Prevalence and Risk Factors for Cancers of the Member Countries in the "Belt and Road" Initiative

Background We analyze the prevalence and risk factors of cancer in the member states of the “Belt and Road”, to explore the basis of health and medical cooperation between countries, and to provide a foundation for formulating cancer prevention and control policies for building the healthy "Belt and Road". Methods We apply incidence, mortality, age-standardized rates, and population attributable fractions (PAFs) to measure the prevalence and risk factors of cancers in the “Belt and Road” countries. Results Lung, breast, colorectal, stomach, liver, prostate, cervical, esophageal, thyroid, and uterine cancers are the most common and highest mortality cancers in the “Belt and Road” countries. For men, the highest cancer incidence and mortality is Hungary (ASR, 289.3 per 100,000 and ASR, 235.7 per 100,000, respectively), followed by Latvia (ASR, 288.6 per 100,000 and ASR, 196.5 per 100,000, respectively), the United Arab Emirates and Saudi Arabia enjoy the lowest (ASR, 34.3 per 100,000 and ASR, 36.1 per 100,000, respectively). The mortality and incidence rates of cancers in Greek and Brunei are highest in females (ASR, 238.7 per 100,000 and ASR, 192.3 per 100,000, respectively). Tobacco products, infectious factors, and ultraviolet rays are the three main cancer risk factors in the “Belt and Road” countries. Conclusion The overall burden of cancer in the “Belt and Road” member states remains substantial, while the corresponding cancer prevention and control policies need to be improved. Enhancing health cooperation among the member countries will contribute to the joint response to the risks and challenges posed by cancer. (249 words)


Background
More than 2,000 years ago, the industrious and brave people on the Eurasian continent explored many trades and cultural exchange routes that connected the major civilizations of Asia, Europe and Africa, and later generations collectively referred to them as the "Silk Road" [1] . During his visits to Central and Southeast Asian countries in September and October 2013, Chinese President Xi Jinping proposed to jointly build the "Silk Road Economic Belt" and the "21st Century Maritime Silk Road". The "Belt and Road" achieves the common development and common prosperity of all member states by building a community of interests, destiny, and responsibility in all aspects of political mutual trust, economic integration, and cultural inclusiveness.
In recent years, with the development of society and the economy, the disease burden in low human development index (HDI) and medium HDI countries has shifted from being dominated by communicable, maternal, neonatal, and nutritional deficiency diseases (CMNN) to being dominated by non-communicable diseases (NCDs) and injuries [2] . And with the improvement of clinical diagnosis and treatment, cancer has been included in the ranks of chronic non-infectious diseases and is one of the main components of NCD disease burden. Cancer become the second leading cause of premature death after cardiovascular disease, accounting for about 4.5 million (29.8%) deaths globally in 2016 [3] . As health is a core issue of human development, China's the "Belt and Road" initiative provides a great opportunity for cooperation and collective action among multiple countries. In 2016, General Secretary Xi Jinping proposed to work together to build a healthy Silk Road, taking health as one of the important contents of the "Belt and Road" construction. The development of health undertakings is directly related to the national and regional sustainable development goals and is the driving force for the construction of the " Belt and Road" [4] . At present, member states face different types of cancers threats to varying degrees. Understanding the prevalence and risk factors in the "Belt and Road" member states is an important foundation for health cooperation between countries. Therefore, based on the global data of cancer and cancer country profiles released by the World Health Organization in 2020, we analyzed the prevalence and risk factors of cancer in the member countries of the "Belt and Road" to provide a basis for formulating cancer prevention and control policies for building healthy "One Belt and One Road".

