Epidemiologic Study of Gastric Cancer in Iran: A Systematic Review.

BACKGROUND: Gastric cancer (GC) is one of the most common cancers in Iran. Knowledge of the epidemiology of the disease is essential in planning for prevention. So this study aimed to investigate the epidemiological aspects of gastric cancer including prevalence, incidence, mortality, and risk factors of Iran.
METHODS: This systematic review study was based on articles published in both English and Persian languages during the years of 1970-2020 in international databases (PubMed, Web of Science, Scopus) and national databases (including SID, Magiran, and IranDoc). Papers related to epidemiological aspects of the disease including mortality, prevalence, incidence, and risk entered the final review.
RESULTS: According to the studies, the minimum and maximum prevalence of gastric cancer in northwestern Iran (Ardabil) is between 0.2 and 100 per 100,000. Also, the death rate per 100,000 people ranged from 10.6 to 15.72 and the ASMR ranged from 4.2 to 32.2%. On the other hand, the incidence of GC was higher in men than in women (74.9 vs 4.6%). The GC risk ratio was 8-times higher in the elderly than in the other age groups (HR=8.0, 2.7-23.5). The incidence of gastric cancer in patients with H. pylori infection was 18-times and that of smokers 2-times higher than other populations. Low level of economic situation and food insecurity increased the odds of GC by 2.42- and 2.57-times, respectively. It should be noted that there was a direct relationship between consumption of processed red meat, dairy products, fruit juice, smoked and salty fish and legumes, strong and hot tea, and consumption of salt and gastric cancer incidence. There was also an inverse relationship between citrus consumption, fresh fruit, garlic, and gastric cancer. In addition, the mRNA genes are the most GC-related genes.
CONCLUSION: Given the high incidence of GC in Iran, changing lifestyle and decreasing consumption of preservatives in food, increasing consumption of fruits and vegetables, and improving the lifestyle can be effective in reducing the incidence of this disease.

Introduction

Gastric cancer is one of the most common cancers in the world,1 with the highest incidence in the countries of Western Asia, Latin America, and the former Soviet Union. The incidence among Japanese, Korean, and Iranian males were 66.7, 64.6, and 30.4%, respectively.2

Gastric cancer, with an annual incidence of 7300, is one of the five most common cancers in Iranian men and women.3 It is the first cause of cancer death in both genders in Iran as most patients are diagnosed at advanced stages of the disease.4 Also, the 5-year survival rate in Iran is estimated to be less than 25%.5

Helicobacter pylori, genetics, gastric ulcer, cigarettes, alcohol, chemical exposure, reflux, chronic anemia, gastric surgery, obesity, radiation, Epstein-Barr virus, gender, race, ethnicity, economic-social status, Type A blood groups, and food play an important role in the risk of gastric cancer.6 Improving living standards and changing dietary habits as well as reducing H. pylori infection are very effective in reducing the incidence of gastric cancer.7 Understanding the epidemiologic status of the disease and associated risk factors are essential for planning to diminish the disease, so this study aimed to investigate the epidemiological aspects of gastric cancer including prevalence, incidence, mortality, and risk factors of Iran.

Materials and Methods

Eligibility Criteria

In this study, original articles in the Iranian population which are published in Persian and English language, and published in national and international journals during the years of 1970–2020 with accessible full text, were reviewed.

Information Sources

Articles were selected from international databases (PubMed, Web of Science, Scopus) and national databases (SID, Magiran, and IranDoc).

Study Selection

Papers related to epidemiological aspects of the disease including mortality, prevalence, incidence, risk factors and genetics were reviewed. The results of the studies were presented in separate tables including mortality, prevalence, incidence, and risk factors of genetics.

It should be noted that studies lacking necessary information and links to the topic under discussion were excluded from the study.

Data Collection Process

Abstract and full text of articles, independently, by two relevant researchers, reviewing and listing information prepared for this purpose, including: author’s name, year of publication, place of study, gender, sample size, age incidence, prevalence, and factors. The hazards of the genes in the articles and other cases were recorded in separate tables.

In order to increase the accuracy and reliability of the information and to reduce possible bias, the second review was performed by a second researcher and then registered by both researchers.

Summary Measures

Articles related to incidence, mortality, prevalence, risk factors, and genetics were selected in the period of 1970 to 2020 and the results are presented in separate tables.

Synthesis of Results

A total of 3461 articles were initially reviewed. It should be noted that 68 articles were not accessible to the full text, 1823 were duplicate, 822 were fully studied, 593 were irrelevant, and finally 229 were entered (Figure 1).

Figure 1

Flowchart of the included eligible studies in systematic review.

Results

Incidence

The incidence of gastric cancer in Iran increases due to increasing health level, lifestyle, awareness of early symptoms, and early diagnosis.8 On the other hand, with growth of urbanization, the incidence and consequently the mortality rate will increase.9 One of the causes of the rising incidence of gastric cancer in Iran is related to the diagnosis of end stage (non-curable stage=end stage) disease.10,11

Most patients are diagnosed in advanced stages and cannot be diagnosed at an early stage.12 Studies in most parts of Iran indicate a high prevalence of this disease,13 with the provinces located in the north and northwest as high risk areas and those located in southwestern Iran as medium risk areas.14

Epidemiological studies in Iran show a higher incidence of this disease in men than in women (74.9 vs 4.6), On the other hand, the sudden decrease in the incidence of disease over the age of 80 indicates the limitation of healthcare in this age group in Iran (Table 1). Increasing trend of GC is observed in the majority of men in Tehran province and most women in East Azerbaijan, Markazi, Tehran, and Yazd provinces.15

