Tumor Biol. (2014) 35:12665–12670 DOI 10.1007/s13277-014-2590-9
RESEARCH ARTICLE
The ALDH7A1 genetic polymorphisms contribute to development of esophageal squamous cell carcinoma Haiyong Wang & Lei Tong & Jinyu Wei & Wenting Pan & Lichao Li & Yunxia Ge & Liqing Zhou & Qipeng Yuan & Changchun Zhou & Ming Yang
Received: 25 July 2014 / Accepted: 3 September 2014 / Published online: 12 September 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Although the entire etiology of esophageal squamous cell carcinoma (ESCC) is still unclear, alcohol drinking has been identified as a major environmental risk factor. The aldehyde dehydrogenase (ALDH) superfamily members are major enzymes involved in the alcohol-metabolizing pathways. Accumulating evidences demonstrated that ALDH7A1, one of ALDH superfamily members, degrades and detoxifies acetaldehyde generated by alcohol metabolism and have been associated with development and prognosis of multiple cancers. However, it is still unknown if ALDH7A1 single nucleotide polymorphisms (SNPs) contribute to ESCC susceptibility. In this study, we examined the association between sixteen ALDH7A1 SNPs and risk of developing ESCC. Genotypes were determined in 2,098 ESCC patients and 2,150 controls (three independent hospital-based case–control sets from different regions of China). Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by logistic regression. Our data demonstrated that only the ALDH7A1 rs13182402 Haiyong Wang, Lei Tong, and Jinyu Wei contributed equally to this work. H. Wang : J. Wei : W. Pan : L. Li : Y. Ge : Q. Yuan : M. Yang (*) State Key Laboratory of Chemical Resource Engineering, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, P. O. Box 53, Beijing 100029, China e-mail: [email protected] L. Tong Cardiothoracic Surgery of Bethune International Peace Hospital, Shijiazhuang, Hebei Province, China L. Zhou Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian, Jiangsu Province, China C. Zhou (*) Clinical Laboratory, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China e-mail: [email protected]
SNP confer susceptibility to ESCC (For AG genotype, OR= 0.75, 95 % CI=0.66–0.91, P=4.8×10−6; for GG genotype, OR=0.59, 95 % CI=0.41–0.88, P=0.003). These results are consistent to the biological functions of ALDH7A1 during alcohol metabolism and carcinogenesis. Keywords ALDH7A1 . Genetic polymorphism . ESCC . Susceptibility
Introduction As one of the most common malignant tumors worldwide, esophageal squamous cell carcinoma (ESCC) shows a relatively high incidence in Eastern Asian compared to Western countries [1]. The entire etiology of ESCC is still unclear. However, it has been found that alcohol consumption, tobacco smoking, micronutrient deficiency, and dietary carcinogen exposure are known risk factors of this lethal malignancy [2, 3]. High temperature of meals and drinks, limited Vitamin C intake, and low consumption of vegetables and fruits were strong risk indicators of ESCC in Chinese populations. Moreover, the strength of tea and overall tea consumption were independent determinants of the ESCC risk [2, 3]. Nevertheless, only a part of exposed individuals finally develop ESCC, indicating that genetic factors may also contribute to ESCC etiology. This has been proven by multiple ESCC genome-wide association study (GWAS) and candidate gene-based studies [4–9]. The oxidation and detoxification of a great variety of endobiotic and xenobiotic aldehyde compounds are catalyzed by the aldehyde dehydrogenase (ALDH) superfamily [10]. As highly reactive substances, aldehyde compounds could induce multiple cellular damages, such as the formation of mutagenic DNA adducts [11, 12]. Thus, deregulation of ALDH enzymes might contribute to malignant transformation of normal cells. The ALDH7A1 gene encodes an enzyme of the ALDH
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superfamily, which degrades and detoxifies acetaldehyde generated by alcohol metabolism. Interestingly, abused alcohol consumption has been identified as one of the major risk factors in the word. ALDH7A1 is also highly expressed in prostate cancer cell lines and primary human prostate cancer tissue. Elevated ALDH7A1 expression in prostate cancer bone metastases compared to the matched primary tumors indicates that ALDH7A1 may play a part in both tumor initiation and metastasis initiation in prostate cancer [13]. ALDH7A1 expression was also found to be increased in human papilloma virus-immortalized cervical epithelial cells and nodular melanoma [14, 15]. For lung cancer patients, low ALDH7A1 expression has been associated with decreased cancer recurrence. Among stage I lung cancer patients, negative staining for ALDH7A1 was associated with improved recurrence-free and overall survival [16]. Through interaction with cyclin A, ALDH7A1 could influence permissive G1/S cell-cycle progression [17], suggesting its involvement in cellcycle regulation. ALDH7A1 is polymorphic in human beings. The ALDH and ADH single nucleotide polymorphisms (SNP) influence individual diversity in alcohol-oxidizing capability and drinking behavior [18]. Among the ADH family, the major enzymes involved in the alcohol-metabolizing pathways are alcohol dehydrogenase 1B (ADH1B) and ADH1C. ESCC GWAS data and our previous results both demonstrated the ADH1B-ADH1C-ADH7 cluster is curial ESCC susceptible loci [4, 19]. However, the involvement of ALDH7A1 SNPs in ESCC is still largely unknown. Considering the importance of ALDH7A1 in cancer development and in metabolism of in vivo ethanol, we selected 16 haplotype-tagging SNPs (htSNP) across the whole ALDH7A1 locus and conducted three large independent hospital-based case–control studies to investigate the association between ALDH7A1 genotypes and ESCC risk.