Data source
We used data from the Global Cancer Observatory (gco.iarc.fr) [5] and Cancer Country Profiles (https://www.who.int/cancer/country-profiles/en/) [6] in 2020. Global Cancer Observatory, an online data set that provides a comprehensive assessment of the Global Cancer burden in 2020 based on GLOBOCAN estimates of morbidity, mortality, and prevalence for 36 cancer types grouped by sex and age in 185 countries or territories in 2020. The methods used in compiling the estimates in GLOBOCAN are countryspecific, and the quality of the national estimates depends on the coverage, accuracy, and timeliness of the recorded incidence and mortality data in each country, and more details are described in elsewhere [7] . There is a lack of cancer-related data in Palestine and Yemen in this database. Therefore, this study collected and analyzed cancer data in other 64 member states.

Index definition
In this study, we used morbidity, mortality, and age-standardized rates to analyze and compare cancer incidence and death in "One Belt and One Road" countries.
Incidence, generated by population-based cancer registries (PBCRs), is the number of new cases occurring in a specified period and geographic region which conveyed either as an absolute number of cases per annum or as a rate per 100,000 persons per year.
Mortality, similarly, is used to measure the number of deaths per unit of time (overall or attributable to specific factors) in a population of a given size. It is usually expressed in units per 100,000 persons per year. Age-standardized rates (ASRs) per 100,000 person-years are corrected by the direct method and the world standard population to allow for the effects of the differences in age structure of a population. The methods used to estimate the global incidence and mortality in 2020 together with their uncertainty intervals (for all ages) can be found in elsewhere [8,9] . Population attributable fractions (PAFs) refers to the proportion of the incidence or death of a disease attributable to a certain exposure factor in the total morbidity or death of a disease in the population, that is, the proportion of the morbidity or death of related diseases that can be reduced in the population after the elimination of exposure factors. The contribution of selected risk factors and the percentage of premature deaths from noncommunicable diseases due to cancer was measured by PAFS in this article. The specific calculation method is detailed elsewhere [10] .

Data analysis
We conducted a descriptive analysis and comparison of the incidence and death of cancers in the "Belt & Road" countries, as well as a visual presentation.

Road" countries
Breast, lung, colorectum, prostate, stomach, liver, cervix uteri, esophagus, thyroid, and bladder cancers rank amongst the top ten newly cancers, and lung, colorectum, liver, stomach, breast, esophagus, prostate, cervix uteri, bladder, thyroid cancer rank amongst the top ten cancers in terms of deaths, with a total of 12,176,526 new cases and 6,532,679 deaths worldwide, respectively (table 1, figure a1, a2). The cancers with the highest morbidity and mortality in male and female worldwide are lung cancer and breast cancer, respectively (figure1). All along "the Belt & Road" member countries, the top ten new cancers are lung, breast, colorectum, stomach, liver, esophagus, prostate, cervix uteri, thyroid, and corpus uteri cancers. The top ten cancers with the highest mortality rate are lung, liver, stomach, colorectum, oesophagus, breast, cervix uteri, prostate, pancreas, and ovary cancers. Cancers with the highest morbidity and mortality in male and female are the same as in the world. The member countries of the "Belt and Road" has the lower of cancer incidence and the higher of cancer mortality compared to the world ( Figure 1).

Lung, prostate, colorectum, and stomach cancers in men in Kazakhstan and
Uzbekistan is of very high incidence among the Central Asian countries, while the small difference of the incidence and death of cancers are observed in women, breast, cervix uteri, colorectum, corpus uteri, and stomach are the main ones ( Figure 6).

Distribution of major cancers in the " Belt and Road" member states
The main cancer burdens in the member states of the "Belt and Road" are the cancer of lung, breast, colorectal, stomach, liver, prostate, and cervical. In terms of the incidence and mortality of lung cancer, CEE member countries carry the heaviest one, and the burden of men is approximately 4-to 5-fold that of women (Figure 9, i1). The incidence of breast cancer shows a greatly difference, ranging from ASR, 25.46 per 100,000 to ASR, 56.96 per 100,000. However, these is less marked in mortality ( Figure   9, i2). The burden of colorectal cancer in men is twice that of women, and the burden of incidence is twice that of mortality as well. The heaviest burden of colorectal cancer is observed in CEE member states, followed by the CIS and ASEAN (Figure 9, i3). East of the lowest incidence in West Asia, the morbidity and mortality in other member countries ranged from ASR, 11.00 per 100,000 to ASR, 17.00 per 100,000 and ASR, 5.00 per 100,000 to ASR, 10.00 per 100,000, respectively (Figure 9, i7). 10 Figure 9. Bar chart of region-specific incidence and mortality age-standardized rates by sex for cancers in 2020.

