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Association between cytosolic serine hydroxymethyltransferase (SHMT1) gene polymorphism and cancer risk: A meta-analysis
Biomedicine & Pharmacotherapy 68 (2014) 757–762
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Original Article
Association between cytosolic serine hydroxymethyltransferase (SHMT1) gene polymorphism and cancer risk: A meta-analysis Qianqian Wang a,1, Kai Lu b,2, Haina Du a,3, Qian Zhang a,4, Tao Chen b,5, Yongqian Shu a,6, Yibing Hua b,**, Lingjun Zhu a,* a b
Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300, GuangZhou Road, Nanjing 210029, China Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, 300, GuangZhou Road, Nanjing 210029, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 June 2014 Accepted 4 August 2014
Background: The serine hydroxymethyltransferase (SHMT1) is the key enzyme in the folate metabolic pathway to provide one-carbon unit that plays an important role in biosynthesis. Abnormal biosynthesis involved in DNA synthesis and methylation can lead to activation of oncogenes and inactivation of tumor suppressor genes. And the abnormal biosynthesis is closely related to a variety of common tumors’ occurrence and development. A SNP in SHMT1 C1420T may effect the procession of biosynthesis and finally influence cancer occurrence. Methods: Comprehensive searches were performed on PubMed and EMBASE database. We used odds ratio (OR) and 95% confidence interval (95% CI) to assess the strength of associations between SHMT1 C1420T polymorphism and cancer risk. Q-test, I2, and funnel plot were used to assess the heterogeneity and publication bias. Results: Totally, 19 studies containing 9799 cases and 11,841 controls were performed in this metaanalysis. The results showed that there was no association between SHMT1 C1420T polymorphism and cancer risk. But in the subgroup analysis, the significant associations were found in colorectal cancer and Asian population. Publication bias was not observed in the analysis. Conclusions: Our results indicate that the SHMT1 C1420T polymorphism do not have a significant association with the risk of cancer overall. Otherwise, SHMT1 C1420T polymorphism may have a protective effect on colorectal cancer and Asian population. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: SHMT1 Cancer risk Gene polymorphism Meta-analysis Colorectal cancer
1. Introduction
* Corresponding author. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300, GuangZhou Road, Nanjing, 210029, China. Tel.: +86 025 6813 6714; Cell phone: +13 951 807 457. ** Co-corresponding author. Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, 300, GuangZhou Road, Nanjing 210029, Nanjing, China, Tel.: +13 003 423 308. E-mail addresses: [email protected] (Q. Wang), [email protected] (K. Lu), [email protected] (H. Du), [email protected] (Q. Zhang), [email protected] (T. Chen), [email protected] (Y. Shu), [email protected] (Y. Hua), [email protected] (L. Zhu) 1 Cell phone: +15 195 969 579. 2 Cell phone: +15 952 080 782. 3 Cell phone: +18 262 638 611. 4 Cell phone: +18 262 638 735. 5 Tel.: +86 025 681 360 26. 6 Tel.:+86 025 681 367 14. http://dx.doi.org/10.1016/j.biopha.2014.08.002 0753-3322/ß 2014 Elsevier Masson SAS. All rights reserved.
Cancer is an important health problem worldwide. It is one of the most frequent causes of death. Cancer is now becoming the first cause of death in developed countries and the second in developing countries [1]. Based on the GLOBOCAN estimates, approximately 12.7 million new cancer cases and 7.6 million cancer deaths have occurred in 2008 [2]. The burden of cancer increase rapidly worldwide because of population pressure and the adoption of unhealthy lifestyle, including smoking, drinking, physical inactivity and ‘‘westernized’’ diets [3]. Several types of cancer can be caused by environmental factors, which can lead to cancer by inducing DNA damage [4]. Even though the exact mechanisms of cancer have not been identified, it is determined that genetic susceptibility plays an important role on disease etiology [5]. Studies have confirmed that the activity of SHMT1 is elevated in tumor tissues [6]. SHMT (Serine hydroxy methyl transferase) is a key enzyme in the folate metabolism process; it can catalyze the serine and
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tetrahydrofolate to glycine and 5,10-methylenetetrahydrofolate in the cytoplasm reversibly [7]. SHMT has two isozymes (SHMT l and SHMT2), locating in the cytoplasm and mitochondria respectively, and SHMT l is the key enzyme to supply one-carbon unit. Onecarbon unit plays an important role in the synthesis of methionine, thymidylate, and purines, and it also affects gene methylation and DNA synthesis [8]. Abnormal methylation and DNA repair gene function abnormalities can lead to activation of oncogenes and inactivation of tumor suppressor genes, it is closely related to a variety of common tumors’ occurrence and development [9]. So, if the function of SHMT1 was abnormal, many procession can be effected and finally cancer may occur. Studies have found one SNP (single nucleotide polymorphism) at nucleotide 1420 (C1420T, rs1979277), and this SNP can change the transcription and expression of SHMT1. The SNP influence the function of SHMT1 because of a leucine-to-phenylalanine amino acid variation at codon 474 (Leu474Phe) of the protein [10]. Many investigations indicated that SHMT1 polymorphism was associated with many common cancers, including colorectal cancer [11–15], breast cancer [16–21], and other cancers [22– 26], but the results of these studies were not coincident. Hence, we plan to construct a meta-analysis to comprehensively evaluate the role of the SHMT1 polymorphism on the risk of cancer. 2. Material and methods 2.1. Source and search strategy We searched the published case-control studies that investigated the associations between the SHMT1 polymorphism and cancers on PubMed and EMBASE database (by January 31, 2014). The search terms we used as follows: ‘‘SHMT1’’, ‘‘serine hydroxy methyl transferase 1’’, ‘‘polymorphism’’ AND ‘‘cancer’’. Moreover, we also searched the references of retrieved publications by handsearched. The inclusion criteria of all studies included in our metaanalysis was: independent case-control study; evaluation of the associations between SHMT C1420T polymorphism and cancers; supplement of frequency of genotype in detail.