Materials and methods Study subjects This study consisted of three case–control sets: (a) Shandong set, 1,000 cases with ESCC from Shandong Cancer Hospital, Shandong Academy of Medical Sciences (Jinan, Shandong Province, China) and sex- and age-matched (±5 years) 1,000 healthy controls. ESCC cases were consecutively recruited between June 2009 and July 2013 at Shandong Cancer Hospital. Controls were randomly selected from a pool of 4,500 individuals from a community cancer-screening program for early detection of cancer conducted in Jinan city (Shandong Province) during the same time period as the ESCC cases were recruited. (b) Jiangsu set, 588 ESCC cases from Huaian No. 2 Hospital (Huaian, Jiangsu Province, China) and sex-
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and age-matched 600 controls. ESCC cases were recruited between January 2009 and February 2012 at Huaian No. 2 Hospital. Healthy controls were all cancer-free subjects selected from a community cancer-screening program (3,600 individuals) for early detection of cancer conducted in Huaian city. (c) Hebei study, 510 ESCC patients from Bethune International Peace Hospital (Shijiazhuang, Hebei Province, China) and 550 sex- and age-matched healthy controls. ESCC cases were recruited between October 2010 and May 2013 at Bethune International Peace Hospital. Cancer-free controls were individuals who underwent a physical examination in Bethune International Peace Hospital. The diagnosis of all patients was histologically confirmed. Individuals who smoked one cigarette per day for over 1 year were considered as smokers. Subjects were considered as alcohol drinkers if they drank at least once per week. All individuals were ethnic Han Chinese. At recruitment, the informed consent was obtained from each subject. This study was approved by the Institutional Review Boards. SNP selection and genotyping The ALDH7A1 gene covers a 53,550-bp region of chromosome 5q31 and contains many SNPs. Therefore, we used an htSNP approach to analyze the ALDH7A1 polymorphisms globally [20]. Genotyped HapMap SNPs among Han Chinese population (HCB data, HapMap Rel 27, NCBI B36) with a minor allele frequency >5 % were included in the selection. The htSNPs were chosen in a 57,550-bp region (53,550 bp ALDH7A1 locus and 2 kb up-stream as well as 2 kb downstream regions of the ALDH7A1 gene). Sixteen htSNPs were finally selected with Haploview 4.2 software on a block-byblock basis, using a method described previously with the sample size inflation factor, Rh2, of ≥0.8 (Table 1). ALDH7A1 htSNPs were analyzed by the MassArray system (Sequenom Inc., San Diego, California, USA). A 5 % blind, random sample of study subjects was genotyped in duplicates and the reproducibility was 98.5 %. To reduce the costs of the study, we genotyped the ALDH7A1 rs13182402 SNP in the validation sets using the TaqMan assay (C_31889488_10, ABI). Five percent samples were genotyped by two investigators, and the reproducibility was 99.0 %. Statistics To calculate the differences in demographic variables and genotype distributions of sixteen ALDH7A1 SNPs between cases and controls, Pearson’s χ2 test was used. The associations between genotypes of these SNPs and ESCC risk were estimated by odds ratios (ORs) and their 95 % confidence intervals (CIs) computed by logistic regression models. All
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Table 1 HapMap tag-SNPs in the ALDH7A1 locus with HCB data of HapMap Rel 27
Results
No
Test
Alleles captured
1
rs7709115
2 3 4 5 6 7 8 9
rs6898559 rs13182402 rs2306619 rs12514417 rs11241901 rs7715516 rs4836272 rs4626335
rs7709115,rs7736031,rs6595719,rs11742381, rs6870785 rs6898559,rs12513847,rs2306617,rs4379190 rs900641,rs17154671,rs13182402 rs2306619,rs1038378 rs11241902,rs12514417 rs11241901 rs7715516 rs4836272 rs4626335