Three main risk factors for cancers in the "Belt and Road" member states
According to our statistics, tobacco products, infectious factors, and ultraviolet rays are the three main risk factors for cancers in the "Belt and Road" member countries.
Tobacco products are the biggest challenge facing all member states, with the highest burden of cancer incidence and mortality in East Asia and CEE (Figure 10, j1)

Discussion
Cancer poses a growing global threat to human health [11] . In 134 out of 183 countries, cancer is the first or second leading cause of premature death (i.e., 30-69 years of age), and in another 45 countries, cancer is ranked at third or fourth [12] . Death rates from non-communicable diseases, particularly cancer, are declining in most highincome countries, but not in low-income countries. By 2040, cancer incidence is projected to increase by the largest percentage in countries with low and medium HDI: from 2018 to 2040, the estimated increase is 100% in the low HDI tier and 75% in the middle HDI tier, looking at population changes alone [3] . Most of countries of the "Belt solutions to the challenge of the cancer burden in low -and medium-level HDI countries.
Strengthening regional scientific and technological cooperation through targeted, resource-sharing, effective and cost-effective means, such as establishing combined laboratories or research centers, transferring international technology and knowledge， are necessary measure to reduce the burden of cancers [13,14] .
Cancer is a complex disease, and the incidence and death of cancer vary widely among Member States. The highest lung and digestive tract cancers incidence has occurred in East Asia, whereas this condition has a breast cancer and lung cancer predominance in ASEAN, West Asia, South Asia, and Central Asia. In South Asia, lip cancer and oral cavity cancer are the leading causes of cancer deaths. South and Central Asia account for more than a third of the global oral cancer burden. In 2018, India had the highest burden of oral cancer, with approximately 120,000 new cases [3] . In the member countries in CIS and CEE, colorectal cancer and lung cancer are the most diagnosed cancers with the highest mortality, and of which the CEE countries have a high incidence of male's cancers, such as bladder and prostate. These variations might be related to disparities in genetic vulnerability, lifestyle, and local environmental exposures among the different locations. For example, the ASR of alcohol-induced cancer deaths and DALY varies greatly between countries and regions. The highest burden of alcohol-induced cancers was observed in Eastern Europe, and the lowest in North Africa and the Middle East [15] . In countries with high HDI, the risk of colorectal cancer tends to be relatively high, and morbidity and mortality rates have stabilized or declined [16] . The increased prevalence of obesity and the increased consumption of dairy products and calcium have previously been associated with an increase in the risk of prostate cancer. In the black population, for instance, the incidence of prostate cancer is much higher [17] . Further, the inherent and growing disparities in medical practice and health infrastructure within and between countries also affect the patterns and trends in cancer mortality [18,19,20,21] . Two major factors in the decline in prostate cancer deaths are likely to be prostate cancer associated with PSA testing (i.e., more cancers are found at an earlier stage) and better management of their patients [22] .
Lung cancer remains the most common type of cancer globally, with an estimated 2.1 million new cases and 1.8 million deaths worldwide in 2018 [3] . Lung cancer is the leading cause of cancer morbidity and mortality in men among the "Belt and Road" countries as well. Smoking is the leading cause of lung cancer, accounting for 63 per cent of all lung cancer deaths globally and more than 90 per cent in countries where smoking is common in both sexes [23] . However, the burden of cancer deaths from tobacco products in the 'Belt and Road" member countries is heavy, and tobacco control The cancer burden among women in the "Belt and Road" countries is considerably high. Breast cancer remains a serious cancer burden in women. According to the latest data in 2020, breast cancer has surpassed lung cancer and for the first time become the most common cancer in the world (accounting for 11.7% of new cases), ranking the first among