It is noted that hematologic malignancies was excluded. This study was approved by the institutional review board of Nanjing Medical University. 2.2. Data extraction Data were independently extracted by two investigators and the third researcher was asked to check until they reached a consensus. We extracted the data from each eligible article as follows: author, year of publication, methods, cancer type, Hardy– Weinberg equilibrium (HWE), country, ethnicity, sources of controls, and number of cases and controls. Based on ethnicity data were separated to Caucasian, Asians and other (people in case and/or control group come from different ethnics). The included studies were grouped into colorectal cancer, breast cancer, and other cancers according to the tumor types. When a cancer type contain one individual study, we named the group as ‘‘other cancers’’. 2.3. Statistical analysis We performed a Chi2-based Q-test if the genotype distribution of the control population conformed to Hardy–Weinberg
equilibrium. Odds ratio (OR) and 95% confidence interval (95% CI) were used to estimate the strength of the association between SHMT1 C1420T and risk of cancer. The Z-test was used to assess the statistical significance of the pooled OR (P < 0.05 was considered significant). The pooled ORs and 95% CIs were evaluated under homozygous model (TT vs CC), heterozygous model (CT vs CC), recessive model (TT + CT vs CC), dominant model (TT vs CT + CC). Subgroup analysis based on ethnicity, cancer types and source of controls were conducted under those models. The Q-test and I2 value were used to assess the heterogeneity. If P < 0.05, we think the presence of heterogeneity among studies and use a randomeffects model (DerSimonian and Laird method). Otherwise, the fixed-effects model was applied (the Mantel–Haenszel method). Publication bias was evaluated with Funnel plot and Egger’s linear regression test. P < 0.05 means the presence of potential publication bias. All statistical analyses were done with STATA software (version 11.0, USA), and the P values were all two-sided.
3. Results 3.1. Characteristics of studies As shown as Fig. 1, a total of 56 articles were relevant to the search words and manual search. After our carefully reading and screening, 16 articles (contain 19 studies) were included [11–26]. Table 1 shows the details of those recruited articles. These casecontrol studies included in our analysis consist of 7colorectal cancers, 7 breast cancers and 5 other cancers (including lung cancer, bladder cancer, head and neck cancer, osteosarcoma, prostate cancer). Among these articles, there were 4 studies of Asians and 9 of Caucasians and 6 of mixed populations (named ‘‘other’’). In addition, 8 studies were hospital-based (HB) and 9 were population-based (PB), in 2 studies the controls come from the entire population, so we excluded the 2 studies and another studies which did not say the source. Our studies contain 9799 cases and 11,841 controls. There were 4 studies did not accord with HWE [12,14,17,26], but none of them have any effect on the final result. 3.2. Overall analysis As shown in Table 2, there was no significant association between the SHMT1 C1420T polymorphism and cancer risk in any of the genetic models (TT vs CC: OR = 0.93, 95% CI = 0.85–1.02, P = 0.121; CT vs CC: OR = 0.99, 95% CI = 0.93–1.05, P = 0.650; TT + CT vs CC: OR = 0.97, 95% CI = 0.92–1.03, P = 0.334; TT vs CT + CC: OR = 0.91, 95% CI = 0.81–1.03, P = 0.123). 3.3. Stratified analysis In subgroup analysis of cancer types, we found that compared to CC genotype, SHMT1 1420TT have an protection effect on colorectal cancer (TT vs CC: OR = 0.84, 95% CI = 0.73–0.97, P = 0.020; TT vs CT + CC: OR = 0.84, 95% CI = 0.73–0.96, P = 0.013), but no significantly decreased risk was found for breast cancer and other cancers (Fig. 2). When we performed stratified analysis based on ethnicity, significant associations was only found in the Asian population (TT vs CC: OR = 0.63, 95% CI = 0.46–0.87, P = 0.002; CT vs CC: OR = 0.75, 95% CI = 0.62–0.90, P = 0.002; TT + CT vs CC: OR = 0.73, 95% CI = 0.61–0.87, P = 0.000; TT vs CT + CC: OR = 0.68, 95% CI = 0.52–0.88, P = 0.003). We did not find any association in both the Caucasian population and other populations. Moreover, significantly results were not found for all genetic models when performed the stratified analysis by source of controls.
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Fig. 1. The detailed process of identifying eligible studies.
Table 1 Characteristics of SHMT 1 gene polymorphisms included in the meta-analysis. Author
Year
Methods
Cancer type
HWE
Country
Ethnicity
Source
Case/control
Chen et al. [11] Steck et al. [12] Steck et al. [12] Komlo´si et al. [13] Komlo´si et al. [13] Curtin et al. [14] Liu et al. [15] Lissowska et al. [16] Yu et al. [17] Cheng et al. [18] Mohammad et al. [19] Naushad et al. [20] Barbosa et al. [21] Barbosa et al. [21] Wang et al. [22] Moore et al. [23] Succi et al. [24] Weiner et al. [25] ˜ o-Garcı´a et al. [26] Patin
2004 2008 2008 2010 2010 2011 2013 2007 2007 2008 2011 2011 2012 2012 2007 2007 2013 2012 2009
PCR-RFLP TaqMan PCR TaqMan PCR PCR-RFLP PCR-RFLP PCR PCR-RFLP TaqMan PCR PCR-RFLP PCR-RFLP PCR-RFLP/AFLP PCR-RFLP/AFLP PCR-RFLP PCR-RFLP PCR-RFLP TaqMan PCR TaqMan PCR TaqMan PCR TaqMan PCR
Colorectal Colon Cancer Colon Cancer Colon Cancer Rectal Cancer Rectal Cancer Colon Cancer Breast cancer Breast cancer Breast cancer Breast cancer Breast cancer Breast cancer Breast cancer Lung cancer Bladder cancer Head and neck cancer Prostate Cancer Osteosarcoma
0.79 0.17 0.004 0.11 0.14 0.005 0.82 0.26 0.00 0.72 0.82 0.99 0.96 0.60 0.32 0.91 0.13 0.81 0.01
USA USA USA Hungary Hungary USA USA Poland Taiwan Taiwan India India Brazil Brazil USA Spain Brazil Russia Spain
Caucasian-Americans African-American Caucasian Caucasian Caucasian Caucasian Mixed Caucasian Asian Asian Asian Asian Brazil Brazil Caucasian Caucasian Brazil Caucasian Caucasian
HB PB PB PB PB HB+PB HB+PB PB PB HB HB PB HB HB HB HB PB PB HB
271/458 239/322 307/533 476/461 479/478 726/928 1414/1774 1959/2257 105/403 354/534 222/235 244/244 120/120 55/57 1032/1145 1092/1011 237/488 371/284 96/109
PB: population-based; HB: hospital-based.
