Disparities in cancer incidence among Chinese population ... · 12/7/2018 · Page 5 of 28...

Page 1 of 28 Comparisons of cancer risk among global Chinese populations

Research Article 1

Disparities in cancer incidence among Chinese population versus migrants to 2

developed regions: a population based comparative study 3

Zhenqiu Liu1,2,3

*, Oumin Shi4*, Ning Cai

1,2,3, Yanfeng Jiang

1,2, Kexun Zhang

1,2,3, 4

Zhen Zhu1,2,3

, Huangbo Yuan3, Qiwen Fang

3, Chen Suo

3, Silvia Franceschi

5, Tiejun 5

Zhang3†

, Xingdong Chen1,2,6†

6

1. State Key Laboratory of Genetic Engineering and Collaborative Innovation Center 7

for Genetics and Development, School of Life Sciences, Fudan University, 8

Shanghai 200438, China. 9

2. Fudan University Taizhou Institute of Health Sciences, Taizhou, China. 10

3. Department of Epidemiology, School of Public Health, Fudan University, 11

Shanghai, China. Key Laboratory of Public Health Safety (Fudan University), 12

Ministry of Education, China. 13

4. Department of Neurology, Shenzhen Second People’s Hospital, The First 14

Affiliated Hospital of Shenzhen University, Shenzhen, China. 15

5. Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Itlay. 16

6. Human Phenome Institute, Fudan University, 825 Zhangheng Road, Shanghai 17

201203, China. 18

19

Running title: Comparisons of cancer risk among global Chinese populations 20

†: Correspondence to Tiejun Zhang MD., PhD., Professor of Epidemiology, School of 21

Public Health, Fudan University, Shanghai, 200032, China. Email: 22

on August 20, 2021. © 2019 American Association for Cancer Research.cebp.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on April 3, 2019; DOI: 10.1158/1055-9965.EPI-18-0827

http://cebp.aacrjournals.org/


[email protected]; TEL/FAX: +86−21−54237410; or Xingdong Chen MD., PhD., 1

School of Life Sciences, Fudan University, Shanghai, 200032, China. Email: 2

[email protected]; TEL/FAX: +86-21-51630602. 3

*: These authors contributed equally to this study. 4

Declaration of interest: We declare no conflicts of interest. 5

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13

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Abstract 1

Background: The incidence of cancer was determined by genetic and environmental 2

factors and varied across the world. The discrepancies in cancer profile among 3

Chinese people living in different regions remained obscure. 4

Methods: Chinese people living in urban Shanghai, Hong Kong, Taiwan, Macau, 5

Singapore and Los Angeles were included in this study. The cancer case data and 6

population data were collected from either the Cancer Incidence in Five Continents 7

plus database or the regional cancer registry. A rate model was applied to examine the 8

regional differences in cancer risk with Shanghai was set be the reference. 9

Results: From 1983 to 2013, the cancer profiles in most regions were changed. 10

Significant differences in cancer incidence, by sex, period, and age, were detected 11

across regions. The most pronounced disparities were found between Shanghai people 12

and American Chinese in Los Angeles. For cancer site, the most significant 13

differences were detected in prostate, gastrointestinal, gynecological, oral cavity and 14

pharynx, brain and central nervous system (CNS) cancers. Specifically, Shanghai was 15

significantly higher in stomach, liver, esophageal, pancreatic, and brain and CNS 16

cancers, while lower in colon, prostate, breast, cervical, oral cavity and pharynx 17

cancers compared with other five populations. 18

Conclusions: Cancer profile was distinct across Chinese populations, which sharing a 19

similar genetic background but living in different regions. The disparities indicate that 20

cancer development, were majorly determined by environmental factors, and suggest 21

that region-tailored cancer prevention strategies were warranted. 22





Impact: The cancer patterns in populations sharing the same genetic background 1

significantly influenced by different living conditions. 2

3





Introduction 1

With increasing incidence and mortality, cancer is the leading cause of death in 2

China and is a major public health concern (1). Much of the changing burden is 3

attributable to population growth, aging, and socio-demographic changes. For 4

example, the persistent decreases of liver cancer and gastric cancer in the last decade 5

were mainly due to the effective control of chronic infections (1). Contrariwise, the 6

prostate cancer in men and thyroid cancer in women experienced significant rises 7

since the beginning of this century (1-3), which might ascribe to the shifting to 8

Western diet and the increased use of new imaging technologies in the assessment of 9

the thyroid gland, respectively. 10

11

Understanding the etiology of cancer has kept researchers occupied for centuries, 12

though it has become increasingly clear that cancer can be considered neither purely 13

genetic nor purely environmental (4). Previous Genome wide association study 14

(GWAS) studies have suggested that the nuance in gene might have significant 15

impact on cancer development (5, 6). However, growing evidence showed that 16

cancer may be predominantly an environmental disease (7, 8), because only a small 17

proportion of cancer follow a Mendelian pattern of inheritance, and the incidence of 18

cancer changes when people are exposed to different culture and lifestyles (9-11). 19

Briefly, cancer is the detrimental derivative of interaction between gene and 20

environment. Nevertheless, it is hard to disentangle the absolute impacts of gene and 21

environment on oncogenesis. 22





1

To further understand the environmental influence on cancer, we designed a 2

comprehensive migration study based on the cancer registry data covering the last 3

three decades. Chinese people living in Shanghai, Hong Kong, Macau, Taiwan, 4

Singapore and Los Angeles were included in the current study. Chinese are the 5

largest ethnic group in the world, composing 20% of the entire global human 6

population (12). Chinese people living in Shanghai, Hong Kong, Macau and Taiwan 7

were either indigenous or immigrated from elsewhere in China. While, majority of 8

their counterparts in Singapore and Los Angeles were descendants of the immigrants 9

landed in the 1800s. Compared with Shanghai, the other five regions are inconsistent 10

in many ways, including the social system, diet pattern and natural environment. 11