10 11 12 13 14 15 16
rs2306618 rs4835913 rs4626334 rs4836277 rs1060856 rs1038381 rs4836276
rs2306618 rs4835913 rs4626334 rs4836277 rs1060856 rs1038381 rs4836276
In terms of median age and sex distribution, no statistically significant differences were found between ESCC patients and healthy controls for three hospital-based case–control set (all P>0.05), elucidating that the frequency matching was appropriate (Table 2). More smokers and alcohol drinkers were observed among ESCC cases compared with controls in all three case–control sets (all P57 (>59) Sex Male Female Smoking status Yes No Drinking status Yes No
Pa
Jiangsu case–control set (validation set 1) Cases No. (%)
Controls No. (%)
588
600
288 (49.0) 300 (51.0)
300 (50.0) 300 (50.0)
413 (70.2) 175 (29.8)
428 (71.3) 172 (28.7)
437 (74.3) 151 (25.7)
203 (33.8) 397 (66.2)
334 (56.8) 254 (43.2)
242 (40.3) 358 (59.7)
0.474
Pa
Hebei case–control set (validation set 2) Cases No. (%)
Controls No. (%)
510
550
271 (53.1) 239 (46.9)
279 (50.7) 271 (49.3)
398 (78.0) 112 (22.0)
446 (81.1) 104 (18.9)
381 (74.7) 129 (25.3)
263 (47.8) 287 (52.2)
288 (56.5) 222 (43.5)
228 (41.5) 322 (58.5)
0.725
0.426
0.433
0.678
C rs7715516 C>T rs4836272 C>T rs4626335 C>T rs2306618 T>C rs4835913 A>G rs4626334 C>T rs4836277 T>G rs1060856 G>A rs1038381 C>T rs4836276 A>C
ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control
0.690 0.688 0.647 0.645 0.685 0.626 0.390 0.381 0.758 0.761 0.438 0.441 0.325 0.322 0.457 0.455 0.375 0.373 0.881 0.874 0.487 0.493 0.676 0.673 0.776 0.773 0.768 0.772 0.868 0.875 0.360 0.367
0.280 0.279 0.272 0.270 0.285 0.330 0.372 0.371 0.226 0.228 0.409 0.411 0.512 0.513 0.381 0.382 0.452 0.453 0.110 0.114 0.326 0.321 0.267 0.269 0.194 0.190 0.202 0.205 0.120 0.115 0.394 0.390
0.030 0.033 0.081 0.085 0.030 0.044 0.238 0.248 0.016 0.011 0.153 0.148 0.163 0.165 0.162 0.163 0.173 0.174 0.009 0.012 0.187 0.186 0.057 0.058 0.030 0.037 0.030 0.023 0.012 0.010 0.246 0.243
1.02 (0.86–1.20)
0.834
1.02 (0.87–1.19)
0.818
0.79 (0.67–0.93)
0.003
1.04 (0.92–1.18)
0.544
0.96 (0.80–1.17)
0.704
0.98 (0.86–1.12)
0.792
1.01 (0.89–1.15)
0.873
1.01 (0.88–1.15)
0.921
1.01 (0.88–1.14)
0.923
1.08 (0.84–1.40)
0.526
0.98 (0.86–1.12)
0.816
1.01 (0.86–1.19)
0.872
1.05 (0.87–1.26)
0.638
0.95 (0.79–1.15)
0.603
0.93 (0.73–1.20)
0.576
0.98 (0.86–1.11)
0.750
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
SNP single nucleotide polymorphism, ESCC esophageal squamous cell carcinoma, OR odds ratio, CI confidence interval a
Data were calculated by logistic regression
associated with ESCC risk in either Jiangsu or Hebei Chinese Han population. The odds of having the ALDH7A1 rs13182402 AG or GG genotype in patients was 0.75 (95 % CI=0.62–0.91, P=0.009) or 0.55 (95 % CI=0.29–0.94, P= 0.023) compared with the AA genotype in the Jiangsu set. Similar results were found for ADH1B rs13182402 AG genotype (OR=0.69, 95 % CI=0.51–0.89, P=0.008) in the Hebei validation set. However, rs13182402 GG carriers showed no significantly decreased ESCC risk compared with those carrying the AA genotype in the Hebei set (OR=0.76, 95 % CI= 0.40–1.66, P=0.003) (Table 3). In the pooled analyses (2,098 cases and 2,150 controls), we observed that the rs13182402 AG or GG genotype was significantly associated with ESCC susceptibility (OR=0.75, 95 % CI=0.66–0.91, P=4.8×10−6 or, OR=0.59, 95 % CI=0.41–0.88, P=0.003) (Table 3). All ORs were adjusted for sex, age, smoking, and alcohol drinking status. We also examined whether there are gene-covariant
interactions between the ALDH7A1 rs13182402 genetic variant and age, sex, smoking status, or alcohol drinking history but the results were negative (data not shown).