Table 1

Incidence Rate of Gastric Cancer in Iran

First Author/Year (Reference Number)	Province(District)	Type of Study	Sample-Size	ASRa
Ahmadi (2018)72	Chaharmahal and Bakhtiari	Retrospective	2918
Aghaei (2013)73	Tehran	-	4463	-
Almasi (2015)74	All of Iran	Cross-sectional	35,171	7.115.1
Almasi (2016)75	All of Iran	Cross-sectional	9660	15.2
Amani (2015)76	Ardabil	Cross-sectional	1056
Amoori (2014)77	Khuzestan	Retrospective	14,893	M=13.8F= -
Amori (2017)78	All of Iran	Retrospective	301,055	M=15.02F=7.05
Eishi (2016)79	Western Azerbaijan	Sectional & retrospective	2972	-
Babaei(2009)80	Ardabil	-	M=727F=311	M=51.8F=24.9
Babaei(2005)81	Semnan		M=936F=796	M=36.9F=14.8
Behnampour (2014)65	Golestan	Case-control	M=107F=49	13.93
Jenab (2019)82	All of Iran	Ecological	4484	15.93
Hassanzade (2011)83	Fars	-	M=46F=31	M=9.99F=4.66
Chamanpara (2015)84	Golestan		1087	0.8–1.2
Haghdoost (2008)85	kerman	-	1112
Haghigh (1971)86	Fars		182
Khodadost (2015)87	Ardabil		857
Sadjadi (2005)88	Golestan,Mazandaran, Kerman, Ardabil	-	51,000	M=26.1F=11.1
Khazaei (2018)89	All of Iran	-	M=5398F=2353	M=19.1F=10
Masoompour (2016)90	Fars		-	M=5.56F=11.21
Masoompour (2011)91	Fars	-	M=597F=273	M=9.2F=4.4
Kavousi (2015)93	All of Iran	Ecologic	M=20,882F=8592
Moradpour (2013)94	Isfahan	-	2001: Male=190Female=104	2001: Male=9.9Female=5.6
			2010: Male=272Female=162	2010: Male=12.8 Female=7.9
			2015: Male=390Female=250	2015: Male=14.7Female=9.5
Khazaei (2016)8	All of Iran	Ecological	951,594
Fateh (2013)95	Semnan	-	2240	15.52
Fararouei (2015)96	Kohgiluyeh and Boyer-Ahmad	Cohort	106	11.08
Keyghobadi (2015)97	Kerman	Cross-sectional	Male: 2004=671	Male: 2004=74.93
			2005=691	2005=71.43
			2006=915	2006=85.85
			2007=837	2007=79.2
			2008=1070	2008=104.22
			2009=1609	2009=131.61
			Female: 2004=572	Female: 2004=75.69
			2005=554	2005=61.79
			2006=765	2006=82.72
			2007=727	2007=78.88
			2008=851	2008=91.94
			2009=1333	2009=128.26
Faramarzi (2013)98	fars	Cross-sectional	Male=1652	Male=74.9
			Female=1072	Female=49.8
Mashhadi(2010)99	Sistan & Blouchestan	-	100	22%
Yasemi (2015)14	ILAM	Retrospective cross-sectional	307
Mohebbi (2011)100	Mazandaran	ecologic	2665	Male=Ardabil=49.1
Yavari (2006)101	Ardabil and KermanIranian immigrants (BC Iranians)	-	-	Kerman=10.2
				Female=Ardabil=25.4
				Kerman=5.1
				BC Iranians=6.5
Vakili (2014)102	Yazd	Cross-sectional	4631	Female: 2005=3.3
				2006=4.8
				2007–4.2
				2008=4.6
				2009=4.3
				Male: 2005=7.2
				2006=8.2
				2007–7.5
				2008=9.4
				2009=8.5
Darabi (2016)103	All of Iran	-	Male: 2001=1105	Male: 2001=4.18
			2010=5192	2010=17.06
			Female: 2001=484	Female: 2001=2.41
			2010=2238	2010=8.85
Salehiniya (2016)17	Gilan, Mazandran and Golstan	Cross-sectional	Mazandran=2382
			Gilan=1824
			Golestan=709
Talaiezadeh (2013)104	Khuzestan	Retrospective	Male=667Female=322	Male=7.17Female=2.34
Mohagheghi (2009)31	Tehran	-	Male=2119Female=1033	Male=19.7Female=10.0
Norouzinia (2012)105	Tehran, Khorasan,Lorestan, Mazandaran, Khuzestan, East Azarbaijan,Kurdestan, and Sistan and Baluchesta	Retrospective	140	Lorestan=10.24
				Tehran=5.01
				Tabriz=2.21
				Zahedan=2.31
				Sanandaj=7.07
				Sari=4.23
				Ahvaz=2.3
				Mashhad=4.48
Askarian (2014)106	Fars	-	1171	85.04
Sadjadi (2014)16	Ardabil	Cohort	928
Norouzirad (2018)107	khozestan	Cross-sectional		M=10.88F=3.29
Mohammadian (2016)13	Sistan and Baluchestan	-	255	Male: 2004=0–24 years=0
				25–29 years=1.06
				30–34 years=0
				35–39 years=1.48
				40–44 years=0
				45–49 years=2.0
				50–54 years=3.39
				55–59 years=18.42
				60–64 years=22.61
				65–69 years=11.19
				70–74 years=10.83
				75–79 years=7.47
				>80 years=0
				Female: 2004=0–29 years=0
				30–34 years=1.30
				35–39 years=1.53
				40–44 years=1.69
				45–49 years=6.88
				50–54 years=7.73
				55–74 years=0
				75–79 years=10.46
				>80 years=0
				2005: male=0–24 years=0
				25–29 years=0.97
				30–34 years=1.19
				35–39 years=4.08
				40–44 years=3.17
				45–49 years=0
				50–54 years=6.24
				55–59 years=20.33
				60–64 years=23.76
				65–69 years=10.29
				70–74 years=34.87
				75–79 years=20.63
				80–84 years=40.54
				>85 years=54.38
				Female: 2005=0-19 years=0
				20–24 years=0.82
				25–29 years=1.08
				30–34 years=0
				35–39 years=1.41
				40–44 years=0
				45–49 years=2.11
				50–54 years=2.37
				55–59 years=0
				60–64 years=4.44
				65–69 years=14.77
				70–74 years=5.66
				75–79 years=9.62
				>80 years=0
				2006: 0-24 years=0
				25–29 years=0.97
				30–39 years=0
				40–44 years=12.69
				45–49 years=3.68
				50–54 years=9.36
				55–59 years=6.78
				60–64 years=14.85
				65–69 years=17.15
				70–74 years=29.89
				80–84 years=40.54
				>85 years=0
				Female: 2006=0.14=0
				15–19 years=0.61
				20–24 years=0
				25–29 years=1.08
				30–34 years=0
				35–39 years=2.82
				40–44 years=3.11
				45–49 years=6.3
				50–54 years=4.74
				55–59 years=3.56
				60–64 years=13.33
				65–69 years=0
				70–74 years=11.32
				75–79 years=19.25
				80–84 years=0
				>85 years=29.52
				Male: 2007=0–9=0
				10–14 years=0.58
				15–19 years=0
				20–24 years=0.87
				25–39 years=0
				40–44 years=4.76
				45–49 years=3.68
				50–54 years=15.60
				55–59 years=13.55
				60–64 years=8.91
				70–74 years=39.85
				75–79 years=13.75
				80–84 years=60.80
				>85 years=0
				Female: 2007=0–44 years=0
				45–49 years=4.22
				50–54 years=2.37
				55–59 years=3.56
				60–64 years=0
				65–69 years=4.92
				70–74 years=5.66
				75–79 years=19.25
				80–>85 years=0
Najafi (2011)108	Kermanshah	-		1993=10.6
				1994=13.8
				1995=8.3
				1996=15.8
				1997=15.5
				1998=5.1
				1999=6.7
				2000=8.7
				2001=7.3
				2002=6.7
				2003=8.5
				2004=10.0
				2005=8.7
				2006=9.1
				2007=9.1
Mousavi (2009)109	All of Iran	-	2003–2004: Male=3088Female=1166	2003–2004: Male=11.37Female=5.20
			2004–2005: Male=3770Female=1439	2004–2005: Male=13.74Female=6.42
				2005–2006: Male=15.21Female=6.89
Enayatrad (2014)110	All of Iran	-	Male: 2003=3088	Male: 2003=11.37
			2004=3770	2004=13.74
			2005=4212	2005=14.90
			2006=4299	2006=15.24
			2007=4485	2007=15.93
			2008=5398	2008=19.16
			2009=4891	2009=16.01
			Female: 2003=1166	Female: 2003=5.20
			2004=14402005=1624	2004=6.422005=6.74
			2006=167	2006=6.65
			2007=173	2007=7.38
			2008=2353	2008=10.0
			2009=1995	2009=7.78
Haidari (2012)111	All ofIran	Cross-sectional	21,348	2000=2.8 (2.7–2.9)
				2001=2.6 (2.5–2.7)
				2002=4.6 (4.4–4.7)
				2003=7.1 (6.9–7.4)
				2004=7.9(7.7–8.1)
				2005=9.1(8.8–9.3)
Hosseintabar Marzoni (2015)112	Golestan	-	1122
Rastaghi, Tohid (2019)15	All of Iran	Cross-sectional ecological	M=26,041F=10,756