3.4. Heterogeneity and sensitivity analysis
3.5. Publication bias analysis
Obviously, substantial heterogeneity was observed in overall analysis (TT vs CC: I2 = 39.3%, Pheterogeneity = 0.041; TT + CT vs CC: I2 = 27.6%, Pheterogeneity = 0.129; TT vs CT + CC: I2 = 33.3%, Pheterogeneity = 0.079). Then, we explored the source of heterogeneity by subgroup meta-analysis based on cancer type, ethnicity, and source of controls (Table 3). I2 test indicated that heterogeneity only present in the subgroup of breast cancer (Ph = 0.005). So, we considered it may be the main source of heterogeneity. We performed sensitivity analysis to assess the influence of each individual study on the pooled OR by leave-one-out method. The results suggested that there was no any study could change the pooled ORs obviously which means that our meta-analysis is stable.
We performed the Begg’s funnel plot and Egger’s test to assess the publication bias of studies. As shown in Fig. 3, the shape of the funnel plot seems symmetry in all genetic models. And the results of Egger’s test did not show the presence of publication bias (for the CC vs TT: Begg’s test P = 0.861, Egger’s test P = 0.836, t = –0.21, 95% CI = –1.62–1.33). 4. Discussion The meta-analysis investigates the associations between SHMT1 C1420T polymorphism and cancer risk. We did not find any significant association between the SHMT1 C1420T polymorphism and overall cancer risk in any of the genetic models, but
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Fig. 2. Forest plot of malignant tumor associated with the SHMT1C1420T polymorphisms (a) TT vs CC and (b) TT vs CT + CC for colorectal, (c) TT vs CC, (d) CT vs CC, (e) TT vs CT + CC and (f) TT + CT vs CC in Asian population. A fixed-effects model was used. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI.
significant association was found in colorectal cancer and Asian population. SHMT1, locating at chromosome 17p11.2 [27], is a pyridoxal phosphate dependent enzyme in the folate metabolic pathway [8]. Folate is an important nutrient for biosynthesis [28] because folate metabolic pathway can provide one-carbon unit for biosynthesis of purine, thymidylate and methionine [29], which are necessary for
DNA synthesis and methylation. In this process, SHMT1 can downregulate enzymes activity in its biosynthetic pathway [30], so, the SHMT1 polymorphism may have some influence on biosynthesis. In this study, we found that SHMT1 C1420T polymorphism have no effect on the cancer risk overall. Several reasons can explain the result:
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Table 2 Pooled ORs and 95%CIs of stratified meta-analysis for cancers. Stratification
No. case/controla
TT vs CC OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
Total Cancer type Colorectal cancer Breast cancer Other cancers Ethnicity Asian Caucasian Other Source of control HB PB
19 (9799/11,841)
0.92 (0.80,1.02)
0.192
0.99 (0.93,1.05)
0.650
0.97 (0.92,1.03)
0.334
0.91 (0.81,1.03)
0.123
7 (3912/4954) 7 (3059/3850) 5 (2828/3037)
0.84 (0.73,0.97)b 0.89 (0.61,1.29) 1.07 (0.89,1.27)
0.020 0.526 0.476
1.01 (0.92,1.10) 0.90 (0.71,1.13) 0.98 (0.88,1.10)
0.903 0.361 0.743
0.97 (0.89,1.06) 0.88 (0.68,1.13) 1.00 (0.90,1.11)
0.476 0.318 0.960
0.84 (0.73,0.96)b 0.89 (0.67,1.18) 1.08 (0.91,1.28)
0.013 0.424 0.384
0.59 (0.42,0.82)b 0.94 (0.80,1.10) 1.00 (0.84,1.21)
0.002 0.428 0.958
0.72 (0.58,0.90)b 1.00 (0.93,1.07) 1.05 (0.94,1.18)
0.003 0.891 0.378
0.68 (0.55,0.84)b 0.99 (0.92,1.05) 1.04 (0.93,1.16)
0.000 0.667 0.472
0.65 (0.50,0.85)b 0.94 (0.80,1.09) 0.98 (0.82,1.17)
0.001 0.411 0.833
1.04 (0.81,1.34) 0.84 (0.67,1.05)
0.751 0.118
0.93 (0.79,1.10) 1.01 (0.93,1.11)
0.404 0.738
0.95 (0.80,1.14) 0.99 (0.91,1.07)
0.576 0.764
1.03 (0.83,1.26) 0.84 (0.69,1.02)
0.811 0.082
7 (925/1416) 15 (6538/7206) 8 (2336/3219) 10 (3421/4277) 17 (6798/9266)
CT vs CC
TT + CT vs CC
TT vs CT + CC
a
Involved studies’number. Results that are statistically significant. Random model was chosen for data pooling when P < 0.10 and/or I2 > 50%; otherwise fixed model was used b
In subgroup analysis, SHMT1 1420TT may be a protection factor for colorectal cancer. There was a meta-analysis about SHMT1 gene polymorphism and colorectal cancer previously [32]. But, the result was opposite to our analysis. In our subgroup analysis, we identified that SHMT1 TT may decrease colorectal cancer risk, but in Pabalan’s study, SHMT1 do not have effect on colorectal risk. After carefully checking, we found that some studies on colorectal adenomas were mixed in their meta-analysis [33,34]. In addition, new studies were added in our meta-analysis, which contributed to the appearance of different result to some extent [15]. According to the statistic result, ethnic also have some influence on the effects of SHMT1 C1420T polymorphism. The TT genotype can decrease cancer risk in Asian population. One possible reason is that individuals of different races live in respective geographical environment cause genetic information undergo some changes. The diet differences between western and eastern make a contribution to this result. This maybe another reason. This shows the exit of gene–environment interactions. The presence of consensus results in different cancer types may due to different cancer carcinogenesis in different kinds of tumors [7]. Larger sample size studies are still needed to validate. There are still some limitations that must be considered in our updated meta-analysis. Firstly, when all eligible data were included in our analysis, significantly heterogeneities were observed across studies, and some of the controls were not
Fig. 3. Begg’s funnel plot for publication bias test (homozygote comparison). Each point represents a separate study for the indicated association.
