Esophageal cancer genetics in South Africa

Figures & data

Figure 1 Incidence and mortality rates of EC.

Notes: (A) Worldwide in both sexes and (B) in men and women in Africa. The highest incidence rate is in South Africa and East Africa, with the highest incidence in both sexes being found in Kenya, Uganda and Malawi. A high incidence rate of EC is found in both sexes in Guinea Bissau. (C) The incidence and mortality rates per 100,000 in South Africa and the Eastern Africa and Southern Africa regions is much higher in males than in females.⁴
Abbreviation: EC, esophageal cancer.

Table 1 Alcohol consumption and tobacco use in China and South Africa

		Males					Females
		Number of new cases		Crude incidence/100,000		ASIRW	Number of new cases			Crude		ASIRW
China^Citation184		13,161		26.46		18.03	5,763			10.85		5.81
South Africa^Citation185		848		3.2		4.7	650			2.35		2.67
China
Alcohol per capita (15+) consumption (in liters of pure alcohol)^Citation2
	Average 2003–2005				Average 2008–2010			Males			Females
	4.9				6.7			10.9			2.2
Prevalence of smoking any tobacco product among persons aged ≥15 years^Citation186
	Male			Female							Total 2015
	2000		2015	2000					2015
	55.8		47.6	3.5					1.8		25.3
South Africa
Alcohol per capita (15+) consumption (in liters of pure alcohol)^Citation2
	Average 2003–2005				Average 2008–2010			Males			Females
	10.1				11.0			11.4			4.2
Prevalence of smoking any tobacco product among persons aged ≥15 years^Citation186
	Male			Female							Total 2015
	2000		2015	2000					2015
	35.3		31.4	12.5					6.5		18.4

Notes: The amount of pure alcohol consumed per capita and the prevalence of tobacco use in China and South Africa are presented in the above table. For alcohol consumption, data are shown for the periods 2003–2005 and 2008–2010 and for males and females in 2010. The trend observed in both countries is an increase in alcohol consumption over time.¹⁸⁷ In terms of tobacco use, data are given as percentages of the population that uses tobacco.

Abbreviations: ASIRW, age-standardized incidence rate by world standard population.

Figure 2 Geographic locations of the four high-risk areas in China.

Notes: The counties Cixian, Shexian and Linxian are located on the borders of the Henan and Hebei provinces. These three counties are located in an area with a radius of 60 km. The Taihang Mountains straddle the border of the Shanxi and Hebei provinces and have some of the highest mortality rates of esophageal cancer in the world. Another high-risk area for esophageal cancer is Yanting in Sichuan Province. Data from Lin et al.³⁷

Table 2 Comparison of the risk factors for adenocarcinoma and ESCC

Factor	Adenocarcinoma	ESCC
Gastroesophageal reflux disease	Approximately 6-fold increased risk, mainly in young adults^Citation188	50 times greater risk^Citation188
Obesity	Strong increase in associated risk, linked to abdominal apidosity^Citation189	Increased BMI commonly associated with a decreased risk of developing ESCC. May be due to reverse causation or other confounding factors^Citation190
Tobacco smoking^Citation115,Citation118,Citation121	Strong associated risk. Quitting smoking for 10 years or longer reduces the risk greatly^Citation189	Greatly increased risk. From 3- to 9-fold increase in relative risk^Citation190
Alcohol	No increase in risk^Citation189	Consumption of alcohol increases the risk of developing ESCC between 2- and 6-fold^Citation190
Diet	Increased dietary fat increases the risk of adenocarcinoma. Nutrients such as vitamin C, magnesium, folate, vitamin B6 and iron decrease the risk of adenocarcinoma^Citation189	Most studies on specific foodstuffs show no relationship with ESCC risk. Fruits and vegetables decrease the risk of developing ESCC. Hot beverages and foods increase the risk of developing ESCC.^Citation190 Pickled vegetable consumption leads to an increase in the risk of developing ESCC. It is suspected that mycotoxin contamination occurs during the pickling process.^Citation190 Consumption of foods contaminated with Fusarium mycotoxins may lead to increased risk of ESCC
Exercise	Reduced risk^Citation191	No clear association^Citation191
Helicobacter pylori infection	H. pylori decreases the risk of adenocarcinoma^Citation192	No significant association between H. pylori infection and ESCC^Citation193
Reproductive, sex-related factors	Menopause, oral contraceptives and hormone therapy all reduce the risk^Citation194	Hormone therapy and menopause may have protective effects^Citation190
Medicines	Both NSAIDs and statins decrease the risk of adenocarcinoma^Citation189	Aspirin has been shown to reduce the risk and mortality of ESCC^Citation195