Abbreviation: ASR, age standardized rate.

Non-use of refrigerator in some parts of the country, incorrect food preservation methods, high prevalence of H. pylori, and consumption of salty and nitrogen-containing foods, drinking hot tea, smoking and drinking contaminated water, smoking, and opium are important causes of gastric cancer in Iran.16,17 In contrast, in the southern regions of Iran due to high consumption of dates as an antioxidant, the incidence of GC decreases.15

Mortality

In 2012, the rate of gastric cancer deaths in Iran was 11.4%, and it was reported as the second leading cause of death from common cancers in Iran. In fact, 15.5% of all cancer deaths in Iran are attributable to gastric cancer.18,19 Currently, the highest mortality rate in Southwest and Central Asian countries is observable in Iran (19.9 per 100,000).20

GC is one of the most important causes of cancer death in Iran21 which is due to individual or environmental factors, H-Pylori infection, and gastric atrophy in an Iranian population.22 It should be noted that the incidence of GC mortality has decreased over the last five decades worldwide.15 Thus, the number of deaths due to GC in Iranian military has been steady, which may be due to early diagnosis of this disease.23 ASMR ranged from 4.2–32.2% (Table 2).

Table 2

The Death Rate of Gastric Cancer in Iran

First Author/Year (Reference Number)	Province (District)	Type of Study	Sex	Sample-Size	Age-Standardized Mortality Rate per 100,000(ASMR)	Death Numberand Percent	Death per 100,000 People	RR (Relative Risk)	CumulativeRisk	Annual Mortality Rate/100,000
Ahmadipanah (2019)113	All provinces in Iran except for Tehran	Ecological study	MF	395,002	-	-	-	RR>1.75
AghamohammadI (2017)114	All provinces in Iran except for Tehranfor 2006 & 2011Isfahan & TehranFor 2007 & 2011	-	MF	2006–2011=1,172,278	-	-	Ministry of HealthAnd Medical Education: 1385=12.201386=11.751387=11.311388=11.181389=11.061390=10.17United Nations:1385=15.051386=15.721387=15.471388=15.351389=14.801390=13.56	-
Almasi (2016)75	All of Iran	Cross-sectional	MF	8247	12.9				1.44
Amoori (2016)115	All of Iran	cross-sectional	MF	34,950	-	-	2006=11.202007=11.752008=11.312009=11.172010=11.06
Babaei(2009)80	Ardabil	-	MF	M=465F=206	M=32.2F=16.3
Pourhoseingholi (2013)12	All of Iran	-	MF							1995=1.681996=3.041997=3.381998=2.291999=5.702000=6.042001=6.472002=9.862003=9.672004=8.78
Hassan Zade (2011)83	Fars	-	MF	M=46F=31	M=11.54F=4.21
Khorasani (2015)116	All of Iran	-	MF	M=5665F=2582	-	M=18.8%F=11.11%
Khazaei (2016)8	All of Iran	Ecological	MF	723,073			10.2
Moradpour (2013)94	Isfahan	-	MF	2001: M=116F=682010: M=183F=972015: M=283 F=166	2001: M=7.9 f=4.22010: M=9.3F=5.22015: M=10.6F=6.3
Sadjadi (2005)88	Golestan,Mazandaran, Kerman, Ardabil	-	MF	7843		6638
Mousavi (2009)109	All of iran	-	MF				12.0
Nalini (2018)117	Golestan	Cohort	MF	432		1.39%
Mohammadi (2017)118	All of Iran	Cross-sectional	MF	514,550	M: 2006=16.72011=12.5F: 2006=9.02011=6.9

Note: Malekzadeh (2013),119 cox hazard ratio =1.19.