some studies reported that SHMT2 can also provide the onecarbon units for cytosolic folate metabolism [31], so, SHMT2 may be the real gene which contribute to folate pathway. It is obvious that there was no association between the SHMT1 C1420T polymorphism and cancer risk; sample size is not large enough, and the statistic can not reflect the real facts; the heterogeneity was evident, some errors may be exist.
Table 3 Heterogeneity test for cancer. Stratification
TT vs CC heterogeneity
P Total Cancer type Colorectal cancer Breast cancer Other cancers Ethnicity Asian Caucasian Other Source of control HB PB a b
CT vs CC 2
a
, I (%)
heterogeneity
P
TT + CT vs CC 2
a
, I (%)
heterogeneity
P
TT vs CT + CC 2
a
, I (%)
Pheterogeneity, I2 (%)a
0.041, 39.3
0.413, 3.5
0.129, 27.6
0.079, 33.3
0.397, 3.8 0.015, 62.0b 0.448, 0.0
0.865, 0.0 0.036, 55.4b 0.673, 0.0
0.720, 0.0 0.005, 67.3b 0.644, 0.0
0.448, 0.0 0.048, 52.7b 0.464, 0.0
0.934, 0.0 0.084, 42.5 0.233, 26.8
0.564, 0.0 0.852, 0.0 0.619, 0.0
0.834, 0.0 0.621, 0.0 0.427, 0.0
0.957, 0.0 0.093, 41.2 0.377, 6.3
0.101, 41.6 0.042, 50.0
0.081, 44.7 0.859, 0.0
0.024, 56.6 0.435, 0.0
0.195, 29.2 0.062, 46.2
I2 index: a quantitative measurement which indicates the proportion of total variation in study estimates that is due to between-study heterogeneity. These genotype was considered as potential heterogeneity and the results can not pooled together.
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uniform, so, the statistical power is relatively weak to assess the association between SHMT1 C1420T polymorphism and cancer risk. Secondly, the sample size of the included literatures was not large enough, especially in stratified analysis. Thirdly, some unpublished studies were not enrolled in this meta-analysis, so potentially bias would be existed in the results, although the data did not reflect it. Finally, gene–gene and gene–environment interactions, which may modulate the cancer susceptibility, were excluded in our analysis, and this may cause some errors. In conclusion, this updated meta-analysis can probably reflect the association between SHMT1 C1420T polymorphism and the cancer risk. Although some limitations still exist, our results suggest that SHMT1 1420TT may be a potential protection factor for Asian population and colorectal cancer patients. It may be a potential biomarker for cancer prevention. More well-designed studies about SHMT1 C1420T with detailed information and large sample size are needed to validate our findings. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments This study was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) (JX10231801), the Health Department guidance project of Jiangsu Province (Z201201), the Jiangsu Province Clinical science and technology projects (Clinical Research Center, BL2012008) and the Summit of the Six Top Talents Program of Jiangsu Province (WSN-034). References [1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61(2):69–90. [2] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127(12):2893–917. [3] Hua RX, Li HP, Liang YB, Zhu JH, Zhang B, Ye S, et al. Association between the PARP1 Val762Ala polymorphism and cancer risk: evidence from 43 studies. PLoS One 2014;9(1):e87057. [4] Levi F, Pasche C, La Vecchia C, Lucchini F, Franceschi S. Food groups and colorectal cancer risk. Br J Cancer 1999;79(7–8):1283–7. [5] Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer – analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000;343(2):78–85. [6] Snell K, Natsumeda Y, Eble JN, Glover JL, Weber G. Enzymic imbalance in serine metabolism in human colon carcinoma and rat sarcoma. Br J Cancer 1988;57(1):87–90. [7] Wang Y, Guo W, He Y, Chen Z, Wen D, Zhang X, et al. Association of MTHFR C677T and SHMT(1) C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China. Cancer Causes Control 2007;18(2):143–52. [8] Girgis S, Suh JR, Jolivet J, Stover PJ. 5-Formyltetrahydrofolate regulates homocysteine remethylation in human neuroblastoma. J Biol Chem 1997;272(8): 4729–34. [9] Wang YM, Guo W, Zhang XF, Li Y, Wang N, Ge H, et al. [Correlations between serine hydroxymethyltransferase1 C1420T polymorphisms and susceptibilities to esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma]. Ai Zheng 2006;25(3):281–6. [10] Heil SG, Van der Put NM, Waas ET, den Heijer M, Trijbels FJ, Blom HJ. Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Mol Genet Metab 2001;73(2):164–72.