However, Shanghai is a metropolis with a higher human development index than the 12

average of China, and Hong Kong, Los Angeles, Singapore, Taiwan and Macau had 13

similar or slightly higher development index compared with Shanghai. Moreover, the 14

cancer registries in these regions have a long history, and wide coverage and high 15

quality in cancer data. All these indicate the equivalence of gross income, health 16

service accessibility, life expectancy, and education among these regions, thereby 17

provided the possibility and reduced the bias to compare the cancer incidence among 18

the selected regions. The results of our study might provide further insights into the 19

understanding of the exogenous factors in the etiology of cancer. 20

21

Materials and Methods 22





Study data 1

We collected annual cancer case data of Shanghai, Hong Kong, Taiwan and Macau 2

from their cancer registry system, respectively. Cancer data of Chinese people living 3

in Los Angeles and Singapore were collected from Cancer Incidence in Five 4

Continents plus (13) (http://ci5.iarc.fr) (The details of cancer registries were 5

presented in Supplement Table 1 [S-Table 1]). The time coverage of these data was 6

showed in Supplementary Figure 1 (S-Figure 1). The original cancer data were 7

categorized by sex, age (five−year interval from 0−4 years to ≥ 85 years) and cancer 8

sites, which were identified via the International Classifications of Diseases, 10th 9

version (ICD-10). For example, the code “C22” denotes primary liver cancer, 10

including liver cell carcinoma, intrahepatic bile duct carcinoma, and so on. However, 11

the histology of cancer was not taken into account due to the paucity of histologic 12

information. Finally, a total of 27 cancers were included in this study, details see 13

Table 1. All recorded cases have been validated for its demographical data, 14

information on the topography and histology, if provided, by the health professional 15

work staff. 16

17

To better match the data from different regions, the whole period has been separated 18

into three un-overlapped intervals, 1983−1994, 1995−2007 and 2008−2013 19

(S-Figure 1). Cancer data in children (0−14 years) were excluded, and then the age at 20

diagnosis of cancer (≥ 15 years) has been integrated into three categories: 15−34, 21

35−64 and ≥ 65 years, denoting adolescents and young adults, middle-aged people, 22



http://ci5.iarc.fr/



and elderly people, respectively. Meanwhile, we collected the corresponding 1

population data either from regional statistical bureau or from International 2

Association for Research on Cancer (IARC). Likewise, we processed the population 3

data as the cancer data described above. 4

5

Statistical methods 6

The standard world population 2000 was used to estimate age-standardized rates 7

(ASRs) of cancers per 100,000 person years for all groups. The estimated annual 8

percentage change (EAPC) was used to quantify the ASRs trends. A regression linear 9

model was fitted to the natural logarithm of the ASRs, i.e. y = α + βx + δ, where y = 10

ln(ASRs) and x = calendar year, and the EAPC calculated as 100 × (𝑒𝛽 − 1). 11

12

Instead of traditional Poisson regression model as previous studies used (14, 15), a 13

rate model was applied to estimate the incidence rate ratios (IRRs) of cancers with 14

Shanghai set as reference, because the number of cancers observed was largely 15

depended on the population size. The rate model can be termed as the following 16

formula. 17

ln (𝑐𝑎𝑠𝑒

𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛) = 𝛼 + 𝛽𝑿

Furthermore, this can be rearranged as: 18

ln(𝑐𝑎𝑠𝑒) = 𝛼 + ln (𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛) + 𝛽𝑿

Where ln(population) is the log-offet for population at risk in each category. The 19

population has been standardized by the World Population 2000 and the case was 20





accordingly the expected case to overcome the bias introduced by different 1

population structures in different regions. As a result, the original rate model can be 2

termed as: 3

ln (∑ 𝐶𝑎𝑠𝑒𝑖 ×

𝑖

𝜔𝑖) = 𝛼 + ln (∑ 𝑃𝑜𝑝𝑖 ×

𝑖

𝜔𝑖) + 𝛽𝑿

where Casei and Popi denotes the cancer cases and population in age group i, 4

respectively. The ωi denotes the weight of this age group. And the vector X 5

represents the region variable here. 6

7

All statistical tests were implemented with R (R core team, version 3.4.0). A P value 8

of less than 0.05 was considered statistically significant. 9

10

Results 11

The ASRs trends over time 12

As shown in Table 1 a & b, the ASR of all cancer sites combined (ICD10 code: 13

C00-96bC44) varied considerably among regions, with the highest rate found in 14

Hong Kong, followed by Singapore, Los Angeles, Taiwan, Shanghai and Macau in 15

both sexes. In men, the incidence of cancer was annually decreased in Singapore and 16

Hong Kong by 0.32% (95% CI = -0.52% to -0.12%) and 1.49% (95% CI = -1.62% 17

to -1.37%), respectively; whereas increased in Los Angeles and Taiwan by 0.97% 18

(95% CI = 0.54% to 1.40%) and 2.87% (95% CI = 1.48% to 3.85%), respectively. 19

Cancer in Shanghai and Macau remained stable in the study period (Table 1a; 20

S-Figure 2). In women, the incidence of cancer increased in all regions except Hong 21





Kong (EAPC = -0.72%; 95% CI = -0.90% to -0.54%) and Macau (EAPC = 0.74%; 1

95% CI = -3.22% to 3.13%) (Table 1b; S-Figure 2). 2

3

For specific cancer site, the gastrointestinal cancers, prostate cancer, gynecologic 4

cancers, and thyroid cancer were among those with most significant temporal trends. 5

In Shanghai, the most striking decreases were detected in upper gastrointestinal 6

carcinomas (stomach, liver, and esophagus). However, colon, rectum−anus, pancreas 7

and gallbladder cancers were experienced significant increases over the last three 8

decades. Of note, the most pronounced increase was found in prostate cancer in men 9

and thyroid cancer in women (EAPC = 9.27, 95% CI = 8.57 to 9.97; EAPC = 9.46, 10

95% CI = 8.28 to 10.65, respectively). Similar changing patterns were found in 11

Singapore and Hong Kong in both sexes, with the most significant increase seen in 12

prostate cancer in men and Hodgkin lymphoma in women. Different to Shanghai, 13

most cancers in Los Angeles and Macau remained stable but increased in Taiwan in 14

both men and women over time. Unexpectedly, in Los Angeles, the ASR of liver 15

cancer increased by 1.30% per year (95% CI = 0.11% to 2.51%) in men and by 3.85% 16

per year (95% CI = 0.95% to 6.83%) in women, respectively (Table 1 a & b). The 17

temporal trends of cancers, by sex and regions, were presented in S-Figures 3-29. 18