Prevalence

Gastric cancer is one of the most common cancers among Iranian men and women,12 as it become the first common cancer among Iranian men.9 The higher prevalence of males than females can be due to risky occupations such as agriculture, which may lead to exposure to nitrate-contaminated soil and chemical fertilizers as well as men’s genetic susceptibility and, in turn, women’s greater sensitivity to healthcare than men.24,25 The minimum and maximum prevalence of gastric cancer in the previous studies was observed in northwestern Iran (Ardabil) between 0.2–100%. Other provinces were within the mentioned range (Table 3).

Table 3

The Prevalence Rate Of Gastric Cancer In Iran

First Author/Year (Reference Number)	Province(District)	Sample-Size	Sex	Prevalence
Ostadrahimi (2017)120	East-Azerbaijan	111	MF	36.9%
Islami (2004)121	Golestan	116	M	Gastric cardia adenocarcinoma=16%Gastric noncardia adenocarcinoma=16%
Eishi (2016)79	Western Azerbaijan	2972	MF	9.7%
Almasi (2015)74	All of Iran	35,171	MF	Male: Adenocarcinoma, Nos: 2003==68.392004=68.59 2005=65.172006=61.60 2007=59.302008=61.54
				Signet Ring Cell Carcinoma: 2003=9.422004=9.63 2005=9.902006=10.26 2007=11.952008=9.73
				Adenocarcinoma, Intestinaltype: 2003=6.802004=8.51 2005=10.832006=12.82 2007=13.942008=10.58
				Carcinoma, Diffuse Type: 2003=2.91 2004=3.37 2005=3.96 2006=4.07 2007=3.77 2008=4.87
				Carcinoma, Nos: 2003=2.75 2004=10.9 2005=0.28 2006=1.88 2007=0.91 2008=0.74
				Mucinous adenocarcinoma: 2003=1.912004=1.64 2005=2.11 2006=1.88 2007=1.87 2008=1.50Mucin-Producing Adenocarcinoma: 2003=2.17
				2004=1.86 2005=2.04 2006=1.63 2007=1.56 2008=1.33
				F: Adenocarcinoma, Nos: =62.61 2004=65.60 2005=60.84 2006=55.33 2007=56.08 2008=58.90
				Signet Ring Cell Carcinoma: 2003=11.752004=12.44 2005=13.672006=13.60 2007=14.01 2008=12.07
				Adenocarcinoma, Intestinaltype: 2003=6.69 2004=6.46 2005=8.93 2006=12.98 2007=11.76 2008=9.14Carcinoma, Diffuse Type: 2003=4.12 2004=3.752005=4.0 2006=5.61 2007=5.712008=5.10Carcinoma, Nos: 2003=3.00 2004=1.46 2005=0.37 2006=1.81 2007=1.382008=0.72Mucinous Adenocarcinoma:2003=1.722004=1.95 2005=2.59 2006=2.432007=1.67 2008=1.57Mucin-Producing Adenocarcinoma: 2003=2.57 2004=1.74 2005=1.42 2006=1.372007=1.79 2008=1.23
Amani (2015)20	Ardabil	1056	MF	Male: Ardabi)=73.1% Bilesvar=62.5 Germi=65.7 Kousar=88.9 Khalkhal=74.7Meshkinshahr=74.3 Naming=74.4Nir=83.9 Parsabad=84.2 Sarein=100 Other=68.2Female: Ardabil=26.9 Bilesvar=37.5Germi=34.3 Kousar=11.1 Khalkhal=25.3 Meshkinshahr=25.7 Naming=16.1Nir=16.1 Parsabad=15.8 Sarein=0Other=31.8%
Barekat (1971)122	Fars	M=131F=42	MF	M=6.59 F=3.26
Bashash (2011)123	Ardabil	261	MF	M=70.9% F=28.7%
Pourhoseingholi (2008)124	Tehran	2674	MF	34.5%
Tabrizchee (1998)125	Kerman	2881	MF	M=9.70% F=6.30%
Tavoli (2007)126	Tehran	142	MF	30%
Hajmanoochehri (2013)127	Tehran	729	MF	64.3
Yasemi (2015)14	Ilam	307	MF	34.2%
Mohebbi (2008)92	Mazandaran	1663	MF	44.7%
Khademloo (2018)128	Mazandaran	1232		2008=20% 2009=23.8%2010=20% 2011=19.5% 2012=16.7%
Tayebi (2012)129	Mazandaran	596	MF	4.1%
Nikfarjam (2014)130	Mashhad	495	MF	10.7%
Hashemi (2017)131	Mashhad,	30	MF	Intestinal type =90%Diffuse type =10%
Yazdizadeh (2005)132	Shiraz and the Tehran	1516	MF	Tehran=4% Shiraz=4%
Mehrabian (2010)133	–	3439	MF
Kadivar (2016)134	Tehran	147	MF	32.6%
Karami (2014)135	Khuzestan	273	MF	1.4%
Moradpour (2013)94	Isfahan	2001: male=366 Female=209	MF
		2010: male=582 female=357
		2015: male=852 female=559
Keyghobadi (2015)97	Kerman	789	MF	7.45%
Mehrabani (2013)9	Fars	574	MF	<35age=8.9% 36–44=10.6%45–54=20.7% 55–64=20.2%65–75=27.7% >75=11.7%
Malekzadeh (2004)22	Ardabil	1011	MF	Erythema=68.1% Erosion=10.6 Friability=0.3Nodularity=4.7Polyp=0.9 Ulcer gastric=3.0Ulcer (duodenal)=1.9Atrophic mucosa=0.2Raised/thickened area=0.3

Risk Factors

H.pylori

In Iran, more than 80% of the population over 40 years have a history of H. pylori infection.26,27 H. pylori is the most prominent risk factor for gastric cancer.28 Age of infection seems to be very low in Iran. According to a study in southern Iran, 89% of 9-month-old children and 98% of 2-year-olds have been infected.29 Studies have shown that H. pylori infection has an 18% higher chance of developing gastric cancer than those without the above-mentioned infection (OR=18.58; CI=1.63–221.520)

Cigarette Smoking and Alcohol

Studies show a 25.4% prevalence of smoking among Iranian adults. High smoking in Iran requires special attention as a risk factor for gastric cancer.20 Furthermore, the prevalence of gastric cancer is directly related to the frequency of smoking.9,30

Some surveys in Iran reveal increasing prevalence of cigarette smoking at an early age and subsequently, rising trend of smoking-related cancers is similar to GC.31 According to studies, smoking has a 2-fold chance of developing gastric cancer (OR=2.07; 1.14–3.75) (Table 4).