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Dietary intake of B-vitamins, polymorphisms in thymidylate synthase and serine hydroxymethyltransferase 1, and colorectal adenoma risk: a Dutch case-control study. Cancer Lett 2007;250(1):146–53. [34] Hazra A, Wu K, Kraft P, Fuchs CS, Giovannucci EL, Hunter DJ. Twenty-four nonsynonymous polymorphisms in the one-carbon metabolic pathway and risk of colorectal adenoma in the Nurses’ Health Study. Carcinogenesis 2007;28(7): 1510–1519.
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Original Article
Association between cytosolic serine hydroxymethyltransferase (SHMT1) gene polymorphism and cancer risk: A meta-analysis Qianqian Wang a,1, Kai Lu b,2, Haina Du a,3, Qian Zhang a,4, Tao Chen b,5, Yongqian Shu a,6, Yibing Hua b,**, Lingjun Zhu a,* a b
Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300, GuangZhou Road, Nanjing 210029, China Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, 300, GuangZhou Road, Nanjing 210029, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 18 June 2014 Accepted 4 August 2014
Background: The serine hydroxymethyltransferase (SHMT1) is the key enzyme in the folate metabolic pathway to provide one-carbon unit that plays an important role in biosynthesis. Abnormal biosynthesis involved in DNA synthesis and methylation can lead to activation of oncogenes and inactivation of tumor suppressor genes. And the abnormal biosynthesis is closely related to a variety of common tumors’ occurrence and development. A SNP in SHMT1 C1420T may effect the procession of biosynthesis and finally influence cancer occurrence. Methods: Comprehensive searches were performed on PubMed and EMBASE database. We used odds ratio (OR) and 95% confidence interval (95% CI) to assess the strength of associations between SHMT1 C1420T polymorphism and cancer risk. Q-test, I2, and funnel plot were used to assess the heterogeneity and publication bias. Results: Totally, 19 studies containing 9799 cases and 11,841 controls were performed in this metaanalysis. The results showed that there was no association between SHMT1 C1420T polymorphism and cancer risk. But in the subgroup analysis, the significant associations were found in colorectal cancer and Asian population. Publication bias was not observed in the analysis. Conclusions: Our results indicate that the SHMT1 C1420T polymorphism do not have a significant association with the risk of cancer overall. Otherwise, SHMT1 C1420T polymorphism may have a protective effect on colorectal cancer and Asian population. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: SHMT1 Cancer risk Gene polymorphism Meta-analysis Colorectal cancer
1. Introduction
* Corresponding author. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300, GuangZhou Road, Nanjing, 210029, China. Tel.: +86 025 6813 6714; Cell phone: +13 951 807 457. ** Co-corresponding author. Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, 300, GuangZhou Road, Nanjing 210029, Nanjing, China, Tel.: +13 003 423 308. E-mail addresses: [email protected] (Q. Wang), [email protected] (K. Lu), [email protected] (H. Du), [email protected] (Q. Zhang), [email protected] (T. Chen), [email protected] (Y. Shu), [email protected] (Y. Hua), [email protected] (L. Zhu) 1 Cell phone: +15 195 969 579. 2 Cell phone: +15 952 080 782. 3 Cell phone: +18 262 638 611. 4 Cell phone: +18 262 638 735. 5 Tel.: +86 025 681 360 26. 6 Tel.:+86 025 681 367 14. http://dx.doi.org/10.1016/j.biopha.2014.08.002 0753-3322/ß 2014 Elsevier Masson SAS. All rights reserved.
Cancer is an important health problem worldwide. It is one of the most frequent causes of death. Cancer is now becoming the first cause of death in developed countries and the second in developing countries [1]. Based on the GLOBOCAN estimates, approximately 12.7 million new cancer cases and 7.6 million cancer deaths have occurred in 2008 [2]. The burden of cancer increase rapidly worldwide because of population pressure and the adoption of unhealthy lifestyle, including smoking, drinking, physical inactivity and ‘‘westernized’’ diets [3]. Several types of cancer can be caused by environmental factors, which can lead to cancer by inducing DNA damage [4]. Even though the exact mechanisms of cancer have not been identified, it is determined that genetic susceptibility plays an important role on disease etiology [5]. Studies have confirmed that the activity of SHMT1 is elevated in tumor tissues [6]. SHMT (Serine hydroxy methyl transferase) is a key enzyme in the folate metabolism process; it can catalyze the serine and
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tetrahydrofolate to glycine and 5,10-methylenetetrahydrofolate in the cytoplasm reversibly [7]. SHMT has two isozymes (SHMT l and SHMT2), locating in the cytoplasm and mitochondria respectively, and SHMT l is the key enzyme to supply one-carbon unit. Onecarbon unit plays an important role in the synthesis of methionine, thymidylate, and purines, and it also affects gene methylation and DNA synthesis [8]. Abnormal methylation and DNA repair gene function abnormalities can lead to activation of oncogenes and inactivation of tumor suppressor genes, it is closely related to a variety of common tumors’ occurrence and development [9]. So, if the function of SHMT1 was abnormal, many procession can be effected and finally cancer may occur. Studies have found one SNP (single nucleotide polymorphism) at nucleotide 1420 (C1420T, rs1979277), and this SNP can change the transcription and expression of SHMT1. The SNP influence the function of SHMT1 because of a leucine-to-phenylalanine amino acid variation at codon 474 (Leu474Phe) of the protein [10]. Many investigations indicated that SHMT1 polymorphism was associated with many common cancers, including colorectal cancer [11–15], breast cancer [16–21], and other cancers [22– 26], but the results of these studies were not coincident. Hence, we plan to construct a meta-analysis to comprehensively evaluate the role of the SHMT1 polymorphism on the risk of cancer. 2. Material and methods 2.1. Source and search strategy We searched the published case-control studies that investigated the associations between the SHMT1 polymorphism and cancers on PubMed and EMBASE database (by January 31, 2014). The search terms we used as follows: ‘‘SHMT1’’, ‘‘serine hydroxy methyl transferase 1’’, ‘‘polymorphism’’ AND ‘‘cancer’’. Moreover, we also searched the references of retrieved publications by handsearched. The inclusion criteria of all studies included in our metaanalysis was: independent case-control study; evaluation of the associations between SHMT C1420T polymorphism and cancers; supplement of frequency of genotype in detail.