Discussion In this study, we investigated the association between sixteen ALDH7A1 SNPs and risk of developing ESCC in a two-stage case–control design. To the best of our knowledge, this is the first study to examine the role of ALDH7A1 genetic polymorphism in ESCC carcinogenesis. Among these ALDH7A1 htSNPs, only rs13182402 was significantly associated with decreased ESCC risk in Chinese. In the validation studies, we also found statistically significant association between this genetic polymorphism and ESCC susceptibility in Chinese from different geographic regions. Our observations also
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Table 4 Genotype frequencies of the ALDH7A1 rs13182402 SNP among cases and controls and their association with ESCC risk Studies
Genotypes
Shandong set
AA AG GG
Jiangsu set
Hebei set
Pooled
Cases no. (%)
Controls no. (%)
AA AG
n=1,000 685 (68.5) 285 (28.5) 30 (3.0) n=588 407 (69.2) 165 (28.1) 16 (2.7) n=510 352 (69.0) 144 (28.2) 14 (2.7) n=2,098 1,444 (68.8) 594 (28.3)
n=1,000 616 (61.6) 340 (34.0) 44 (4.4) n=600 366 (61.0) 205 (34.2) 29 (4.8) n=550 338 (61.5) 195 (35.4) 17 (3.1) n=2,150 1,320 (61.4) 740 (34.4)
GG
60 (2.9)
90 (4.2)
AA AG GG AA AG GG
ORa (95 % CI)
Pa
1.00 (reference) 0.80 (0.66–0.91) 0.64 (0.41–0.98)
0.006 0.033
1.00 (reference) 0.75 (0.62–0.91) 0.55 (0.29–0.94)
0.009 0.023
1.00 (reference) 0.69 (0.51–0.89) 0.76 (0.40–1.66)
0.008 0.492
1.00 (reference) 0.75 (0.66–0.91)
4.8×10−6
0.59 (0.41–0.88)
0.003
ESCC esophageal squamous cell carcinoma, OR odds ratio, CI confidence interval a
Data were calculated by logistic regression with adjustment for age, sex, smoking and drinking status
support the hypothesis that the ALDH7A1 rs13182402 SNP is an ESCC susceptibility genetic variant in Chinese populations. There are two studies on the ALDH7A1 SNPs in either type 2 diabetes [21] or osteoporosis [22]. Using a candidate SNP approach, Zhou et al. examined associations between risk of type 2 diabetes and the KCNQ1 rs2237892, AP3S1 rs3756555, MAN2A1 rs2015698, or ALDH7A1 rs2306617 polymorphism in the Chinese Northern Han population. No association was observed for ALDH7A1 rs2306617 in 537 unrelated individuals with type 2 diabetes and 510 normal controls [21]. For osteoporosis, Guo et al. performed a case– control GWAS in 700 elderly Chinese Han subjects (350 with hip OF and 350 healthy matched controls). A follow-up replication study was conducted to validate our major GWAS findings in an independent Chinese sample containing 390 cases with hip osteoporotic fractures and 516 controls. They identified the same genetic variant rs13182402 within the ALDH7A1 gene, which was strongly associated with osteoporotic fractures with evidence-combined GWAS and replication studies (P=2.08×10−9) [22]. They speculated that the association might be due to the degradation and detoxification of acetaldehyde by ALDH7A1 since acetaldehyde inhibits osteoblast proliferation and results in decreased bone formation. There are multiple GWAS published and many ESCC susceptibility loci have been found. Cui et al. firstly identified functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk in Japanese [23]. Two GWAS with relatively large sample
size found that PLCE1 and C20orf54 are ESCC susceptibility loci in different populations [24, 25]. In Chinese Han population, Wu et al. identified several new ESCC susceptibility loci on chromosomes 3q27, 4q23, 5q11, 6p21, 10q23, 12q24, 16q12.1, 17p13, 17q21, 21q22, 22q12, and 18p11 [4, 5]. However, biological function of most loci is still unclear. Several limitations may exist in the current case–control study. First, because this was a hospital-based study and the cases were from the hospital, there might be inherent selection bias. Therefore, it is crucial to validate these findings in a population-based prospective study from the same geographic regions. Second, future functional studies to address the biological function of the polymorphisms during ESCC development are needed. In all, our study indicated that the ALDH7A1 rs13182402 polymorphism was associated with risk of ESCC in Chinese populations. Our results support the hypothesis that multiple alcohol metabolism genes are involved in ESCC etiology as other coding [26–29] and noncoding genes [6, 30]. Our study also highlights the importance of genetic components in cancer development.
Funding supports This study was funded by the open project of State Key Laboratory of Molecular Oncology (SKL-KF-2013-03), National Natural Science Foundation of China (31271382 & 81201586), Beijing Natural Science Foundation (5122020), Beijing Higher Education Young Elite Teacher Project (YETP0521), Beijing City Talent Training Project (2012D009016000002), and Program for Changjiang Scholars and Innovative Research Team in University (IRT13045).