Table 4

Risk Factors Associated with Gastric Cancer in Iran

First Author	Province	Sample-Size	Sex	Risk Factors	OR (Odds Ratio)
Islami (2004)121	Golestan	Gastric cardia=42Gastric noncardia=40	m	Alcohol
				Smoking
				Nass
				Opium (new user)
				Opium (old user)
				Four risk factors (alcohol, cigarette, nass or opium)
Etemadi (2014)42	Ardabil, Guilan, Mazandaran, Kordestan, and West Azarbaijan	197	M&F	Blood Type A+	-
				A−
				B+
				O+
				O_
				AB+
				N/AAlcoholconsumpti on(yes)
				Alcoholconsumpti on(NO)
				Alcoholconsumpti onN/A
				Smoking(heavy smoker)
				Smoker
				No smoking
				N/A
				Smoked foodLowModerateHighN/A
				Salty foodLowModerateHighN/A
				NitriteLowModerateHighN/A
				Hp InfectionYESNON/A
Amoueian (2018)47	Khorasan Razavi	Case=56Control=56	MF	Epstein–Barr virus (EBV)	-
Behnampour (2014)65	Golestan	M=107F=49	MF	2.07 (1.14-3.75)	History of smoking
				Unwashed hands after defecation	2.61 (1.43-4.76)
				History of gastric cancer in first-degree relatives	2.46 (1.21–4.99)
				Other cancers (except for gastrointestinal cancer) in first-degree relatives	2.34 (0.92–5.96)
				Other cancers (except for gastrointestinal cancer) in second-degree relatives	4.38 (1.14-6.79)
				History of X-ray dye exposure	1.56 (0.85–2.85)
				History of CT scan encounter	2.32 (1.21-4.44)
				Charred flesh	1.65 (0.99-2.88)
				Irregular lunch-time	3.96 (0.96-6.32)
				Achalasia	76.97 (28.35-208 .92)
				Helicobacter pylori	18.58 (1.63- 211.52)
				Gastric ulcer	2.71 (1.15-6.36)
				Low mobility and lack of appropriate activities	4.78 (1.34–16.99)
Boreiri (2013)136	Ardabil	1011	MF	Age (years) 51–60
				2:61
				Family history
				Positive smoking
				History Histological finding (Atrophic gastritis)
				(Intestinal metaplasia)
				Gastric ulcer
Pakseresht (2011)60	Ardabil	Case=286Control=304	MF	Total fat intake	1.33 (1.12–1.57)
				Carbohydrate (per 50 g)	1.00 (0.88– 1.13)
				Selenium (per 50 lg)	1.11 (0.80–1.54)
				Protein (per 10 g)	0.87 (0.76–0.99)
				Vitamin C (per 10 mg)	0.82 (0.76–0.87)
				Vitamin E (per 10 mg)	0.67 (0.44–1.03)
				0.37 (0.25–0.56)	Iron (per 5 mg)
				Zinc (per 5 mg)	0.47 (0.32–0.70)
				Energy (per 100 kcal)	0.99 (0.97–1.02)
Daneshi-Maskooni (2017)36	Tehran	Case=120Control=120	MF	Food insecurity	2.57 (1.41- 4.66)
				Low economic level	2.42 (1.23- 4.76)
				Family history	1.98 (1.03- 3.80)
Safaee (2012)43	Tehran	746	MF	Family history	2.12 (1.72 – 3.28)
Ebrahim Tahaei (2011)50	Tehran	Case=201Control=219	MF	HTLV-1 antibodies
Sadjadi (2014)16	Ardebil	928	MF	Family history
				Cigarette smoking
				Hookah smoking
				Opium use
				Salt intake >6 gr/day
Moghimi-Dehkordi (2011)137	Tehran	FDR=113SDR=180	MF	Having a family history	-
Zendehdel (2010)138	Tehran	808	MF	Family history
Faghihloo (2014)46	Tehran	90	MF	Epstein-Barr virus (EBV)
Mashhadi (2009)56	Sistan & Blouchestan	100	MF	Family historysmoking and tobaccoH. pylori infection
Naghibzadeh Tahami (2014)32	Kerman	89	MF	Opium use	3.0(1.6–5.6)
				Amount of daily use (>median)	13.0 (4.2 -41.9)
				≤median	5.5 (1.0– 28.4)
				Duration(>median)	10.5 (2.4–46.1)
				≤median	6.8 (1.7–26.8)
				Cumulative useof Opium(>median)	9.2 (2.5–33.7)
				≤median	7.3 (1.2–43.0)
				Cigarette smokingAmount of daily use (>median)	1.4 (0.8–2.3)1.9 (0.7–5.2)
				≤median	0.8 (0.2 –2.8)
				Duration(>median)	1.2 (0.3–4.2)
				≤median	1.5 (0.5–4.2)
				Cumulative useof smoking (>median)	2.4 (0.8–7.2)
				≤median	1.0 (0.2–3.8)
				Alcohol	1.2 (0.3–.4.4)
Pourfarzi (2004)53	Ardabil	Case=217Control=394	MF	Tobacco	0.90 (0.54–1.49)
				Cigarette	0.87 (0.52–1.46)
				Hubble-bubble	1.14 (0.29–4.42)
				Current smoker	0.71 (0.41–1.25)
				Ex-smoker	1.40 (0.63–3.12)
				Age at start (years)<2020–29>30	0.54 (0.22–1.29)1.28 (0.65–2.54)0.75 (0.36–1.54)
				Average cigarette daily >20<20	0.67 (0.35–1.30)1.07 (0.57–1.99)
				Total smoking years–>3521-35<20	0.87 (0.45–1.70)1.11 (0.51–2.46)0.61 (0.26–1.47)
				Non-filterFilteredBoth equally	0.99 (0.23–4.31)0.86 (0.51–1.47)0.71 (0.15–3.41)
				Smoke inhalation (Deeply)Moderately or slightly	0.51 (0.27–0.99)1.90 (0.91–4.01)
				Alcohol	2.03 (0.44–9.31)
				Agriculture	1.96 (0.95–4.01)
				Manufacturing	0.80 (0.25–2.58)
				Construction	1.78 (0.67–4.76)
				Wholesale and retailer	1.32 (0.39–4.49)
				Raw vegetables (3 times/week)(1-2 times/week)	2.08 (1.13–3.82)1.56 (0.89–2.73)
				Yellow-orange vegetables (3times/week)1–2	1.78 (0.81–3.89)2.07 (1.15–3.70)
				Garlic (3 times/week)(1–2 times/week)	0.35 (0.13–0.95)0.48 (0.25–0.91)
				Onion≥once per day(3–4 times/week)	0.34 (0.19–0.62)1.28 (0.73–2.23)
				Fresh fruits≥3 times/week1–2 times/week	0.89 (0.43–1.86)0.44 (0.22–0.89)
				Citrus fruits (≥3 times/week)1–2 times/week	0.31 (0.17–0.59)0.18 (0.10–0.33)
				Juice≥once/week	1.29 (0.73–2.29)
				Red meat≥once/day3–4/week	3.40 (1.79–6.46)2.20 (1.26–3.85)
				Fresh fish≥once/week	0.37 (0.19–0.70)
				Chicken≥once/day3–4/week	0.93 (0.39–2.20)1.40 (0.80–2.42)
				Dairy products ≥once/day3–4/week	2.28 (1.23–4.22)3.77 (1.92–7.42)
				Cheese≥once/day3-4/week	1.16 (0.54–2.51)1.00 (0.39–2.56)
				Smoked meats≥once/month	0.91 (0.40–2.09)
				Smoked fish≥once/month	1.09 (0.63–1.89)
				Processed meats≥once/month	1.14 (0.55–2.37)
				Salted fish≥once/month	1.08 (0.57–2.05)
				Pickled vegetables≥once/week	1.47 (0.84–2.58)
				Beans> once/week	1.04 (0.65–1.66)
				Sweets≥once/week	0.70 (0.38–1.29)
				Seeds≥once/month	0.96 (0.37–2.46)
				Salt preference	3.10 (1.88–5.10)
				Strength of tea	2.64 (1.45–4.80)
				Warmth of teaHot	2.85 (1.65–4.91