the types of cancer worldwide [24] . The rising prevalence of breast cancer is associated with the trend of earlier age at menarche, later age at birth, and parity [25] . In addition, cervical cancer carries the highest burden in less developed countries and regions in the "Belt and Road" countries [26] , and nearly 100% of cervical cancers are caused by high-risk human papilloma virus (HPV) infection [27] . While cervical cancer is the only common cancer with a clear etiology and can be completely effectively prevented by tertiary prevention [28] , and HPV vaccination can protect at least 80% of the target population [29] . Therefore, the implementation of HPV vaccination plan and the development of the corresponding screening strategy is the main task of cervical cancer prevention and control in the "Belt and Road" member states.
Infectious agents are the key cause of cancer, particularly in low-and middleincome countries. It was estimated that in 2018, about one-eighth of the 18 million new cancer cases in the world were caused by infection [30] . Hepatitis B virus (HBV) infection, Hepatitis C virus (HCV) infection, liver fluke and Clonorchis's sinensis remain the leading infectious factors leading to cancer in low-and middle-income countries [30,31,32] . Among other infectious factors, including HTLV-1 and large parasites, contribute little to the global burden of cancer, but are significant cause of cancer in endemic populations [33] . What's more, Helicobacter pylori is responsible for a large number of gastrointestinal cancers and deaths [34] . Combination therapy with antibacterial drugs has potential preventive effects. Since 1982, vaccines have been available to prevent HBV, and direct-acting antiviral drugs have the potential to cure more than 95 per cent of people infected with HCV [3] . Adequate infection control strategies, including cheap and reliable point-of-care diagnostic tests for specific infectious agents for screening, effective treatments, and therapeutic and preventive vaccines, should all play a broader role in cancer control programs. However, to realize these aspirations, a large amount of international investment is required. Therefore, the "Belt and Road" initiative provides a new platform for international health cooperation.
Ultraviolet radiation directly or indirectly induces DNA damage, leads to mutations, triggers inflammation and immunosuppression, finally leads to tumor growth. Photocarcinogenesis is a complex, multi-step pathway, which is triggered by the formation of dipyrimidine photoproducts and leads to the formation of mutations (initial stage). Sunburn and inflammation caused by persistent DNA lesions (including dipyrimidine photoproducts and oxidative DNA lesions) play a role in promoting the process of photocarcinogenesis [35] . The dipyrimidine photoproduct triggers ultravioletinduced immunosuppression, leading to the failure of immune surveillance and the growth and development of cancer cells [36] . The incidence of both melanoma and non-melanoma skin cancer is increasing worldwide, not only in Caucasians [37] , but also in Asians, where UV mutations are significantly more common in sun-exposed skin areas than in non-sun-exposed skin areas [38] . The most effective way to reduce the incidence of skin cancer is to avoid unnecessary sun exposure and take personal precautions, such as wearing protective clothing, hats, applying sunscreen, and staying in a cool place, which can significantly reduce the risk of sun damage.

Conclusion
In summary, the challenges posed by cancer are consistent in the "Belt and Road" member countries: Lung cancer, breast cancer, gastrointestinal cancer, prostate cancer, cervical cancer, thyroid cancer, and uterine cancer are the biggest cancer burdens in the "Belt and Road" countries, and tobacco products, infectious factors, and ultraviolet rays are the main risk factors, while the corresponding cancer prevention and control policies need to be improved. Therefore, in the context of the health "Belt and One Road" initiative, the collaboration of multi-stakeholder and the sharing of resources will play a positive role in jointly coping with the risks and challenges brought by cancer and promoting the healthy development of the medical and health undertakings of all member states and the world.

Declarations
-Ethics approval and consent to participate Not Applicable.
-Consent to publish Yes.
-Availability of data and materials Yes.