12670 Conflict of interest None
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RESEARCH ARTICLE
The ALDH7A1 genetic polymorphisms contribute to development of esophageal squamous cell carcinoma Haiyong Wang & Lei Tong & Jinyu Wei & Wenting Pan & Lichao Li & Yunxia Ge & Liqing Zhou & Qipeng Yuan & Changchun Zhou & Ming Yang
Received: 25 July 2014 / Accepted: 3 September 2014 / Published online: 12 September 2014 # International Society of Oncology and BioMarkers (ISOBM) 2014
Abstract Although the entire etiology of esophageal squamous cell carcinoma (ESCC) is still unclear, alcohol drinking has been identified as a major environmental risk factor. The aldehyde dehydrogenase (ALDH) superfamily members are major enzymes involved in the alcohol-metabolizing pathways. Accumulating evidences demonstrated that ALDH7A1, one of ALDH superfamily members, degrades and detoxifies acetaldehyde generated by alcohol metabolism and have been associated with development and prognosis of multiple cancers. However, it is still unknown if ALDH7A1 single nucleotide polymorphisms (SNPs) contribute to ESCC susceptibility. In this study, we examined the association between sixteen ALDH7A1 SNPs and risk of developing ESCC. Genotypes were determined in 2,098 ESCC patients and 2,150 controls (three independent hospital-based case–control sets from different regions of China). Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by logistic regression. Our data demonstrated that only the ALDH7A1 rs13182402 Haiyong Wang, Lei Tong, and Jinyu Wei contributed equally to this work. H. Wang : J. Wei : W. Pan : L. Li : Y. Ge : Q. Yuan : M. Yang (*) State Key Laboratory of Chemical Resource Engineering, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, P. O. Box 53, Beijing 100029, China e-mail: [email protected] L. Tong Cardiothoracic Surgery of Bethune International Peace Hospital, Shijiazhuang, Hebei Province, China L. Zhou Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian, Jiangsu Province, China C. Zhou (*) Clinical Laboratory, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China e-mail: [email protected]
SNP confer susceptibility to ESCC (For AG genotype, OR= 0.75, 95 % CI=0.66–0.91, P=4.8×10−6; for GG genotype, OR=0.59, 95 % CI=0.41–0.88, P=0.003). These results are consistent to the biological functions of ALDH7A1 during alcohol metabolism and carcinogenesis. Keywords ALDH7A1 . Genetic polymorphism . ESCC . Susceptibility
Introduction As one of the most common malignant tumors worldwide, esophageal squamous cell carcinoma (ESCC) shows a relatively high incidence in Eastern Asian compared to Western countries [1]. The entire etiology of ESCC is still unclear. However, it has been found that alcohol consumption, tobacco smoking, micronutrient deficiency, and dietary carcinogen exposure are known risk factors of this lethal malignancy [2, 3]. High temperature of meals and drinks, limited Vitamin C intake, and low consumption of vegetables and fruits were strong risk indicators of ESCC in Chinese populations. Moreover, the strength of tea and overall tea consumption were independent determinants of the ESCC risk [2, 3]. Nevertheless, only a part of exposed individuals finally develop ESCC, indicating that genetic factors may also contribute to ESCC etiology. This has been proven by multiple ESCC genome-wide association study (GWAS) and candidate gene-based studies [4–9]. The oxidation and detoxification of a great variety of endobiotic and xenobiotic aldehyde compounds are catalyzed by the aldehyde dehydrogenase (ALDH) superfamily [10]. As highly reactive substances, aldehyde compounds could induce multiple cellular damages, such as the formation of mutagenic DNA adducts [11, 12]. Thus, deregulation of ALDH enzymes might contribute to malignant transformation of normal cells. The ALDH7A1 gene encodes an enzyme of the ALDH
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superfamily, which degrades and detoxifies acetaldehyde generated by alcohol metabolism. Interestingly, abused alcohol consumption has been identified as one of the major risk factors in the word. ALDH7A1 is also highly expressed in prostate cancer cell lines and primary human prostate cancer tissue. Elevated ALDH7A1 expression in prostate cancer bone metastases compared to the matched primary tumors indicates that ALDH7A1 may play a part in both tumor initiation and metastasis initiation in prostate cancer [13]. ALDH7A1 expression was also found to be increased in human papilloma virus-immortalized cervical epithelial cells and nodular melanoma [14, 15]. For lung cancer patients, low ALDH7A1 expression has been associated with decreased cancer recurrence. Among stage I lung cancer patients, negative staining for ALDH7A1 was associated with improved recurrence-free and overall survival [16]. Through interaction with cyclin A, ALDH7A1 could influence permissive G1/S cell-cycle progression [17], suggesting its involvement in cellcycle regulation. ALDH7A1 is polymorphic in human beings. The ALDH and ADH single nucleotide polymorphisms (SNP) influence individual diversity in alcohol-oxidizing capability and drinking behavior [18]. Among the ADH family, the major enzymes involved in the alcohol-metabolizing pathways are alcohol dehydrogenase 1B (ADH1B) and ADH1C. ESCC GWAS data and our previous results both demonstrated the ADH1B-ADH1C-ADH7 cluster is curial ESCC susceptible loci [4, 19]. However, the involvement of ALDH7A1 SNPs in ESCC is still largely unknown. Considering the importance of ALDH7A1 in cancer development and in metabolism of in vivo ethanol, we selected 16 haplotype-tagging SNPs (htSNP) across the whole ALDH7A1 locus and conducted three large independent hospital-based case–control studies to investigate the association between ALDH7A1 genotypes and ESCC risk.