Opium has traditionally been used in many Southeast Asian countries, especially Iran.32 It is noteworthy that tobacco use in the north and south of Iran is higher than in other parts of Iran.33,34 According to some investigations in Iran, the chance of gastric cancer in smokers, especially opium consumers, is 3-times higher than those who did not consume (OR=3.0; 1.6–5.6) (Table 4). Because of the risk of hookah, especially for cancer, being less well known and the perception that tobacco is safer than cigarette smoking, the filtration of tobacco in water and the lower cost of hookah than smoking, the tendency for hookah smoking in Iran is increasing.35 Studies show gastric cancer patients are 14% more likely to develop gastric cancer than others (OR=1.14; 0.29–4.42).

In the studies, alcohol consumption increased (OR=2.03; 0.44–9.31) times the chance of developing gastric cancer (Table 4). It should be noted that, due to the legal prohibition of alcohol consumption in Iran, under-reporting may be found in the studied investigations (Table 4).

Low Economic Level and Food Insecurity

In a survey in Iran, farmers and ranchers are considered to be high risk occupations in the prevention of gastric cancer. Findings suggest that gastric cancer is more common in underclass and lower socioeconomic groups.20,36 Increasing food insecurity in developing countries like Iran is due to lower economic levels and rising food costs. As the prevalence of food insecurity in Iran is estimated to be around 50%,37 it is important to note that food insecurity is associated with low economic levels.38 Because of the fat that income is an important factor to access adequate food in the community, people with higher economic status can have more choice in their diet.39 For this reason, Iranian policymakers have emphasized the need to improve the economic status by the resistance economy.40 Based on studies of low levels of economic and food insecurity, the odds of developing gastric cancer by 2.42- and 2.57-times is increasing, respectively (Table 4).

Family History and Blood Type A+

Family history is an important predictor of gastric cancer. Families with a history of gastric cancer have unique clinical manifestations.41 Disease among young people of Iranian families with gastric cancer emphasize the role of family history in disease.42 At the same time, family members experience similar environmental and lifestyle conditions. Family history of gastric cancer may not necessarily be related to genetic effects,43 because environmental factors such as H. pylori infection play a more important role than genetic effects.44 In the studied investigation, family history increased 2.12-times the chance of developing gastric cancer (Table 4). According to the studies, the prevalence of blood type A in an Iranian population is 30.25%.27,45 In this survey, blood group A+ was 18.8% (Table 4).

Epstein-Barr Virus (EBV) and HTLV-1

EBV prevalence in gastric cancer patients ranged from 6.25–6.6% (Table 4). Studies in Iran show low prevalence of EBV among GC patients.46 This is estimated to be between 3–6.66%.47 The differences in EBV abundance reflect socio-economic, health and cultural differences in individuals,48 hence the relationship between incidence of GC and EBV in different regions may reflect epidemiological and clinical-pathological factors, dietary habits and, ultimately, genetic differences.49 Epidemiological studies indicate HTLV-1 is endemic in some part of Iran such as Khorasan, where HTLV are reported as around 0.77–1.7% in blood donors of different regions.50 The prevalence of blood group A was 18.8% (Table 4).

Diet

Studies have shown an inverse relationship between citrus fruits, fresh fruits, garlic consumption, and gastric cancer (Table 4). Fruits are rich in antioxidants due to their fiber, vitamins, and minerals that can prevent initiation or progression of cancer.51–53 Ascorbic acid and carotene in vegetables and fruits can eliminate nitrite.54 Consuming some vegetables such as onions less than twice a week does not have any protective effect for this cancer (OR=1.28; 0.73–2.23). This is ambiguous, but may be related to the constituents of the soil (Table 4).