19

The comparisons of cancer incidence across regions 20

The gastrointestinal cancers 21

Figures 1-2 displayed the rank of cancer sites, by regions and periods, in terms of the 22





log-scale cancer incidence in men and women, respectively. Seven gastrointestinal 1

cancers (stomach, liver, esophagus, colon, rectum−anus, pancreas, and gallbladder) 2

were included to compare the incidence across regions. As shown in Figures 1-2, 3

gastrointestinal cancers ranked high in terms of the ASR regardless of sex, regions, 4

and periods. 5

6

In both sexes, the ASR of stomach cancer was highest in Shanghai (55.14 per 7

100,000 in men and 26.24 per 100,000 in women) compared to all other regions and 8

nearly threefold higher than that in Los Angeles, with similarly large reductions in 9

risk seen separately in Hong Kong, Singapore, Taiwan and Macau (Table 1; Figure 10

3). Likewise, similar patterns were found in pancreatic cancer in both sexes. The 11

ASR was 10.60 per 100,000 in Shanghai men and 7.57 per 100,000 in Shanghai 12

women, while approximate 20% to 40% reductions in risk witnessed in other regions 13

(Figure 3). Different to stomach and pancreatic cancer, reverse pattern, especially in 14

men, was found in colon cancer. Men in Shanghai have a nearly 20% to 40% 15

reductions in cancer risk when compared with their counterparts in other regions 16

(Figure 3). However, the disparities in women were not as significant as that in men. 17

For example, there was no significant difference between Shanghai and Macau (IRR 18

= 1.17, 95% CI = 0.84 to 1.39). An analogous pattern was found in rectum−anus 19

cancer when compared with colon cancer, though the differences between Shanghai 20

and Los Angeles in both men and women were non-significant (IRR = 1.06, 95% CI 21

= 0.91 to 1.22; IRR = 0.98, 95% CI = 0.95 to 1.06, respectively) (Figure 3). For liver 22





cancer, in men, a significant higher ASRs were found in Hong Kong and Taiwan, 1

whereas a significant lower ASRs were found in Los Angeles and Singapore, in 2

contrast to Shanghai, with the IRRs were 1.11 (95% CI = 1.04 to 1.17), 1.87 (95% 3

CI = 1.80 to 1.96), 0.70 (95% CI = 0.58 to 0.81) and 0.93 (95% CI = 0.90 to 0.96), 4

respectively. In women, the ASR of liver cancer was the second highest in Shanghai, 5

behind Taiwan (IRR = 2.03, 95% CI = 1.95 to 2.10). There were also substantial 6

differences between Shanghai and the rest of regions, with IRRs of 0.62 (Los 7

Angeles), 0.93 (Hong Kong), 0.78 (Singapore) and 0.82 (Macau), respectively (P < 8

0.001). For esophagus cancer, the ASR was the second highest and highest in 9

Shanghai men and women, respectively (14.93 per 100,000; 5.55 per 100,000). The 10

most pronounced differences were detected between Shanghai and Los Angeles in 11

both sexes, with the IRRs of 0.35 (95% CI = 0.31 to 0.40) and 0.23 (95% CI = 0.17 12

to 0.28), respectively (Figure 3). Gallbladder cancer was rarely diagnosed in general 13

population compared with other gastrointestinal cancers. In men, the ASR was 14

highest in Hong Kong, followed by Shanghai (IRR = 1.11, 95% CI = 1.07 to 1.16). 15

There were also considerable differences between Shanghai and other regions 16

(Figure 3). In women, the ASR was highest in Shanghai (6.20 per 100,000), and 17

approximately half that in Los Angeles, Singapore and Macau (Figure 3). 18

19

Lung cancer 20

Over the past decades, lung cancer was the most common malignancy in men 21

irrespective of region and periods (Figure 1). The lung cancer ASRs were varied 22





across regions, ranging from 49.88 per 100,000 in Los Angeles to 97.01 per 100,000 1

in Hong Kong. When compared with Shanghai, men in Los Angeles and Taiwan 2

have nearly 40% and 25% reduction in risk, respectively (IRR = 0.58, 95% CI = 0.52 3

to 0.67; IRR = 0.75, 95% CI = 0.70 to 0.80). In contrast, men in Hong Kong and 4

Singapore have an approximately 20% to 30% rise in risk (IRR = 1.29, 95% CI = 5

1.22 to 1.36; IRR = 1.21, 95% CI = 1.16 to 1.26). In women, lung cancer ranked top 6

three in most regions and periods (Figure 2). The significant difference was only 7

detected between Shanghai and Hong Kong (IRR = 1.42, 95% CI = 1.36 to 1.47) 8

(Figure 3). 9

10

The gynecological cancers 11

The most common four gynecological cancers (breast, cervical, corpus, ovary and 12

other uterine adnexa cancer) were included in this study. As shown in Figure 2, 13

breast cancer was the leading malignancy in most regions and periods. The ASR of 14

breast cancer was lower in Shanghai compared to Los Angeles, Singapore, Hong 15

Kong and Taiwan but slightly higher than Macau. Substantial differences between 16

Shanghai and these regions were detected, with the most striking disparity was found 17

between Los Angeles (IRR = 1.78, 95% CI = 1.72 to 1.85) (Figure 3). For cervical 18

and corpus cancer, the ASRs were lowest in Shanghai and varied threefold across 19

regions (Table 1b). Significant disparities in risk were found between Shanghai and 20

any other regions, with the exception of Macau in corpus cancer (Figure 3). For 21

ovary and other uterine adnexa cancer, women in Shanghai have a relatively lower 22





ASR than that in Los Angeles, Singapore and Hong Kong, but a higher ASR 1

compared to that in Taiwan and Macau. The regional differences were significant, 2

with the point estimates of IRR ranging from 0.73 in Macau to 1.28 in Singapore 3

(Figure 3). 4

5

Prostate cancer 6

The rank of prostate cancer remained stable in American Chinese from 1983 to 2007. 7

However, in other regions, a dramatic increase in prostate cancer rank was observed. 8