Materials and methods Study subjects This study consisted of three case–control sets: (a) Shandong set, 1,000 cases with ESCC from Shandong Cancer Hospital, Shandong Academy of Medical Sciences (Jinan, Shandong Province, China) and sex- and age-matched (±5 years) 1,000 healthy controls. ESCC cases were consecutively recruited between June 2009 and July 2013 at Shandong Cancer Hospital. Controls were randomly selected from a pool of 4,500 individuals from a community cancer-screening program for early detection of cancer conducted in Jinan city (Shandong Province) during the same time period as the ESCC cases were recruited. (b) Jiangsu set, 588 ESCC cases from Huaian No. 2 Hospital (Huaian, Jiangsu Province, China) and sex-
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and age-matched 600 controls. ESCC cases were recruited between January 2009 and February 2012 at Huaian No. 2 Hospital. Healthy controls were all cancer-free subjects selected from a community cancer-screening program (3,600 individuals) for early detection of cancer conducted in Huaian city. (c) Hebei study, 510 ESCC patients from Bethune International Peace Hospital (Shijiazhuang, Hebei Province, China) and 550 sex- and age-matched healthy controls. ESCC cases were recruited between October 2010 and May 2013 at Bethune International Peace Hospital. Cancer-free controls were individuals who underwent a physical examination in Bethune International Peace Hospital. The diagnosis of all patients was histologically confirmed. Individuals who smoked one cigarette per day for over 1 year were considered as smokers. Subjects were considered as alcohol drinkers if they drank at least once per week. All individuals were ethnic Han Chinese. At recruitment, the informed consent was obtained from each subject. This study was approved by the Institutional Review Boards. SNP selection and genotyping The ALDH7A1 gene covers a 53,550-bp region of chromosome 5q31 and contains many SNPs. Therefore, we used an htSNP approach to analyze the ALDH7A1 polymorphisms globally [20]. Genotyped HapMap SNPs among Han Chinese population (HCB data, HapMap Rel 27, NCBI B36) with a minor allele frequency >5 % were included in the selection. The htSNPs were chosen in a 57,550-bp region (53,550 bp ALDH7A1 locus and 2 kb up-stream as well as 2 kb downstream regions of the ALDH7A1 gene). Sixteen htSNPs were finally selected with Haploview 4.2 software on a block-byblock basis, using a method described previously with the sample size inflation factor, Rh2, of ≥0.8 (Table 1). ALDH7A1 htSNPs were analyzed by the MassArray system (Sequenom Inc., San Diego, California, USA). A 5 % blind, random sample of study subjects was genotyped in duplicates and the reproducibility was 98.5 %. To reduce the costs of the study, we genotyped the ALDH7A1 rs13182402 SNP in the validation sets using the TaqMan assay (C_31889488_10, ABI). Five percent samples were genotyped by two investigators, and the reproducibility was 99.0 %. Statistics To calculate the differences in demographic variables and genotype distributions of sixteen ALDH7A1 SNPs between cases and controls, Pearson’s χ2 test was used. The associations between genotypes of these SNPs and ESCC risk were estimated by odds ratios (ORs) and their 95 % confidence intervals (CIs) computed by logistic regression models. All
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Table 1 HapMap tag-SNPs in the ALDH7A1 locus with HCB data of HapMap Rel 27
Results
No
Test
Alleles captured
1
rs7709115
2 3 4 5 6 7 8 9
rs6898559 rs13182402 rs2306619 rs12514417 rs11241901 rs7715516 rs4836272 rs4626335
rs7709115,rs7736031,rs6595719,rs11742381, rs6870785 rs6898559,rs12513847,rs2306617,rs4379190 rs900641,rs17154671,rs13182402 rs2306619,rs1038378 rs11241902,rs12514417 rs11241901 rs7715516 rs4836272 rs4626335