According to several studies, there is also a direct relationship between consumption of processed red meat, dairy products, fruit juice, smoked and salty fish, grain, strong and hot tea, and salt consumption, with a chance of incidence of gastric cancer (Table 4). Meats that are cooked at high temperatures such as frying and kebabs produce various types of carcinogens such as polycyclic aromatic hydrocarbons that cause gastric cancer.56 Also, salt by stimulating and damaging gastric mucosal tissue is effective in the development of gastric cancer.55 It should be noted that canned foods, spicy pickle, and animal protein are the dominant food among Iranian populations.56 Pickles are an important risk factor for gastric cancer due to their high salt and nitrate compounds. It should be noted that the ingredients of pickles vary from country to country due to the amount of vegetables, salt and acidity.57

Studies have found a direct relationship between pickling and gastric cancer (Table 4) (OR=1.47; 0.84–2.58). Some surveys in Iran show low levels of selenium in gastric cancer patients.58 The protective effect of selenium on cancer may be due to oxidative stress and DNA damage reduction, recovery of damaged DNA and apoptosis through the p53 tumor suppressor gene and induction of Phase II enzymes to detoxify carcinogenic cells.59 Investigations show protein intake reduces the chance of gastric cancer (Table 4). High protein intake in a low-income Iranian rural population indicates a healthy lifestyle.60 In addition, vitamins and minerals play an important role in preventing tumorigenesis. Iron or detoxification of oxidative free radicals can prevent DNA damage.61 Irregular food intake appears to cause gastric ulcers, which is not unexpected if gastric cancer is not treated in the long-term. The findings of the studies confirm the above (Table 4).

Age

GC is more common in people over 50 years of age62 and is more common in people between the ages of 70 and 80 years. The incidence of GC is also increasing at ages younger than 20 and 40 years.63 In general, the highest incidence of GC is observed in the fifth and sixth decades of life, while the risk is reduced at ages younger than 44.15 According to some investigations, the risk ratio of GC in older people is eight times higher than in other age groups (HR=8.0; 2.7–23.5) (Table 4).

Achalasia

Achalasia is the most well-known esophageal motor disease. Many patients are treated for gastroesophageal reflux disease before detection of achalasia. Gastric adenocarcinoma is the most common malignancy causing pseudo-achalasia.64 In conducted surveys, patients with achalasia are 97% more likely to have GC other than those who do not have achalasia (Table 4).

Unwashed Hands After Defecation

Studies show that unwashed hands increase the odds of developing gastric cancer by 2.61-times (OR=2.61; 1.43–4.76) (Table 4). In recent decades, hand-eating has become very common in Iranian culture. Although it is good to wash your hands with water, it is not enough to eliminate contaminated microorganisms after excretion or exposure to toxic substances. Due to the frequent stool excretion and improper hand washing, the emergence of diseases associated with infected microorganisms (H.pylori) such as gastric ulcer or gastric cancer are expected.65

History of X-Ray Dye Exposure and History of CT Scan Encounter

The use of modern technology such as computed tomography and radiography in the diagnosis of diseases has been widely observed in recent decades, irrespective of its side-effects and subsequent consequences.66 According to the study, the odds of developing gastric cancer as a consequence of advanced technology are 91% and 39%, respectively (Table 4).

Genetics

mi-RNAs are a subset of non-coding RNAs that contain approximately 22 nucleotides. They also play important functions in various cellular processes including differentiation, proliferation, and apoptosis; furthermore, they play an important role in the development of some cancers, including GC.

Disruption in the regulation of genes such as miR-383 is associated with cancer.67 It appears that more than one-third of the genes encoding human protein are controlled by mi-RNAs and have their genetic pathways exerting their effects.68

In H-pylori-infected individuals, IL-18mRNA and IL-18 levels in gastric mucosa are increased,69 so that IL-18 cytokines increase inflammatory conditions in chronic diseases with immune pleiotropic function,70 and directly increase the IL-1, IL-6, and TNF-a cytokine from macrophages, promoting GC progression.71 According to research, mi-RNAs group genes are the most GC related genes (Table 5).