For example, prostate cancer ranked 14th

in 1983-1994 in Shanghai, and then 9

increased to 3rd

in 2008-2013 (Figure 1). The highest incidence was observed in 10

American Chinese, with the overall ASR of 55.20 per 100,000, which was nearly 11

five times higher than that in Shanghai (IRR = 4.78, 95% CI = 4.61 to 5.13). 12

Moreover, nearly threefold higher risks of prostate cancer were found in other 13

regions when compared with Shanghai (Figure 3). 14

15

Oral cavity and pharynx cancer 16

The rank of oral cavity and pharynx cancer remained relatively stable over the last 17

three decades in both men and women (Figures 1 & 2). The ASR was lowest in 18

Shanghai, with the highest rates were seen in Taiwan in men (Table 1a), and Hong 19

Kong in women (Table 1b). Subsequently, the strikingly increased risks were found 20

in other regions in relative to Shanghai (Figure 3). 21

22





Thyroid cancer 1

The rank of thyroid cancer remained stable in regions other than Shanghai, in which 2

the rank increased from 19th

and 18th

in 1983-1994 to 13th

and 5th

in 2008-2013 in 3

men and women, respectively (Figures 1 & 2). In men, the ASR of thyroid cancer 4

was lower in Shanghai than that in Macau, while higher when compared with other 5

regions (Table 1a; Figure 3). For women, the ASR of thyroid cancer was 6

significantly higher in Shanghai than that in Los Angeles, Singapore and Hong Kong 7

while lower than that in Taiwan and Macau, despite non-significant IRRs (Table 1b; 8

Figure 3). 9

10

Brain and central nervous system cancer 11

The incidence of brain and central nervous system cancer was highest in Shanghai 12

irrespective of sex (Table 1 a & b). An approximate 30-70% reduction in cancer risk 13

was resultantly seen in other regions (Figure 3). 14

15

To be more precise, we further elucidated the disparities in cancers across regions by 16

age, period, and sex. The results were detailed in S-Tables 2-3 and S-Figures 30-35. 17

18

The changes of IRRs over time 19

We divided the study period into three non-overlapped intervals as described in 20

Methods to investigate the changes of IRRs over time. The IRRs altered with time 21

due to the changes of cancer incidences among regions, especially in cancer 22





experienced significant trend, despite the heterogeneity among age groups. For 1

example, in elderly people (≥ 65 years), the ASR of colon cancer was nearly three 2

times higher in Los Angeles than in Shanghai in 1983-1994 (IRR = 2.87, 95% CI = 3

2.46 to 3.32). This regional gap, however, had narrowed considerably in 1995-2007 4

(IRR = 1.29, 95% CI = 1.17 to 1.42). The gaps of breast cancer and liver cancer in 5

these two regions were narrowed with time as well. Nevertheless, for lung cancer, 6

the regional gaps were widening, with the cancer risk totally reversed in most 7

regions over time. More details can be seen in S-Figures 36-43. 8

9

Discussion 10

This is the first report, to our knowledge, to compare the cancer incidence among 11

Chinese populations living in different regions in the world. The remarkable 12

geographical disparities in cancers among people sharing similar genetic background 13

might suggest the critical roles of environmental factors such as diet, ambient air 14

pollution and infections for most cancer development (16-19). 15

16

Dietary exposures, including foods, individual nutrients, methods of preparation, and 17

habits of consumption (20-22), have been proposed to protect against or increase risk 18

for cancers, especially the GI cancers. For instance, esophageal cancer, gastric cancer, 19

and some premalignant conditions of the upper gastrointestinal tract are all 20

negatively associated with fruit and vegetable intake (23, 24). Consumption of red or 21

processed meat has been linked to increased risk of GI cancers (25, 26). 22





Subsequently, the dietary patterns were deemed to be significantly associated with 1

cancer risk. For example, epidemiological data are concordant in suggesting that the 2

Mediterranean Diet (MD) decreases the risk of a variety of cancers, though the 3

underpinning mechanisms are still unclear (27-29). China is vast in territory and 4

varied in dietary patterns across 31 provinces (30, 31). Diet in Shanghai is various 5

but dominated by traditional southern dietary pattern, characterized by high intakes 6

of rice, fresh leafy vegetables, pork, poultry, sodium and fish/seafood, and low 7

intakes of beef, processed meat, wheat buns/breads, cakes/cookies, deep-fried grains, 8

fruits, milk and instant noodles (31). On the contrary, American Chinese were prone 9

to Western foods such as butter, lunchmeats, and snack chips (32). The dietary 10

patterns among Chinese people living in Hong Kong, Macau, Singapore and Taiwan 11

might be the mix of that in Shanghai and Los Angeles (33-35). Diet influences the 12

cancer development through many potential ways such as interaction with gut 13

microbiota via regulation of host metabolism and immune (36, 37) and can explain 14

the majority of the disparities in GI cancers as well as breast and prostate cancer 15

across regions. But the underlying mechanism also remains unclear and therefore 16

warrants further investigations. 17

18

The relatively higher incidences of stomach and liver cancers in Shanghai were 19

mainly due to the high prevalence of infections, including Helicobacter pylori for 20

stomach cancer, and HBV and HCV for liver cancer (38, 39). By the enormous 21

efforts to control infections, striking decreasing trends were found in these two 22





cancers in Shanghai, and the gaps across regions were subsequently narrowed over 1

time. Interestingly, consistent with other Asian American groups, minor increases of 2

liver cancer among American Chinese in Los Angeles were detected in both sexes 3

(40), which underscore the need for improving HBV vaccination rates and HBV and 4

HCV screening in the at−risk population. 5

6

Lung cancer, the leading malignancy in men, was mainly ascribed to smoking and 7

ambient air pollution (41). In our study, the highest lung cancer incidence was found 8

in Hong Kong, followed by Singapore, in both men and women, which might be the 9

result of the relatively high smoking prevalence (42, 43). However, a significant 10

decrease in lung cancer incidence was observed in these regions, which might be 11

majorly attributed to the effective control of smoking. Of note is that a slight 12

increase in lung cancer ASR was detected in women in Shanghai, albeit lower 13

smoking rate of 3.5% was found in this population (44). Possible explanations for 14

this increase include: 1) women are much more suffered from cooking oil fumes, a 15

defined risk factor for lung cancer (45); 2) women benefitted less from smoking 16

control than men. 17

18

For cervical cancer, a cancer closely related with human papillomavirus (HPV) 19

infection, the lowest incidence was found in Shanghai compared with other regions, 20

but a significant increasing trend has seen in Shanghai while decreasing trends seen 21