It is noted that hematologic malignancies was excluded. This study was approved by the institutional review board of Nanjing Medical University. 2.2. Data extraction Data were independently extracted by two investigators and the third researcher was asked to check until they reached a consensus. We extracted the data from each eligible article as follows: author, year of publication, methods, cancer type, Hardy– Weinberg equilibrium (HWE), country, ethnicity, sources of controls, and number of cases and controls. Based on ethnicity data were separated to Caucasian, Asians and other (people in case and/or control group come from different ethnics). The included studies were grouped into colorectal cancer, breast cancer, and other cancers according to the tumor types. When a cancer type contain one individual study, we named the group as ‘‘other cancers’’. 2.3. Statistical analysis We performed a Chi2-based Q-test if the genotype distribution of the control population conformed to Hardy–Weinberg
equilibrium. Odds ratio (OR) and 95% confidence interval (95% CI) were used to estimate the strength of the association between SHMT1 C1420T and risk of cancer. The Z-test was used to assess the statistical significance of the pooled OR (P < 0.05 was considered significant). The pooled ORs and 95% CIs were evaluated under homozygous model (TT vs CC), heterozygous model (CT vs CC), recessive model (TT + CT vs CC), dominant model (TT vs CT + CC). Subgroup analysis based on ethnicity, cancer types and source of controls were conducted under those models. The Q-test and I2 value were used to assess the heterogeneity. If P < 0.05, we think the presence of heterogeneity among studies and use a randomeffects model (DerSimonian and Laird method). Otherwise, the fixed-effects model was applied (the Mantel–Haenszel method). Publication bias was evaluated with Funnel plot and Egger’s linear regression test. P < 0.05 means the presence of potential publication bias. All statistical analyses were done with STATA software (version 11.0, USA), and the P values were all two-sided.
3. Results 3.1. Characteristics of studies As shown as Fig. 1, a total of 56 articles were relevant to the search words and manual search. After our carefully reading and screening, 16 articles (contain 19 studies) were included [11–26]. Table 1 shows the details of those recruited articles. These casecontrol studies included in our analysis consist of 7colorectal cancers, 7 breast cancers and 5 other cancers (including lung cancer, bladder cancer, head and neck cancer, osteosarcoma, prostate cancer). Among these articles, there were 4 studies of Asians and 9 of Caucasians and 6 of mixed populations (named ‘‘other’’). In addition, 8 studies were hospital-based (HB) and 9 were population-based (PB), in 2 studies the controls come from the entire population, so we excluded the 2 studies and another studies which did not say the source. Our studies contain 9799 cases and 11,841 controls. There were 4 studies did not accord with HWE [12,14,17,26], but none of them have any effect on the final result. 3.2. Overall analysis As shown in Table 2, there was no significant association between the SHMT1 C1420T polymorphism and cancer risk in any of the genetic models (TT vs CC: OR = 0.93, 95% CI = 0.85–1.02, P = 0.121; CT vs CC: OR = 0.99, 95% CI = 0.93–1.05, P = 0.650; TT + CT vs CC: OR = 0.97, 95% CI = 0.92–1.03, P = 0.334; TT vs CT + CC: OR = 0.91, 95% CI = 0.81–1.03, P = 0.123). 3.3. Stratified analysis In subgroup analysis of cancer types, we found that compared to CC genotype, SHMT1 1420TT have an protection effect on colorectal cancer (TT vs CC: OR = 0.84, 95% CI = 0.73–0.97, P = 0.020; TT vs CT + CC: OR = 0.84, 95% CI = 0.73–0.96, P = 0.013), but no significantly decreased risk was found for breast cancer and other cancers (Fig. 2). When we performed stratified analysis based on ethnicity, significant associations was only found in the Asian population (TT vs CC: OR = 0.63, 95% CI = 0.46–0.87, P = 0.002; CT vs CC: OR = 0.75, 95% CI = 0.62–0.90, P = 0.002; TT + CT vs CC: OR = 0.73, 95% CI = 0.61–0.87, P = 0.000; TT vs CT + CC: OR = 0.68, 95% CI = 0.52–0.88, P = 0.003). We did not find any association in both the Caucasian population and other populations. Moreover, significantly results were not found for all genetic models when performed the stratified analysis by source of controls.
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Fig. 1. The detailed process of identifying eligible studies.
Table 1 Characteristics of SHMT 1 gene polymorphisms included in the meta-analysis. Author
Year
Methods
Cancer type
HWE
Country
Ethnicity
Source
Case/control
Chen et al. [11] Steck et al. [12] Steck et al. [12] Komlo´si et al. [13] Komlo´si et al. [13] Curtin et al. [14] Liu et al. [15] Lissowska et al. [16] Yu et al. [17] Cheng et al. [18] Mohammad et al. [19] Naushad et al. [20] Barbosa et al. [21] Barbosa et al. [21] Wang et al. [22] Moore et al. [23] Succi et al. [24] Weiner et al. [25] ˜ o-Garcı´a et al. [26] Patin
2004 2008 2008 2010 2010 2011 2013 2007 2007 2008 2011 2011 2012 2012 2007 2007 2013 2012 2009
PCR-RFLP TaqMan PCR TaqMan PCR PCR-RFLP PCR-RFLP PCR PCR-RFLP TaqMan PCR PCR-RFLP PCR-RFLP PCR-RFLP/AFLP PCR-RFLP/AFLP PCR-RFLP PCR-RFLP PCR-RFLP TaqMan PCR TaqMan PCR TaqMan PCR TaqMan PCR
Colorectal Colon Cancer Colon Cancer Colon Cancer Rectal Cancer Rectal Cancer Colon Cancer Breast cancer Breast cancer Breast cancer Breast cancer Breast cancer Breast cancer Breast cancer Lung cancer Bladder cancer Head and neck cancer Prostate Cancer Osteosarcoma
0.79 0.17 0.004 0.11 0.14 0.005 0.82 0.26 0.00 0.72 0.82 0.99 0.96 0.60 0.32 0.91 0.13 0.81 0.01
USA USA USA Hungary Hungary USA USA Poland Taiwan Taiwan India India Brazil Brazil USA Spain Brazil Russia Spain
Caucasian-Americans African-American Caucasian Caucasian Caucasian Caucasian Mixed Caucasian Asian Asian Asian Asian Brazil Brazil Caucasian Caucasian Brazil Caucasian Caucasian
HB PB PB PB PB HB+PB HB+PB PB PB HB HB PB HB HB HB HB PB PB HB
271/458 239/322 307/533 476/461 479/478 726/928 1414/1774 1959/2257 105/403 354/534 222/235 244/244 120/120 55/57 1032/1145 1092/1011 237/488 371/284 96/109
PB: population-based; HB: hospital-based.