Table 5

Genes Associated with Gastric Cancer in Iran

First Author(Year)(Reference Number)	Gene
Kulsom Ahmadi (2017)139	DNMT3B −579 G>T
Shirin Azarbarzin (2017)140	miR-383
Shirin Azarbarzin (2016)67	miR-299-5p
Fatemeh Azarkhazin (2017)141	Casp8 and Apaf1
Ramin Azarhoush (2008)142	p53
Malek H. Asadi (2010)143	OCT4
Ahmad Ismaili (2015)144	IL-1B+3954
Saeed Mahboubi Aghdam (2014)145	oipA and iceA2
Hassan Akrami (2016)146	PI3K/Akt1 and p38MAPK
Sakineh Amoueian (2015)147	CD56, CD68, CD117 and CD1a
Mohammad Amini (2019)148	GHSR DNA
Mostafa Iranpour (2019)149	PI3KCA
Nooshin Ayremlou (2015)150	miR-107
Ali Basi (2012)151	HER2
Nader Bagheri (2013)71	IL-18 mRNA
Vahid Bagheri (2019)152	mRNA
Nader Bagheri (2014)153	TLR-4
Nader Bagheri (2018)154	MMP-3 and MMP-9
Seyedeh Zahra Bakhti (2015)154	vacA 3ʹ-end
Gholam Basati (2017)155	PPARγ
Zeinab Basiri (2014)156	vacA d1
Ali Bahadori (2017)157	cagPAI and vacA
Ali Bahadori (2017)158	cagPAI and vacA
Bahari (2015)159	MIR17HG
Mohammadreza Beheshtizadeh (2017)160	G3BP1 and VEZT
Shahab Bohlooli (2012)161	KYSE30
Modjtaba Emadi Baygi (2012)162	MTDH
Sanaz Savabkar (2013)163	PD-1.5C/T (rs2227981, +7785)
Ghasem Janbabai (2015)164	EGFR, ErbB2 and MET
Naser Jafargholizadeh (2017)165	LC3 mRNA
Fereshteh Jafar (2008)166	vacA
Milad Javanbakht (2017)167	Oct-4 and MUC5AC
Fereshteh Jeivad (2012)168	tyrosine kinas
Mina Rezaee Cherati (2017)169	N58E59
Nasim Hafezi (2015)170	CD1d
Maryam Habibzadeh (2017)171	TLR2-196 to -174 ins/del, Arg753Gln and Arg677Trp
Afshin Habibi (2015)172	CD34
Asghar Hosseinzadeh (2016)173	mRNA
N. R. Hussein (2010)174	dupA
Mohammad Reza Haghshenas (2009)175	(IL)-18
Khatoon Heidari (2017)176	BabA2, Hpa
Abdulkuddous Heydari-Mehrabadi (2018)177	ASIC1 and IL-6
Fatemeh Khatami (2009)178	DNA methyltransferase 1
Malihea Khaleghian (2015)179	C-MYC
Mitra Khalili (2015)180	miR-302, miR-145, SOX2, c-MYC, and P21
Mitra Khalili (2012)181	Mir-302b
Maryam Daneshpour (2018)182	miR-106a and let-7a
Zohreh Salehi (2017)183	miRNAs
Sabahi (2010)184	MDR1
ahra Sedarat (2018)185	HopQ and SabA
Negar Souod (2013)186	cagA and vacA
Reza Safaralizadeh (2017)187	miR-216a and miR-217
Amin Talebi Bezmin Abadi (2011)188	cagA, homA, and homB
Amin Talebi Bezmin Abadi (2012)189	dupA
Amin Talebi Bezmin Abadi (2013)190	babA2
Saeid Abediankenari (2013)191	EGFR
Esmat Abdi (2016)192	babA2
Rana Ezzeddini (2019)193	HIF-1α and SREBP-1c
Hosein Effatpanah (2015)194	mir-21 and mir-221
Akbar Oghalaie (2016)195	HP0175
Hossein Dabiri (2017)196	vacA, cagA, cagE, oipA, iceA, babA2 and babB
Dardaei Alghalandis (2009)197	CEA
L. Dardaei (2011)198	CEA, CK20, TFF1 and MUC2
Mehdi Nikbakht Dastjerdi (2015)199	PLC/PRF5
Masoumeh Douraghi (2009)200	vacA intermediate region cagA Anti-VacA
Mahboobeh Razmkhah (2013)201	SDF-1alpha G801A
Masoumeh Rostami (2013)202	H-ras
Ali Zare (2018)203	miR-335, miR-124, miR-218 and miR-484
Ali Zare (2019)204	miR-155-5p, miR-15a, miR-15b, and miR-186
Seiran Zandi (2018)205	sirt2
Alireza Sadjadi (2013)206	Serum Ghrelin
Iraj Saadat (2001)207	GSTM1 and GSTT1
Azam Soleimani (2016)208	miR-146a
Sareh Sohrabi (2017)209	PTEN and CDKN1C/p57kip2
Zahra Shahhoseini (2016)210	rs3130932
Samaneh Saberi (2012)211	MTHFR C677T
Zeinab Imani-Saber (2015)212	PML
Mohammad Masoudi (2009)213	GSTM1 GSTO2 GSTT1
Mehdi Moghanibashi (2012)214	TFF1
Meysam Moghbeli (2014)215	hMLH1 and E-Cadherin
Meysam Moghbeli (2019)216	ErbB1 and ErbB3
Sharareh Mokmeli (2016)217	ERCC1 C8092A
Zahra Malek-Hosseini (2015)218	IL-17A
Maryam Mansoori (2015)219	ABCB1
Seyedeh Habibeh Mirmajidi (2015)220	bcl2
Rouhallah Najjar Sadeghi (2010)221	p53
Nowruz Najafzadeh (2015)222	CD44
Seyedeh Elham Norollahi (2017)223	WNT16
Mina Noormohammad (2016)224	miR-222
Parvaneh Nikpour (2013)225	MSI1
Parvaneh Nikpour (2014)226	EYA1
Parvaneh Nikpour (2012)227	ZFX
Mohammadreza Hajjari (2013)228	SUZ12
Akbar Hedayatizadeh-Omran (2018)229	P53
Abolghasem Hadinia (2007)230	CTLA-4
Alireza Andalib (2013)231	anti-CCR5, anti-CXCR3, anti-CCR3 and anti-CCR4
Roya Kishani Farahani (2015)232	IGF-1
Shirin Farjadian (2018)233	HLA-G
Mahdie Hemati (2019)234	Q192R and L55M
Sahar Honarmand-Jahromy (2015)235	CagA EPIYA-C
Saeid Latifi-Navid (2013)236	vacA d1/-i1
Batool Mottaghi (2016)236	vacA i
M. Motovali-Bashi (2015)238	GT-repeat
Mojtahedi (2010)239	p53
Maedeh Mohsenzadeh (2017)240	RAR-β
Saghar Mohammadi (2017)241	SIRT3
Farideh Mohammadian (2016)242	miR-18a, miR-21 and miR-221
Ashraf Mohamadkhani (2013)243	Pepsinogen I, Pepsinogen II
Mohammadi (2015)244	mRNA
Seyed-Hamid Madani (2015)245	Her2-neu
Mohammad-Taher Moradi (2014)246	p53,MDM2 SNP309
Mohammad-Taher Moradi (2015)247	MnSOD Val-9Ala
Mohammad-Taher Moradi (2017)248	GPX1 Pro198Leu
Hamid Ghaedi (2018)249	miRNAs
Nasrin Gharaati-Far (2017)169	cationic lipids-mediated
Ghalandary M (2015)250	CBX8
Seyed Mohammad Hossein Kashf (2015)251	IL-16
Dor Mohammad Kordi Tamandani (2015)252	THRβ
Elham Kalantari (2017)253	Lgr5, DCLK1
Behnam Kamalidehghan (2006)254	DmtDNA4977
Sholeh Kiani (2018)255	CDX1 and CDX2
Pegah Larki (2018)256	miR-21, miR-25, miR-93, and miR-106b
Rajeeh Mohammadian Amiri (2016)257	NOD1 and NOD2
Seyedeh Habibeh Mirmajidi (2016)258	Bcl2
Dor Mohammad Kordi-Tamandani (2014)259	CTLA4

Conclusion

Given the high incidence of GC in Iran, changing lifestyle and decreasing consumption of preservatives in food, increasing consumption of fruits and vegetables, and improving lifestyle can be effective in reducing the incidence of this disease.