Abbreviations: BMI, body mass index; ESCC, esophageal squamous cell carcinoma.

Table 3 Genetic polymorphisms affecting the genes related to changing the risk of developing esophageal cancer in South Africa and China

Country and polymorphism	OR	Environmental factors	Postulated mechanisms/effect
PLCE1 is involved in the regulation of cell growth, differentiation, apoptosis and angiogenesis
China
rs10882379^Citation196 GG => GA GG => AA GG => A/AA	At 95% CI 0.68 0.69 0.75	No association with smoking and alcohol use	SNP is in the promoter region/decreased ESCC risk
rs829232^Citation196 GG => GA GG => AA GG => GA/AA	At 95% CI 1.32 1.88 1.42	No association with smoking and alcohol use.	SNP is in the promoter/increased ESCC risk
rs2274223 at 10q23^Citation43 AA => AG AA => GG AA => AG/GG	At 95% CI 1.27 1.47 1.30	No association with environmental factors	SNP in exon 26 of PLCE1 gene is associated with increased risk of ESCC. AG and GG genotypes lead to lower PLCE1 mRNA and protein levels
rs11187870^Citation197 GG => CG GG => CC GG => CG/CC	At 95% CI 1.1 1.54 1.21	No association with environmental factors	SNP is in the 3′UTR. Associated with increased risk of ESCC
South Africa
Arg548Leu (rs17417407)^Citation198	0.75 at 95% CI	No evidence for an association with smoking or alcohol	Associated with a reduced risk of ESCC in the black population
NAT1 and NAT2 are the main Phase II xenobiotic metabolizing enzymes involved in either detoxification or activation of carcinogenic arylamines
China
NAT2 rs1565684^Citation199 T > C SNP CC = TC/CC	At 95% CI 1.14 1.77	Alcohol consumption had no effect on ESCC risk	Genotype was associated with an increased risk for ESCC
South Africa
NAT2 341 CC (rs1801280)^Citation200 Mixed ancestry black	At 95% CI 0.31 0.55	In the black population group, smokers with this mutation had a higher risk of ESCC	Mutation resulted in decreased acetylation activity and reduced the risk for EC in mixed ancestry group
NAT1 and NAT2 slow/intermediate acetylation phenotype^Citation200	0.44 at 95% CI		NAT2 slow/intermediate acetylation/reduced risk of ESCC in mixed ancestry group
CASP8 is an initiator of CASP3, a key regulator of apoptosis, and is important in cancer development and progression
China
rs1035142 G>T^Citation201 Heterozygote Homozygote	At 95% CI 1.55 2.34		Associated with an increased risk of ESCC by negatively affecting the cells’ ability to undergo apoptosis
South Africa
(−652 6Ndel:302His)^Citation90	2.37 at 95% CI	Associated with ESCC in current smokers, but not in former smokers	Haplotype associated with ESCC in mixed ancestry population
Asp302His (rs1045485)^Citation90	1.42 at 95% CI		Suggestive association with increased ESCC risk in mixed ancestry population
p53 can induce cell cycle arrest for DNA repair and/or apoptosis in response to cellular stress such as DNA damage or hypoxia
China
Arg72Pro (rs1042522)^Citation6,Citation9,Citation97,Citation202 Pro/Arg vs Pro/Pro Pro vs Arg Pro/Pro vs Arg/Arg + Arg/Pro Pro/Pro vs Arg/Arg Pro/Pro vs Arg/Pro	At 95% CI 1.01 1.83 1.17 1.32 1.35	No significant association with tobacco use	Increased risk of EC in Han Province. Associated with Burkitt’s lymphoma
rs2909430^Citation203	1.94 at 95% CI		Commonly observed in ESCC patients in high-risk area of China
rs78378222 A => C^Citation203	3.22 at 95% CI
Polymorphisms in exon 4^Citation204 C => A, codon 34 G => C, codon 36 G => C, codon 72	At 95% CI 1.03 1.86 0.8	Reactive mutagenic compounds form DNA adducts, which can cause nucleotide changes. TP53 plays an important role responding to DNA damage. Loss of function mutations will increase the threat posed by carcinogens	Strongly associated with EC
Small deletions, insertions and point mutations resulting in frame shifts or amino acid changes in exons 5–8^Citation204			Commonly observed in ESCC patients
16 bp duplication in intron 3 resulting in loss of heterozygosity^Citation204	14 at 95% CI		Commonly observed in ESCC patients