3.4. Heterogeneity and sensitivity analysis
3.5. Publication bias analysis
Obviously, substantial heterogeneity was observed in overall analysis (TT vs CC: I2 = 39.3%, Pheterogeneity = 0.041; TT + CT vs CC: I2 = 27.6%, Pheterogeneity = 0.129; TT vs CT + CC: I2 = 33.3%, Pheterogeneity = 0.079). Then, we explored the source of heterogeneity by subgroup meta-analysis based on cancer type, ethnicity, and source of controls (Table 3). I2 test indicated that heterogeneity only present in the subgroup of breast cancer (Ph = 0.005). So, we considered it may be the main source of heterogeneity. We performed sensitivity analysis to assess the influence of each individual study on the pooled OR by leave-one-out method. The results suggested that there was no any study could change the pooled ORs obviously which means that our meta-analysis is stable.
We performed the Begg’s funnel plot and Egger’s test to assess the publication bias of studies. As shown in Fig. 3, the shape of the funnel plot seems symmetry in all genetic models. And the results of Egger’s test did not show the presence of publication bias (for the CC vs TT: Begg’s test P = 0.861, Egger’s test P = 0.836, t = –0.21, 95% CI = –1.62–1.33). 4. Discussion The meta-analysis investigates the associations between SHMT1 C1420T polymorphism and cancer risk. We did not find any significant association between the SHMT1 C1420T polymorphism and overall cancer risk in any of the genetic models, but
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Fig. 2. Forest plot of malignant tumor associated with the SHMT1C1420T polymorphisms (a) TT vs CC and (b) TT vs CT + CC for colorectal, (c) TT vs CC, (d) CT vs CC, (e) TT vs CT + CC and (f) TT + CT vs CC in Asian population. A fixed-effects model was used. The squares and horizontal lines correspond to the study-specific OR and 95% CI. The area of the squares reflects the weight (inverse of the variance). The diamond represents the summary OR and 95% CI.
significant association was found in colorectal cancer and Asian population. SHMT1, locating at chromosome 17p11.2 [27], is a pyridoxal phosphate dependent enzyme in the folate metabolic pathway [8]. Folate is an important nutrient for biosynthesis [28] because folate metabolic pathway can provide one-carbon unit for biosynthesis of purine, thymidylate and methionine [29], which are necessary for
DNA synthesis and methylation. In this process, SHMT1 can downregulate enzymes activity in its biosynthetic pathway [30], so, the SHMT1 polymorphism may have some influence on biosynthesis. In this study, we found that SHMT1 C1420T polymorphism have no effect on the cancer risk overall. Several reasons can explain the result:
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Table 2 Pooled ORs and 95%CIs of stratified meta-analysis for cancers. Stratification
No. case/controla
TT vs CC OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
OR (95% CI)
P
Total Cancer type Colorectal cancer Breast cancer Other cancers Ethnicity Asian Caucasian Other Source of control HB PB
19 (9799/11,841)
0.92 (0.80,1.02)
0.192
0.99 (0.93,1.05)
0.650
0.97 (0.92,1.03)
0.334
0.91 (0.81,1.03)
0.123
7 (3912/4954) 7 (3059/3850) 5 (2828/3037)
0.84 (0.73,0.97)b 0.89 (0.61,1.29) 1.07 (0.89,1.27)
0.020 0.526 0.476
1.01 (0.92,1.10) 0.90 (0.71,1.13) 0.98 (0.88,1.10)
0.903 0.361 0.743
0.97 (0.89,1.06) 0.88 (0.68,1.13) 1.00 (0.90,1.11)
0.476 0.318 0.960
0.84 (0.73,0.96)b 0.89 (0.67,1.18) 1.08 (0.91,1.28)
0.013 0.424 0.384
0.59 (0.42,0.82)b 0.94 (0.80,1.10) 1.00 (0.84,1.21)
0.002 0.428 0.958
0.72 (0.58,0.90)b 1.00 (0.93,1.07) 1.05 (0.94,1.18)
0.003 0.891 0.378
0.68 (0.55,0.84)b 0.99 (0.92,1.05) 1.04 (0.93,1.16)
0.000 0.667 0.472
0.65 (0.50,0.85)b 0.94 (0.80,1.09) 0.98 (0.82,1.17)
0.001 0.411 0.833
1.04 (0.81,1.34) 0.84 (0.67,1.05)
0.751 0.118
0.93 (0.79,1.10) 1.01 (0.93,1.11)
0.404 0.738
0.95 (0.80,1.14) 0.99 (0.91,1.07)
0.576 0.764
1.03 (0.83,1.26) 0.84 (0.69,1.02)
0.811 0.082
7 (925/1416) 15 (6538/7206) 8 (2336/3219) 10 (3421/4277) 17 (6798/9266)
CT vs CC
TT + CT vs CC
TT vs CT + CC
a
Involved studies’number. Results that are statistically significant. Random model was chosen for data pooling when P < 0.10 and/or I2 > 50%; otherwise fixed model was used b
In subgroup analysis, SHMT1 1420TT may be a protection factor for colorectal cancer. There was a meta-analysis about SHMT1 gene polymorphism and colorectal cancer previously [32]. But, the result was opposite to our analysis. In our subgroup analysis, we identified that SHMT1 TT may decrease colorectal cancer risk, but in Pabalan’s study, SHMT1 do not have effect on colorectal risk. After carefully checking, we found that some studies on colorectal adenomas were mixed in their meta-analysis [33,34]. In addition, new studies were added in our meta-analysis, which contributed to the appearance of different result to some extent [15]. According to the statistic result, ethnic also have some influence on the effects of SHMT1 C1420T polymorphism. The TT genotype can decrease cancer risk in Asian population. One possible reason is that individuals of different races live in respective geographical environment cause genetic information undergo some changes. The diet differences between western and eastern make a contribution to this result. This maybe another reason. This shows the exit of gene–environment interactions. The presence of consensus results in different cancer types may due to different cancer carcinogenesis in different kinds of tumors [7]. Larger sample size studies are still needed to validate. There are still some limitations that must be considered in our updated meta-analysis. Firstly, when all eligible data were included in our analysis, significantly heterogeneities were observed across studies, and some of the controls were not
Fig. 3. Begg’s funnel plot for publication bias test (homozygote comparison). Each point represents a separate study for the indicated association.