10 11 12 13 14 15 16
rs2306618 rs4835913 rs4626334 rs4836277 rs1060856 rs1038381 rs4836276
rs2306618 rs4835913 rs4626334 rs4836277 rs1060856 rs1038381 rs4836276
In terms of median age and sex distribution, no statistically significant differences were found between ESCC patients and healthy controls for three hospital-based case–control set (all P>0.05), elucidating that the frequency matching was appropriate (Table 2). More smokers and alcohol drinkers were observed among ESCC cases compared with controls in all three case–control sets (all P57 (>59) Sex Male Female Smoking status Yes No Drinking status Yes No
Pa
Jiangsu case–control set (validation set 1) Cases No. (%)
Controls No. (%)
588
600
288 (49.0) 300 (51.0)
300 (50.0) 300 (50.0)
413 (70.2) 175 (29.8)
428 (71.3) 172 (28.7)
437 (74.3) 151 (25.7)
203 (33.8) 397 (66.2)
334 (56.8) 254 (43.2)
242 (40.3) 358 (59.7)
0.474
Pa
Hebei case–control set (validation set 2) Cases No. (%)
Controls No. (%)
510
550
271 (53.1) 239 (46.9)
279 (50.7) 271 (49.3)
398 (78.0) 112 (22.0)
446 (81.1) 104 (18.9)
381 (74.7) 129 (25.3)
263 (47.8) 287 (52.2)
288 (56.5) 222 (43.5)
228 (41.5) 322 (58.5)
0.725
0.426
0.433
0.678
C rs7715516 C>T rs4836272 C>T rs4626335 C>T rs2306618 T>C rs4835913 A>G rs4626334 C>T rs4836277 T>G rs1060856 G>A rs1038381 C>T rs4836276 A>C
ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control ESCC Control
0.690 0.688 0.647 0.645 0.685 0.626 0.390 0.381 0.758 0.761 0.438 0.441 0.325 0.322 0.457 0.455 0.375 0.373 0.881 0.874 0.487 0.493 0.676 0.673 0.776 0.773 0.768 0.772 0.868 0.875 0.360 0.367
0.280 0.279 0.272 0.270 0.285 0.330 0.372 0.371 0.226 0.228 0.409 0.411 0.512 0.513 0.381 0.382 0.452 0.453 0.110 0.114 0.326 0.321 0.267 0.269 0.194 0.190 0.202 0.205 0.120 0.115 0.394 0.390
0.030 0.033 0.081 0.085 0.030 0.044 0.238 0.248 0.016 0.011 0.153 0.148 0.163 0.165 0.162 0.163 0.173 0.174 0.009 0.012 0.187 0.186 0.057 0.058 0.030 0.037 0.030 0.023 0.012 0.010 0.246 0.243
1.02 (0.86–1.20)
0.834
1.02 (0.87–1.19)
0.818
0.79 (0.67–0.93)
0.003
1.04 (0.92–1.18)
0.544
0.96 (0.80–1.17)
0.704
0.98 (0.86–1.12)
0.792
1.01 (0.89–1.15)
0.873
1.01 (0.88–1.15)
0.921
1.01 (0.88–1.14)
0.923
1.08 (0.84–1.40)
0.526
0.98 (0.86–1.12)
0.816
1.01 (0.86–1.19)
0.872
1.05 (0.87–1.26)
0.638
0.95 (0.79–1.15)
0.603
0.93 (0.73–1.20)
0.576
0.98 (0.86–1.11)
0.750
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
SNP single nucleotide polymorphism, ESCC esophageal squamous cell carcinoma, OR odds ratio, CI confidence interval a
Data were calculated by logistic regression
associated with ESCC risk in either Jiangsu or Hebei Chinese Han population. The odds of having the ALDH7A1 rs13182402 AG or GG genotype in patients was 0.75 (95 % CI=0.62–0.91, P=0.009) or 0.55 (95 % CI=0.29–0.94, P= 0.023) compared with the AA genotype in the Jiangsu set. Similar results were found for ADH1B rs13182402 AG genotype (OR=0.69, 95 % CI=0.51–0.89, P=0.008) in the Hebei validation set. However, rs13182402 GG carriers showed no significantly decreased ESCC risk compared with those carrying the AA genotype in the Hebei set (OR=0.76, 95 % CI= 0.40–1.66, P=0.003) (Table 3). In the pooled analyses (2,098 cases and 2,150 controls), we observed that the rs13182402 AG or GG genotype was significantly associated with ESCC susceptibility (OR=0.75, 95 % CI=0.66–0.91, P=4.8×10−6 or, OR=0.59, 95 % CI=0.41–0.88, P=0.003) (Table 3). All ORs were adjusted for sex, age, smoking, and alcohol drinking status. We also examined whether there are gene-covariant
interactions between the ALDH7A1 rs13182402 genetic variant and age, sex, smoking status, or alcohol drinking history but the results were negative (data not shown).