in other regions. In 2017, Shanghai initiated its HPV vaccination programming; the 22





accumulative protective effect on population level can be expected to emerge in the 1

next few decades (46). For other gynecological cancers, despite having lower rates 2

compared with Chinese women in other regions, incidence rates were significantly 3

increased in Shanghai women, for whom the breast cancer has surpassed lung cancer 4

and ranked the first one in recent years. Known risk factors for gynecological 5

cancers include obesity, post−menopausal estrogen therapy, nulliparity, early 6

menarche, and late menopause (47). Changes in the prevalence of these risk factors, 7

especially the obesity, in Shanghai women may explain some of the observed 8

increases (48, 49). 9

10

Of particular concern are cancers having dramatic differences in incidence across 11

populations such as prostate cancer. In this study, we found that the prostate cancer 12

incidence in Chinese people in Los Angeles was nearly half the incidence in 13

non-Hispanic whites in the USA (50), while 5-times higher than that in Shanghai. In 14

addition, prostate cancer has been experiencing an unexpected sharp increase in 15

incidence during the last three decades regardless of regions. Consequently, the 16

regional gap between Shanghai and Los Angeles in prostate cancer incidence was 17

narrowed with time in older people (≥ 65 years), but widened in people aged 35-64 18

years. These results were derivatives of changing cancer incidence and might 19

suggest that the lack of emphases in cancer prevention among middle-aged Chinese 20

people in Los Angeles and the impending heavy burden posed by prostate cancer in 21

Shanghai in the near future. The factors driving the increase in prostate cancer are 22





not entirely clear; however, they may include gradual implementation of 1

prostate−specific antigen (PSA) screening and improved biopsy techniques or the 2

impact of an increasingly western life style (51). 3

4

Another noted geographical difference was observed in incidence of oral cavity and 5

pharynx cancer, which was rare in Shanghai and Los Angeles but occurs at relatively 6

high rates in Taiwan, Hong Kong, Singapore and Macau. We speculated that this 7

disparity was mostly ascribed to the difference in incidence of nasopharyngeal 8

carcinoma, a malignancy related with Epstein-Barr virus (EBV) infection (52). It has 9

been well documented that nasopharyngeal carcinoma is commonly occurred in 10

Southern China and Southeast Asia (53). In our study, oral cavity and pharynx cancer 11

experienced decreasing trend in Singapore and Hong Kong but increasing trend in 12

Taiwan, which was calling for the further investigations and more effective 13

preventions. 14

15

Our findings highlight the substantial impact of environmental factors on cancer 16

development, though germline mutations have been emphasized their role in cancer 17

development, such as BRCA1 and BRCA2 in breast cancer (54-56). However, such 18

mutations are rare occurred among populations, and taken together account for a 19

very small proportion of cancer cases. On the other hand, growing evidence 20

suggested that the oncogenesis was mainly driven by the somatic mutations in driver 21

genes (47). But how environmental exposures influence these critically carcinogenic 22





mutations still be not entirely clear. 1

2

There are several caveats worth noting when interpreting these results. First, data 3

used in this study were lack of histology information and thus cannot compare the 4

cancer incidence by its histology, such as the differences in esophageal 5

adenocarcinoma and esophageal squamous cell carcinoma, respectively. Second, no 6

information about the immigration status, an indicator for exposure time, was 7

available. Third, no personal data was available to investigate the association 8

between risk factors and cancer risk in individual level. Finally, it is hard to measure 9

the equivalence in cancer diagnostic criteria across regions due to the changing 10

proportion of different diagnostic criterion over time. All limitations listed here 11

might introduce bias into our results, and therefore cautions were needed when 12

interpret them. 13

14

In summary, in the current study, we firstly reported the geographical disparities of 15

cancer incidence among Chinese populations. The cancer profiles and cancer risks 16

were distinct across regions, which further demonstrated the significant impact of 17

environmental exposures on cancer development, and called for more targeted and 18

precise strategies of cancer prevention for Chinese people living in different regions. 19

For instance, much more priority should be placed on the prostate cancer, especially 20

in Chinese population in Los Angeles, which indicates that the PSA screening should 21

be widely adopted in these populations. Moreover, recommended interventions at the 22





population level include policy regulation to decrease cancer risks, such as HBV 1

vaccination among populations in Los Angeles and EBV monitoring among people 2

in Singapore and Taiwan. 3

4

Acknowledgements: 5

This work was supported by the National Natural Science Foundation of China 6

(grant numbers: 81772170, 81502870); the National Key Research and Development 7

program of China (grant number: 2017YFC0907002, 2017YFC0907501, 8

2017YFC211700); the key basic research grants from Science and Technology 9

Commission of Shanghai Municipality (grant number: 16JC1400500); the 10

International S&T Cooperation Program of China (grant number: 2015DFE32790); 11

and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). 12

13

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Table 1a: The age-standardized incidence rates of cancers and their estimated annual percentage changes in men in different regions. 1

Cancers ICD-10

codes

Shanghai

(1983-2013)

Singapore

(1983-2007)

Los Angeles

(1983-2007)

Hong Kong

(1983-2013)

Taiwan

(1995-2013)

Macau

(2003-2013)

ASR EAPC (95% CI) ASR EAPC (95% CI) ASR EAPC (95% CI) ASR EAPC (95% CI) ASR EAPC (95% CI) ASR EAPC (95% CI)

All sites but

non-melanoma skin C00-96bC44 264.98 -0.11 (-0.40 to 0.19) 377.15 -0.32* (-0.52 to -0.12) 297.76 0.97** (0.54 to 1.40) 406.51 -1.49** (-1.62 to -1.37) 292.48 2.87** (1.48 to 3.85) 253.32 1.99 (-3.28 to 4.74)

Oral cavity and pharynx C00-14 9.49 -0.27 (-0.63 to 0.09) 31.12 -1.22** (-1.56 to -0.89) 16.06 -1.29 (-2.92 to 0.37) 39.39 -2.64** (-2.82 to -2.46) 54.67 3.96** (3.41 to 4.51) 33.41 -0.69 (-3.42 to 2.13)

Oesophagus C15 14.93 -3.74** (-4.10 to -3.38) 11.30 -4.61** (-5.43 to -3.79) 4.30 -1.84 (-5.67 to 2.15) 16.35 -4.37** (-4.57 to -4.16) 14.37 4.49** (4.02 to 4.96) 11.22 0.62 (-5.55 to 7.18)