Abbreviations: EC, esophageal cancer; ESCC, esophageal squamous cell carcinoma; rs, reference SNP cluster ID; SNP, single-nucleotide polymorphism.

Table 4 Genetic polymorphisms in alcohol metabolizing enzymes associated with EC in South Africa and China

Country and polymorphism	OR	Environmental factors	Postulated mechanisms/effect
ALDH2 is responsible for the conversion of acetaldehyde to nontoxic acetate
China
rs671 at 12q24^Citation205,Citation206 GG => AA GG => GA	At 95% CI 0.67 0.85	No evidence for an association with smoking or alcohol	Mutation increases the risk of ESCC in Kazak and Han populations and leads to a poor ESCC prognosis in Kazak population. The variant A allele of rs671 has a reduced ability to metabolize acetaldehyde
ALDH2*2 E487K^Citation87,Citation88 AA => GG	At 95% CI 0.26	There was a difference in tobacco and alcohol use between patients and controls	ALDH2*2 allele results in a glutamate to lysine substitution, leading to an increased risk for EC
ALDH2 (*1/*2)^Citation207 1510G > A487	At 95% CI 2.89	Inactive ALDH2 with moderate to heavy drinking led to a 8.58-fold higher ESCC risk	Genotype frequencies of the inactive enzyme (GA heterozygote) are higher in male patients with ESCC
South Africa
ALDH2*2 results in an allele E487K results in change of glutamate to lysine^Citation89	2.35 at 95% CI	Associated with increased sensitivity to alcohol consumption	The low activity of ALDH2*2 allele is significantly associated with increased risk for EC among black subjects
ALDH2 (rs886205)^Citation90 +82 G > A	At 95% CI 0.70	Nominal evidence of association with ESCC in current smokers	Significantly associated with a reduced risk of ESCC in the mixed ancestry population
ADH catalyzes the reversible oxidation of alcohols to corresponding aldehydes or ketones
China
ADH1B (*1/*1) (rs1229984) *2 mutant allele results from an SNP in Exon 3 of ADH1B, resulting in histidine to arginine change at codon 48^Citation207	3.67 at 95% CI	Moderate-to-heavy drinkers with the less-active ADH1B *1/*1 genotype had significantly increased risk of cancer	The polymorphism influences the enzyme activity. The less-active enzyme is associated with an increased ESCC risk in males
(Arg) at codon 48 8^Citation7	1.67 at 95% CI	There was a significant risk for ESCC attached to alcohol consumption	Increases the risk of EC
ADH1C rs1789924^Citation205	1.20 at 95% CI	Significantly associated with smoking	The variant T allele significantly increases ESCC risk. Rs1789924 is located at 5′ near the gene ADH1C, and is predicted to affect the binding of transcription factor
South Africa
ADH3*2/*2^Citation89	2.19 at 95% CI		Is significantly associated with increased risk for EC in black patients
ADH1B Arg48His (rs1229984)^Citation90	0.52 at 95% CI	Associated with ESCC in current smokers	Is associated with decreased ESCC risk in a mixed ancestry population

Abbreviations: EC, esophageal cancer; ESCC, esophageal squamous cell carcinoma; rs, reference SNP cluster ID; SNP, single-nucleotide polymorphism.