Discussion In this study, we investigated the association between sixteen ALDH7A1 SNPs and risk of developing ESCC in a two-stage case–control design. To the best of our knowledge, this is the first study to examine the role of ALDH7A1 genetic polymorphism in ESCC carcinogenesis. Among these ALDH7A1 htSNPs, only rs13182402 was significantly associated with decreased ESCC risk in Chinese. In the validation studies, we also found statistically significant association between this genetic polymorphism and ESCC susceptibility in Chinese from different geographic regions. Our observations also
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Table 4 Genotype frequencies of the ALDH7A1 rs13182402 SNP among cases and controls and their association with ESCC risk Studies
Genotypes
Shandong set
AA AG GG
Jiangsu set
Hebei set
Pooled
Cases no. (%)
Controls no. (%)
AA AG
n=1,000 685 (68.5) 285 (28.5) 30 (3.0) n=588 407 (69.2) 165 (28.1) 16 (2.7) n=510 352 (69.0) 144 (28.2) 14 (2.7) n=2,098 1,444 (68.8) 594 (28.3)
n=1,000 616 (61.6) 340 (34.0) 44 (4.4) n=600 366 (61.0) 205 (34.2) 29 (4.8) n=550 338 (61.5) 195 (35.4) 17 (3.1) n=2,150 1,320 (61.4) 740 (34.4)
GG
60 (2.9)
90 (4.2)
AA AG GG AA AG GG
ORa (95 % CI)
Pa
1.00 (reference) 0.80 (0.66–0.91) 0.64 (0.41–0.98)
0.006 0.033
1.00 (reference) 0.75 (0.62–0.91) 0.55 (0.29–0.94)
0.009 0.023
1.00 (reference) 0.69 (0.51–0.89) 0.76 (0.40–1.66)
0.008 0.492
1.00 (reference) 0.75 (0.66–0.91)
4.8×10−6
0.59 (0.41–0.88)
0.003
ESCC esophageal squamous cell carcinoma, OR odds ratio, CI confidence interval a
Data were calculated by logistic regression with adjustment for age, sex, smoking and drinking status
support the hypothesis that the ALDH7A1 rs13182402 SNP is an ESCC susceptibility genetic variant in Chinese populations. There are two studies on the ALDH7A1 SNPs in either type 2 diabetes [21] or osteoporosis [22]. Using a candidate SNP approach, Zhou et al. examined associations between risk of type 2 diabetes and the KCNQ1 rs2237892, AP3S1 rs3756555, MAN2A1 rs2015698, or ALDH7A1 rs2306617 polymorphism in the Chinese Northern Han population. No association was observed for ALDH7A1 rs2306617 in 537 unrelated individuals with type 2 diabetes and 510 normal controls [21]. For osteoporosis, Guo et al. performed a case– control GWAS in 700 elderly Chinese Han subjects (350 with hip OF and 350 healthy matched controls). A follow-up replication study was conducted to validate our major GWAS findings in an independent Chinese sample containing 390 cases with hip osteoporotic fractures and 516 controls. They identified the same genetic variant rs13182402 within the ALDH7A1 gene, which was strongly associated with osteoporotic fractures with evidence-combined GWAS and replication studies (P=2.08×10−9) [22]. They speculated that the association might be due to the degradation and detoxification of acetaldehyde by ALDH7A1 since acetaldehyde inhibits osteoblast proliferation and results in decreased bone formation. There are multiple GWAS published and many ESCC susceptibility loci have been found. Cui et al. firstly identified functional variants in ADH1B and ALDH2 coupled with alcohol and smoking synergistically enhance esophageal cancer risk in Japanese [23]. Two GWAS with relatively large sample
size found that PLCE1 and C20orf54 are ESCC susceptibility loci in different populations [24, 25]. In Chinese Han population, Wu et al. identified several new ESCC susceptibility loci on chromosomes 3q27, 4q23, 5q11, 6p21, 10q23, 12q24, 16q12.1, 17p13, 17q21, 21q22, 22q12, and 18p11 [4, 5]. However, biological function of most loci is still unclear. Several limitations may exist in the current case–control study. First, because this was a hospital-based study and the cases were from the hospital, there might be inherent selection bias. Therefore, it is crucial to validate these findings in a population-based prospective study from the same geographic regions. Second, future functional studies to address the biological function of the polymorphisms during ESCC development are needed. In all, our study indicated that the ALDH7A1 rs13182402 polymorphism was associated with risk of ESCC in Chinese populations. Our results support the hypothesis that multiple alcohol metabolism genes are involved in ESCC etiology as other coding [26–29] and noncoding genes [6, 30]. Our study also highlights the importance of genetic components in cancer development.
Funding supports This study was funded by the open project of State Key Laboratory of Molecular Oncology (SKL-KF-2013-03), National Natural Science Foundation of China (31271382 & 81201586), Beijing Natural Science Foundation (5122020), Beijing Higher Education Young Elite Teacher Project (YETP0521), Beijing City Talent Training Project (2012D009016000002), and Program for Changjiang Scholars and Innovative Research Team in University (IRT13045).
12670 Conflict of interest None
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