Stomach C16 55.14 -2.99** (-3.22 to -2.75) 39.51 -3.35** (-3.77 to -2.92) 17.89 -0.64 (-2.04 to 0.79) 24.50 -2.79** (-2.96 to -2.62) 23.74 -1.78** (-2.17 to -1.39) 21.87 -2.14 (-5.73 to 1.58)

Colon C18 21.47 2.58** (2.15 to 3.01) 37.34 1.52** (0.99 to 2.05) 30.24 0.90 (-0.49 to 2.31) 35.92 0.22 (-0.02 to 0.46) 30.72 4.93** (4.36 to 5.50) 33.13 2.19 (-0.96 to 5.45)

Rectum and anus C19-21 16.16 1.67** (1.39 to 1.96) 27.45 1.31** (0.81 to 1.81) 16.97 0.41 (-1.52 to 2.37) 23.53 1.27** (0.93 to 1.62) 24.23 3.21** (2.70 to 3.73) 19.72 5.40 (-1.51 to 12.80)

Liver C22 36.70 -1.79** (-2.09 to -1.50) 32.77 -1.07* (-1.67 to -0.46) 24.54 1.30* (0.11 to 2.51) 46.78 -1.99** (-2.19 to -1.78) 67.92 1.33* (0.40 to 2.28) 33.79 4.95* (2.27 to 7.70)

Gallbladder C23-24 4.40 1.74** (1.04 to 2.45) 2.96 0.76 (-0.76 to 2.30) 3.78 -4.15* (-7.24 to -0.96) 5.11 -1.81** (-2.24 to -1.38) 3.75 2.10** (1.24 to 2.97) 3.96 4.65 (-3.33 to 13.28)

Pancreas C25 10.60 1.34** (1.04 to 1.63) 8.29 1.37* (0.40 to 2.34) 7.63 0.34 (-1.89 to 2.62) 6.86 0.29 (-0.21 to 0.80) 7.28 3.38** (2.74 to 4.03) 5.61 -5.31 (-13.33 to 3.46)

Larynx C32 4.04 -0.96* (-1.53 to -0.38) 7.96 -1.68** (-2.44 to -0.91) 2.38 -0.41 (-3.16 to 2.42) 8.27 -4.46** (-4.82 to -4.10) 5.11 0.97* (0.41 to 1.53) 4.63 2.08 (-4.94 to 9.62)

Lung C33-34 74.00 -1.09** (-1.43 to -0.75) 88.11 -1.87** (-2.17 to -1.57) 49.88 -1.02 (-2.15 to 0.11) 97.01 -2.10** (-2.29 to -1.90) 53.87 1.94** (1.38 to 2.51) 65.39 1.06 (-0.62 to 2.77)

Bone C40-41 1.93 -3.04** (-3.61 to -2.47) 0.83 -1.69 (-3.64 to 0.30) 0.69 -2.12 (-5.74 to 1.63) 1.68 1.05 (-1.69 to 3.87) 0.80 0.00 (-1.24 to 1.25) 1.39 18.66* (8.18 to 30.16)

Melanoma of skin C43 0.61 1.09 (-0.30 to 2.51) 0.72 0.64 (-2.56 to 3.94) 1.23 -1.74 (-5.12 to 1.76) 1.00 0.09 (-1.48 to 1.69) 3.46 0.98* (0.51 to 1.61) 0.64 12.59 (-1.48 to 28.68)

Prostate C61 11.24 9.27** (8.57 to 9.97) 24.39 5.86** (5.36 to 6.37) 55.20 5.78** (4.29 to 7.30) 22.82 4.74** (4.14 to 5.34) 27.50 6.34** (5.51 to 7.17) 47.62 -0.28 (-7.20 to 7.16)

Testis C62 0.95 0.14 (-0.54 to 0.83) 1.25 3.18* (1.37 to 5.03) 1.81 0.52 (-2.96 to 4.12) 1.99 2.55** (1.76 to 3.35) 1.37 8.35** (6.98 to 9.74) 1.40 -5.72 (-20.88 to 12.35)

Kidney etc. C64-66,C68 7.60 6.79** (6.34 to 7.24) 7.74 3.84** (2.63 to 5.06) 6.71 1.54 (-0.88 to 4.01) 6.60 2.66** (2.19 to 3.13) 22.92 1.61** (0.93 to 2.30) 4.89 6.15* (2.05 to 10.42)

Bladder C67 11.66 0.81** (0.47 to 1.16) 12.07 0.24 (-0.48 to 0.95) 15.26 0.82 (-0.49 to 2.13) 16.68 -4.73** (-5.43 to -4.03) 13.12 0.04 (-0.85 to 0.95) 13.61 -7.13* (-12.32 to -1.63)

Eye C69 0.17 -1.37 (-3.69 to 1.01) 0.12 -1.00 (-5.16 to 3.33) 0.03 NA 0.15 -2.10 (-4.43 to 0.29) 0.29 -2.92* (-5.19 to -0.60) NA NA

Brain and CNS C70-72 7.07 0.90* (0.41 to 1.39) 2.55 1.86* (0.16 to 3.59) 3.60 2.08 (-1.42 to 5.70) 4.07 -1.62** (-2.25 to -0.98) 3.33 0.90 (-3.19 to 5.16) 2.70 4.91 (-9.81 to 22.04)

Thyroid C73 4.12 8.82** (7.21 to 10.46) 2.87 1.36 (-0.03 to 2.77) 2.93 1.76 (-1.16 to 4.76) 3.22 2.50** (1.91 to 3.09) 3.86 6.97** (6.31 to 7.63) 4.63 10.20 (-7.75 to 31.65)

Non-Hodgkin lymphoma C82-85,C96 6.60 1.61** (1.08 to 2.16) 10.55 2.47** (1.75 to 3.19) 10.75 3.52* (1.54 to 5.54) 11.62 -0.28 (-0.57 to 0.02) 8.41 3.54 (2.04 to 4.43) 9.34 0.74 (-4.31 to 6.05)