Table 5 GST polymorphisms involved in esophageal cancer

Gene/mutation	OR	Interaction with environmental factors
GSTP1
rs1695^Citation208
rs1138272^Citation208
South Africa
GSTP1*D (rs1138272) Ala113Val (341C4T) in exon 6^Citation209,Citation210 341 C/T 341 T/T	At 95% CI 4.98 10.9	Increased risk in both black Xhosa and mixed ancestry populations in South Africa
313G divergence^Citation211,Citation212	3.60	Decreased activity of the GSTP1 variant within the tobacco smokers, alcohol users or those utilizing wood or charcoal for cooking and heating has a higher risk of developing ESCC
GSTM1
South Africa
GSTM1 null genotype (GSTM1*0) 15 kb omission^Citation209,Citation213	1.71 at 95% CI	The homozygous GSTM1*0 genotype is correlated with a decreased risk for ESCC among mixed ancestry people, whereas no expression of GSTM1 is associated with an increased risk of ESCC occurrence in the Black Xhosa population
China
GSTM1 null genotype (GSTM1*0) 15 kb omission^Citation211	2.17 at 95% CI	GSTM1 null genotype is associated with an increased risk for ESCC in Jiangsu Province
GSTT2 gene
South Africa
GSTT2B null genotype (GSTT2B*0) 37 kb omission^Citation210,Citation214	0.71 At 95% CI	GSTT2B deletion allele is observed at frequencies of 37% and 50% in black Xhosa and mixed ancestry individuals, respectively. The GSTT2B null genotype does not alter the risk for ESCC in the black Xhosa population, but it is linked with a significantly reduced risk in the mixed ancestry group

Note: The table lists the polymorphisms affecting the three GST genes GSTP1, GSTM1 and GSTT2 in South Africa and China and relates how these polymorphisms affect the risk for esophageal cancer.

Abbreviations: ESCC, esophageal squamous cell carcinoma; rs, reference SNP cluster ID; SNP, single-nucleotide polymorphism.

Table 6 Genetic polymorphisms in DNA mismatch repair genes that influence the risk of developing esophageal carcinoma in South Africa and China

Mutation	OR	Effect on ESCC risk
South Africa
G/G vs A/A or A/G genotype polymorphism in MSH3 rs26279^Citation73	2.71 at 95% CI	Allied with increased ESCC susceptibility in mixed ancestry South Africans
G-allele in PMS1 rs5742938 polymorphism (GG vs AA or AG)^Citation73	1.73 at 95% CI	Allied with increased ESCC susceptibility in mixed ancestry South Africans
A-allele in MLH3 rs28756991 polymorphism (AA or GA vs GG) Arg797His^Citation73	2.07 at 95% CI	Allied with increased ESCC susceptibility in mixed ancestry South Africans. Compromises the structure and function of MLH3 protein. The ternary complex formed between heterodimers MSH2–MSH3 and MLH1–PMS1 is a critical incident in ESCC development
China
DNA mismatch repair gene MSH2 (MSH2c.2063G)^Citation153	3.36 at 95% CI	Polymorphisms increase the risk for EC
DNA mismatch repair gene MLH1 (MLH1IVS14-19G)^Citation153	1.70 at 95% CI	Polymorphisms increase the risk for EC
DNA lesion repair enzyme MGMT gene MGMT Rs11016879^Citation152,Citation153 AA vs GG AG vs GG Rs12771882 AA vs GG Rs7075748 (CT vs CC) Rs11016878 AG vs AA Rs7069143 CT vs CC Rs7071825 GG vs AA	At 95% CI 3.11 3.93 2.44 1.95 0.39 0.48 0.49	Some polymorphisms in the gene lead to increased risk of developing ESCC, while others have a protective function decreasing the risk for ESCC
MGMT^Citation153 A allele Rs10734088 C allele Rs475111	At 95% CI 1.97 2.18	Significantly increase the risk for developing ESCC
MGMT A allele Rs2053139^Citation153	0.51 at 95% CI	Associated with a protective effect on ESCC progression
MGMT C allele Rs7068306^Citation152,Citation153	2.20 at 95% CI	Increased risk of ESCC metastasis
WRN gene^Citation215 (WRN c.4330TC)	2.21 at 95% CI	Significantly increased risk for developing ESCC

