
same period [22,23]. Taking environmental factors into consider-
ation, we adjusted our analysis for factors such as smoking,
consumption of alcohol, and consumption of salted sh. However,
we could not exclude the effects of other environmental factors.
Infection is a possible shared factor that could be related to NPC
and cancers of the lung and breast. For example, a recent review
suggested a possible mechanism of carcinogenesis induced by
human papilloma virus (HPV) for the development of lung cancer
[24]. A correlation between latent EBV infection and certain types
of lung cancer has also been identied [25]. Similarly, breast cancer
is generally thought to be estrogen-related, but many observations
have indicated that tumor-associated macrophages, which repre-
sent the major inammatory component of the stroma of breast
tissues, promote angiogenesis, matrix remodeling, and suppres-
sion of adaptive immunity [26]. Furthermore, a clinical study
demonstrated that long-term use of non-steroidal anti-inamma-
tory drugs was associated with reduced risk of breast cancer [27].
There are also reports indicating that EBV may have a role in breast
cancer, since EBV genomes have been detected in 50% of breast
tumor specimens analyzed [28,29]. However, infection or inam-
mation events do not fully explain the increased risk, as family
history of other infection-associated cancers (i.e. esophagus,
gastric) did not increased the risk of NPC. Alternatively, it is
possible that the higher incidence of breast and lung cancer that
correlated with the incidence of NPC may be due to shared
susceptibility genes. For example, chromosome 3p21 has repeat-
edly been found to be a susceptibility locus for NPC in genome-
wide association studies [10,30]. A SNP (rs2212020) in intron 3 of
the gene, ITGA9 (integrin-alpha 9), located at 3p21 has been
strongly associated with NPC [30]. Interestingly, chromosome 3p
deletions have been detected in almost all cases of small-cell lung
cancer, and in more than 80% of breast carcinomas [3133]. Gene
ITGA9 has also been identied as a candidate tumor suppressor
gene for both lung and breast cancer [34].
Our results show that the risk of NPC was signicantly
associated with a family history of head and neck cancer among
rst degree relatives. However, the strength of the association was
much weaker than for the risk of NPC with family history of NPC.
The etiology of other head and neck cancers in the Cantonese
population has rarely been investigated. A study of environmental
risk factors for other head and neck cancers versus NPC has shown
many differences [35]. Although NPC is closely related to other
head and neck cancers anatomically, it is distinct in terms of its
spectrum and geographical distribution [35]. Further characteri-
zation of the risk factors that affect other head and neck cancers
versus NPC needs to be performed.
We investigated the joint effects of family histories of cancer
and environmental risk factors. The interaction between consump-
tion of salt-preserved sh and family history was more than
additive according to the synergism S index and its 95% CI. This
result suggests that salt-preserved sh and family history of cancer
may interact with each other and synergistically increase the risk
of NPC. The carcinogenic potential of salted sh is supported by
experiments in rats where consumption of salted sh resulted in
the development of malignant nasal and nasopharyngeal tumors
[36]. The process of salt preservation allows sh to become
partially putreed, thereby allowing high levels of nitrosamines to
accumulate in the sh [2]. Salted sh also contain bacterial
mutagens, direct genotoxins, and EBV-reactivating substances
[2,37]. The exact mechanism(s) how these derivatives interact
with host susceptibility genes to induce carcinogenesis remain to
be explored.
Given that EBV infection plays a predominant role in NPC
etiology and EBV infection may run within a family and be related
to other lifestyle factors, there is a concern that EBV infection may
confound or modify the effects of other factors including family
history on NPC. To address this concern, we conducted additional
analyses subdividing cases into two groups, e.g., EBV positive and
negative NPC cases. These two groups of cases were compared to
EBV seronegative controls. The results showed that family history
of NPC increased risk of NPC [OR and 95% CI were 3.36 (2.464.57)
and 3.61 (1.635.29), respectively] in both case groups. Similarly,
salted sh consumption was associated with NPC in both case
groups [OR and 95% CI were 2.50 (2.162.88) and 2.65 (1.993.53),
respectively]. Smoking and alcohol consumption were not related
to NPC risk in either case groups. These analyses suggest that
family history of cancers and salted sh consumption are
independent risk factors for NPC.
The present study took advantage of a large investigation with
detailed epidemiological variables, high participation rates, and in-
depth information on family history of cancer and environmental
risk factors. However, there are also potential limitations to this
study. Because of their diagnosis, it is possible that NPC patients
were more aware of cancer-affected relatives than controls, which
would compromise the evaluation of increased risk of NPC with a
family history of cancer. However, since we focused only on
reportingrst degreerelatives andnot onreportingdistant relatives,
the data were likely to have been reported with greater accuracy
[36]. Misclassication of other exposure information is another
possibility in casecontrol studies, especially for case groups. We
restricted cases to incident NPC patients andinterviewedcases soon
after cancer diagnosis to minimize recall bias.
In conclusion, this large casecontrol study found signicant
associations between the risk of NPC and family history of NPC,
lung cancer, and breast cancer after adjustment for known
environmental risk factors for NPC. We also found a possible
interaction between family history of cancer and consumption of
salt-preserved sh. Overall, our ndings provide valuable infor-
mation for the etiology of NPC and other cancers, for cancer risk
counseling, management of high-risk patients, and decisions
regarding the appropriateness of predictive genetic testing.
Conict of interest
None declared.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (30671798, 30471487), the National
Science and Technology Support Program of China
(2006BAI02A11), the National Major Basic Research Program
Z.-F. Ren et al. / Cancer Epidemiology 34 (2010) 419424 423
of China (863:2006AA02A404) and the National Institute of
Health (R03CA113240-01). The authors would like to acknowl-
edge the members involved in the investigation (Guosheng Li,
Daoxin Wang, Liwei Wu, Jun Li, Xiaoqiong Liu, et al.), and we
also wish to thank those inputting and checking the data (Chao
You, Lie Li, Qing Wang, Mo Xian, Yi Lian, Shifu Tang, Xinjia Li,
Xiaobi Lu, Enhua Zhang, et al.) and Rodney Jones at Vanderbilt
Epidemiology Center in the USA for her technical assistance in
the preparation of this manuscript.
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