Hodgkin lymphoma C81 0.45 -0.44 (-1.85 to 0.98) 0.83 4.78* (2.19 to 7.44) 1.04 -1.59 (-5.36 to 2.32) 0.90 2.33* (1.03 to 3.65) 1.18 0.88 (0.39 to 1.46) 0.64 1.10 (-15.49 to 20.94)

Multiple myeloma C88+C90 1.61 3.16** (2.29 to 4.04) 1.94 0.50 (-1.32 to 2.35) 2.89 -0.03 (-3.43 to 3.48) 3.02 0.62* (0.16 to 1.07) NA NA 1.75 -1.65 (-12.12 to 10.07)

Leukaemia C91-95 5.84 0.48* (0.09 to 0.88) 6.36 0.93* (0.00 to 1.87) 7.02 0.09 (-2.73 to 3.00) 6.98 -0.41 (-0.92 to 0.10) 7.00 5.39** (4.58 to 6.21) 5.56 10.30 (0.36 to 21.22)

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16





Table 1b: The age-standardized incidence rates of cancers and their estimated annual percentage changes in women in different regions. 1

Cancers ICD-10

codes

Shanghai

(1983-2013)

Singapore

(1983-2007)

Los Angeles

(1983-2007)

Hong Kong

(1983-2013)

Taiwan

(1995-2013)

Macau

(2003-2013)

ASR EAPC (95% CI) ASR EAPC (95% CI) ASR EAPC (95% CI) ASR EAPC (95% CI) ASR EAPC (95% CI) ASR EAPC (95% CI)

All sites but

non-melanoma skin C00-96bC44 191.55 1.29** (1.02 to 1.55) 280.61 0.72** (0.53 to 0.91) 243.88 1.25** (0.82 to 1.68) 293.77 -0.72** (-0.90 to -0.54) 234.17 1.86** (0.85 to 2.37) 172.88 0.74 (-3.22 to 3.13)

Oral cavity and pharynx C00-14 4.84 -0.99** (-1.41 to -0.57) 10.82 -1.69** (-2.34 to -1.03) 6.60 0.69 (-0.84 to 2.24) 15.10 -2.87** (-3.12 to -2.62) 8.80 0.66* (0.26 to 1.06) 11.13 -8.28* (-12.31 to -4.06)

Oesophagus C15 5.55 -5.40** (-5.80 to -5.00) 2.69 -6.38** (-7.91 to -4.83) 1.23 -5.17* (-8.66 to -1.54) 3.51 -4.77** (-5.26 to -4.28) 1.15 0.72 (-0.31 to 1.76) 2.65 -9.33 (-24.16 to 8.39)

Stomach C16 26.24 -2.21** (-2.48 to -1.93) 18.64 -2.75** (-3.26 to -2.24) 11.59 0.46 (-1.17 to 2.11) 12.52 -2.65** (-2.90 to -2.41) 13.05 -1.73** (-2.25 to -1.20) 7.89 8.22 (-2.79 to 20.48)

Colon C18 19.16 2.40** (1.99 to 2.82) 30.68 0.90** (0.45 to 1.36) 22.78 2.21* (1.06 to 3.37) 27.64 -0.10 (-0.42 to 0.23) 24.42 3.94** (3.45 to 4.43) 24.46 -0.81 (-6.09 to 4.76)

Rectum and anus C19-21 11.77 0.90** (0.57 to 1.24) 16.62 0.48 (-0.12 to 1.08) 11.21 0.49 (-1.03 to 2.03) 14.73 0.20 (-0.09 to 0.50) 16.41 1.56* (0.74 to 2.37) 11.76 -3.41 (-10.55 to 4.31)

Liver C22 12.77 -2.06** (-2.33 to -1.79) 8.54 -1.32* (-1.99 to -0.64) 7.47 3.85* (0.95 to 6.83) 12.48 -1.87** (-2.22 to -1.52) 26.47 1.96* (0.77 to 3.17) 8.36 5.07 (-1.58 to 12.17)

Gallbladder C23-24 6.20 1.40** (0.68 to 2.13) 3.13 1.26 (-0.32 to 2.87) 2.91 -0.37 (-3.16 to 2.49) 4.09 -1.22** (-1.72 to -0.72) 3.39 0.77* (0.00 to 1.54) 2.55 -8.38 (-22.60 to 8.45)

Pancreas C25 7.57 1.73** (1.41 to 2.06) 5.51 1.45* (0.50 to 2.42) 5.49 2.02 (-0.88 to 5.01) 4.75 0.29 (-0.23 to 0.82) 5.08 3.68** (3.07 to 4.28) 3.25 4.04 (-5.19 to 14.17)

Larynx C32 0.44 -5.40** (-6.55 to -4.24) 0.7 -5.78** (-7.78 to -3.75) 0.16 -2.84 (-6.51 to 0.97) 0.76 -6.87** (-8.15 to -5.58) 0.30 -0.27 (-2.02 to 1.50) 3.20 -17.91 (-48.05 to 29.72)

Lung C33-34 28.68 0.59* (0.25 to 0.94) 29.96 -0.81** (-1.09 to -0.53) 26.36 1.47* (0.33 to 2.63) 40.85 -1.77** (-2.02 to -1.51) 27.90 3.32** (2.94 to 3.71) 24.63 3.64 (-2.39 to 10.03)

Bone C40-41 1.50 -2.08** (-2.68 to -1.48) 0.61 -1.71 (-5.35 to 2.07) 0.52 -5.04* (-8.09 to -1.89) 1.27 1.39 (-1.27 to 4.11) 0.59 0.15 (-1.15 to 1.45) 0.50 -4.85 (-21.71 to 15.64)

Melanoma of skin C43 0.51 1.78* (0.35 to 3.22) 0.68 2.34 (-0.04 to 4.77) 1.33 -3.28 (-7.00 to 0.60) 0.84 -0.83 (-1.96 to 0.32) 3.45 0.48 (-0.68 to 0.98) 1.21 -1.48 (-18.94 to 19.73)

Breast C50 47.05 2.76** (2.43 to 3.09) 64.75 3.84** (3.42 to 4.27) 67.74 2.28** (1.64 to 2.93) 60.08 1.90** (1.68 to 2.12) 58.18 3.24** (2.64 to 4.32) 46.91 -0.20 (-2.35 to 1.99)