Note: The table describes genetic polymorphisms in DNA repair pathway genes that are found in South African and Chinese populations.

Abbreviations: ESCC, esophageal squamous cell carcinoma; rs, Reference SNP cluster ID; SNP, single-nucleotide polymorphism.

Table 7 Genetic polymorphisms in CYP/CYP450 genes relating to ESCC in South Africa and China

Country and polymorphism	OR	Interaction with the environment	Effect on ESCC risk
<a>CYP2E1
1053C > T (rs2031920)^Citation216 1293G > C (rs3813867)^Citation216	5.04		Changes in the 5′ UTR of the gene changes the transcription of the gene
China
(*c1/*c1) homozygote (*c1/*c2) heterozygote (*c2/*c2) mutated homozygote^Citation207,Citation217	2.89	In moderate-to-heavy drinkers, the CYP2E1 (*c1/*c1) genotype significantly increased the risk of cancer	The c1/c1 genotype correlated with susceptibility to EC. Differences in CYP gene expression may contribute to individual susceptibility to procarcinogens
South Africa
CYP2E1 (*c1/*c1)^Citation158			Genotype frequencies were higher among patients with ESCC
<a>CYP3A
China
CYP3A5*3A A6986G, C31611T^Citation160		Found in 65%–73% of Chinese individuals	Splicing defect preventing expression
CYP3A5*3C A6986G^Citation160		Found in 70% of Chinese individuals	Splicing defect preventing expression
CYP3A5*4 A14665G Q200R^Citation160		Found in 0.9% of Chinese individuals
CYP3A5*5 T12952C^Citation160		Found in 0.9% of Chinese individuals	Splicing defect leading to alternatively spliced mRNA
South Africa
CYP3A5 *1/*1 CYP3A5 *1/*3 CYP3A5 *1/*6 CYP3A5 *1/*7 CYP3A5 *3/*3 CYP3A5 *3/*6 CYP3A5 *3/*7 CYP3A5 *6/*6 CYP3A5 *6/*7	1.00 1.97 1.37 4.67 0.84 1.17 0.90 0.81 2.92	Black subjects are more likely to convert environmental toxins they are exposed to into more reactive intermediates that may play a role in the initiation of EC	A potentially high CYP3A5 activity may increase EC risk. CYP3A5 mutant alleles are associated with reduced risk for EC^Citation158,Citation160,Citation162,Citation164
CYP3A homozygous (GG) heterozygotes (GA)^Citation158			Declined ESCC risk in homozygous Increased risk of ESCC in heterozygous
<b>CYP1A1
CYP1A1 MspI^Citation218 C vs T CC + CT vs TT	1.25 1.35		Polymorphism increases the risk of ESCC
CYP1A1 exon 7 Val/Val^Citation31	3.35	CYP1A1 Val/Val genotype had synergic interactions with tobacco and alcohol consumption	Individuals carrying CYP1A1 Val/Val genotype compared to those with CYP1A1 Ile/Ile genotype had an increased risk for EC

Abbreviations: EC, esophageal cancer; ESCC, esophageal squamous cell carcinoma; rs, reference SNP cluster ID; SNP, single-nucleotide polymorphism.

Table 8 The extent to which different risk factors influence the odds of developing ESCC in Swedish males and females¹⁶⁵

Risk factor	OR at 95% CI
	Male	Female
Obesity	5.4	10.3
Smoking	2.8	5.3
Reflux	3.4	4.6

Abbreviation: ESCC, esophageal squamous cell carcinoma.

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