some studies reported that SHMT2 can also provide the onecarbon units for cytosolic folate metabolism [31], so, SHMT2 may be the real gene which contribute to folate pathway. It is obvious that there was no association between the SHMT1 C1420T polymorphism and cancer risk; sample size is not large enough, and the statistic can not reflect the real facts; the heterogeneity was evident, some errors may be exist.
Table 3 Heterogeneity test for cancer. Stratification
TT vs CC heterogeneity
P Total Cancer type Colorectal cancer Breast cancer Other cancers Ethnicity Asian Caucasian Other Source of control HB PB a b
CT vs CC 2
a
, I (%)
heterogeneity
P
TT + CT vs CC 2
a
, I (%)
heterogeneity
P
TT vs CT + CC 2
a
, I (%)
Pheterogeneity, I2 (%)a
0.041, 39.3
0.413, 3.5
0.129, 27.6
0.079, 33.3
0.397, 3.8 0.015, 62.0b 0.448, 0.0
0.865, 0.0 0.036, 55.4b 0.673, 0.0
0.720, 0.0 0.005, 67.3b 0.644, 0.0
0.448, 0.0 0.048, 52.7b 0.464, 0.0
0.934, 0.0 0.084, 42.5 0.233, 26.8
0.564, 0.0 0.852, 0.0 0.619, 0.0
0.834, 0.0 0.621, 0.0 0.427, 0.0
0.957, 0.0 0.093, 41.2 0.377, 6.3
0.101, 41.6 0.042, 50.0
0.081, 44.7 0.859, 0.0
0.024, 56.6 0.435, 0.0
0.195, 29.2 0.062, 46.2
I2 index: a quantitative measurement which indicates the proportion of total variation in study estimates that is due to between-study heterogeneity. These genotype was considered as potential heterogeneity and the results can not pooled together.
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uniform, so, the statistical power is relatively weak to assess the association between SHMT1 C1420T polymorphism and cancer risk. Secondly, the sample size of the included literatures was not large enough, especially in stratified analysis. Thirdly, some unpublished studies were not enrolled in this meta-analysis, so potentially bias would be existed in the results, although the data did not reflect it. Finally, gene–gene and gene–environment interactions, which may modulate the cancer susceptibility, were excluded in our analysis, and this may cause some errors. In conclusion, this updated meta-analysis can probably reflect the association between SHMT1 C1420T polymorphism and the cancer risk. Although some limitations still exist, our results suggest that SHMT1 1420TT may be a potential protection factor for Asian population and colorectal cancer patients. It may be a potential biomarker for cancer prevention. More well-designed studies about SHMT1 C1420T with detailed information and large sample size are needed to validate our findings. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments This study was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) (JX10231801), the Health Department guidance project of Jiangsu Province (Z201201), the Jiangsu Province Clinical science and technology projects (Clinical Research Center, BL2012008) and the Summit of the Six Top Talents Program of Jiangsu Province (WSN-034). References [1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61(2):69–90. [2] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127(12):2893–917. [3] Hua RX, Li HP, Liang YB, Zhu JH, Zhang B, Ye S, et al. Association between the PARP1 Val762Ala polymorphism and cancer risk: evidence from 43 studies. PLoS One 2014;9(1):e87057. [4] Levi F, Pasche C, La Vecchia C, Lucchini F, Franceschi S. Food groups and colorectal cancer risk. Br J Cancer 1999;79(7–8):1283–7. [5] Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer – analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000;343(2):78–85. [6] Snell K, Natsumeda Y, Eble JN, Glover JL, Weber G. Enzymic imbalance in serine metabolism in human colon carcinoma and rat sarcoma. Br J Cancer 1988;57(1):87–90. [7] Wang Y, Guo W, He Y, Chen Z, Wen D, Zhang X, et al. Association of MTHFR C677T and SHMT(1) C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China. Cancer Causes Control 2007;18(2):143–52. [8] Girgis S, Suh JR, Jolivet J, Stover PJ. 5-Formyltetrahydrofolate regulates homocysteine remethylation in human neuroblastoma. J Biol Chem 1997;272(8): 4729–34. [9] Wang YM, Guo W, Zhang XF, Li Y, Wang N, Ge H, et al. [Correlations between serine hydroxymethyltransferase1 C1420T polymorphisms and susceptibilities to esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma]. Ai Zheng 2006;25(3):281–6. [10] Heil SG, Van der Put NM, Waas ET, den Heijer M, Trijbels FJ, Blom HJ. Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Mol Genet Metab 2001;73(2):164–72.
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