Cervix uteri C53 5.91 2.07* (0.68 to 3.47) 19.43 -2.58** (-3.07 to -2.09) 9.85 -3.81** (-5.61 to -1.96) 17.43 -3.86** (-4.25 to -3.47) 15.98 -1.56** (-1.91 to -1.13) 11.20 -1.38 (-9.80 to 7.83)

Corpus uteri C54 6.93 2.91** (2.29 to 3.55) 11.96 3.71** (3.07 to 4.34) 11.44 2.94* (0.96 to 4.95) 12.90 2.45** (2.06 to 2.83) 10.69 7.72** (5.74 to 9.74) 9.23 6.93* (2.14 to 11.96)

Ovary and other uterine

adnexa C56, C57.0-4 9.26 1.50** (0.83 to 2.18) 12.57 0.35 (-0.42 to 1.12) 11.08 0.46 (-1.61 to 2.57) 10.78 0.45* (0.03 to 0.87) 8.55 3.25** (2.71 to 3.79) 6.29 15.73 (-3.64 to 39.00)

Kidney etc. C64-66,C68 3.88 5.93** (5.41 to 6.46) 3.64 2.81** (1.61 to 4.02) 3.66 3.25* (0.82 to 5.75) 3.53 1.27** (0.87 to 1.68) 13.30 1.41* (0.50 to 2.32) 3.42 -1.82 (-9.62 to 6.65)

Bladder C67 3.06 1.12** (0.65 to 1.59) 3.21 -0.54 (-1.55 to 0.48) 3.86 0.61 (-2.46 to 3.77) 4.71 -5.29** (-5.99 to -4.59) 5.23 -0.81 (-1.84 to 0.22) 3.66 1.67 (-6.94 to 11.08)

Eye C69 0.14 -1.80 (-4.50 to 0.98) 0.07 0.74 (-3.79 to 5.48) 0.10 -4.53 (-9.84 to 1.10) 0.11 -2.03 (-4.4 to 0.40) 0.22 -4.04* (-7.02 to -0.95) 0.27 NA

Brain and CNS C70-72 7.46 2.47** (1.97 to 2.98) 1.95 1.72 (-0.07 to 3.54) 2.29 0.15 (-3.16 to 3.57) 2.92 -2.51** (-3.09 to -1.92) 2.52 0.74 (-2.97 to 4.59) 2.40 1.83 (-13.66 to 20.10)

Thyroid C73 12.31 9.46** (8.28 to 10.65) 8.6 0.64 (-0.18 to 1.46) 8.49 5.51** (3.62 to 7.42) 11.01 1.84** (1.42 to 2.25) 12.91 5.84** (5.21 to 6.47) 12.84 10.01 (-21.36 to 53.90)

Non-Hodgkin lymphoma C82-85,C96 4.44 2.70** (2.15 to 3.25) 6.52 2.21** (1.45 to 2.97) 8.29 0.54 (-1.58 to 2.72) 8.16 -0.27 (-0.66 to 0.12) 6.22 2.63 (1.94 to 3.53) 4.23 -6.31 (-24.37 to 16.06)

Hodgkin lymphoma C81 0.29 -0.85 (-2.79 to 1.13) 0.54 5.95** (3.74 to 8.20) 0.76 -3.60 (-8.83 to 1.95) 0.64 3.62** (1.77 to 5.51) 0.90 1.32* (0.31 to 1.82) 0.30 0.15 (-12.05 to 14.03)

Multiple myeloma C88+C90 1.03 3.17** (2.30 to 4.05) 1.39 1.01 (-0.21 to 2.23) 1.74 0.60 (-2.48 to 3.78) 2.13 -0.17 (-0.67 to 0.33) NA NA 1.34 -0.24 (-19.78 to 24.07)

Leukaemia C91-95 4.30 0.23 (-0.33 to 0.79) 4.29 2.52** (1.50 to 3.56) 4.86 0.90 (-2.36 to 4.27) 5.06 -0.95* (-1.45 to -0.45) 4.65 4.23* (1.85 to 6.66) 3.86 5.88 (-3.12 to 15.71)

ASR: age standardized incidence rate, the unit is per 100 000; EAPC: estimated annual percentage change, the unit is per 100. NA: Not available or cannot be calculated; CNS: central nervous system. 2

*: P value < 0.05; **: P value < 0.001. 3

4

5

6

7

8

9

10





1

Figure legend 2

3

Figure 1: The ranks of cancers among regions, by period and cancer site, in terms of the age-standardized 4

incidence rate in men. A total of 23 cancer sites were presented on the x-axis. The figure was separated into 5

three panels according to the study period. The numbers (from 1 to 23) presented on each cell represented 6

the rank numbers of each cancer site in terms of their incidence. The brick red represents the higher 7

incidence, while the forest green represents the lower incidence. The deeper the red (green), the higher 8

(lower) the incidence rate. The dark gray means no data available. All incidences have been transformed on 9

logarithm scale. (Abbreviations in regions: sh: Shanghai; sg: Singapore; hk: Hong Kong; cal: Los Angeles; 10

tw: Taiwan; ma: Macau). 11

12

Figure 2: The ranking of cancers among regions by period and cancer site in terms of the age-standardized 13

incidence rate in women. A total of 25 cancer sites were presented on the x-axis. The figure was separated 14

into three panels according to the study period. The numbers (from 1 to 25) presented on each cell 15

represented the rank numbers of each cancer site in terms of their incidence. The brick red represents the 16

higher incidence, while the forest green represents the lower incidence. The deeper the red (green), the 17

higher (lower) the incidence rate. The dark gray means no data available. All incidences have been 18

transformed on logarithm scale. (Abbreviations in regions: sh: Shanghai; sg: Singapore; hk: Hong Kong; 19

cal: Los Angeles; tw: Taiwan; ma: Macau). 20

21

22

Figure 3: The incidence rate ratios (IRRs) of selected cancers among regions with Shanghai set as 23

reference. (A: IRRs in men; B: IRRs in women; sh: Shanghai; sg: Singapore; hk: Hong Kong; cal: Los 24

Angeles; tw: Taiwan; ma: Macau) 25

26

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Published OnlineFirst April 3, 2019.Cancer Epidemiol Biomarkers Prev Zhenqiu Liu, Oumin Shi, Ning Cai, et al. comparative studyversus migrants to developed regions: a population based Disparities in cancer incidence among Chinese population

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