The polymorphisms in the three main heat shock protein 70 (HSP70-1, HSP70-2, and HSP70-hom) genes were identified to be associated with cancer risk. However, the results are inconsistent. We perform a meta-analysis to evaluate the association between the three HSP70 polymorphisms and cancer risk. Relevant studies were identified using PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases up to March 29, 2014. The cancer risk associated with the HSP70 polymorphisms was estimated for each study by odds ratios (OR) together with its 95% confidence interval (CI), respectively. Twenty case-control studies from eighteen publications were included; a significant association was observed for HSP70-2 polymorphism (dominant model: OR = 1.53, 95% CI: 1.11–2.09; recessive model: OR = 1.91, 95% CI: 1.06–3.45; AG versus AA: OR = 1.38, 95% CI: 1.03–1.84; GG versus AA: OR = 2.34, 95% CI: 1.21–4.54), while there was no significant association for HSP70-1 and HSP70-hom polymorphisms. Besides, in stratification analyses by ethnicity, cancer type, and source of control, significant association was detected for HSP70-2 polymorphism, while for HSP70-hom polymorphism, we found a significant association in hospital-based population under homozygote comparison model. This meta-analysis suggests that the HSP70-2 polymorphism rather than HSP70-hom and HSP70-1 polymorphisms was associated with the risk of cancer.
Cancer is recognized as one of the leading causes of death in economically developed countries as well as in developing countries. According to the estimation of GLOBOCAN, approximately 12.7 million new cases and 7.6 million deaths of cancer had occurred in 2008, it has become a major public health challenge [
Heat shock proteins (HSPs) are evolutionarily highly conserved stress proteins expressed and induced by heat shock, infection, inflammation, ischemia hypoxia, oxidative stress, carcinogens, and so on [
To date, several studies have investigated the association between the three HSP70 polymorphisms and risk of cancer [
We searched for relevant studies before March 29, 2014, by using electronic PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases with the following terms: “heat shock protein 70 or HSP70,” “genetic polymorphism or polymorphisms or variant or SNP,” and “cancer or carcinoma or tumor.” The search was restricted to humans and without language restrictions. Additional studies were identified by a hand search of references of original or review articles on this topic. If more than one geographic or ethnic heterogeneous group was reported in one report, each was extracted separately.
The inclusion criteria were as follows: (1) studies that evaluated the association between the HSP70 polymorphisms and cancer, (2) a case-control study design, and (3) studies that had detailed genotype frequency of cases and controls or could be calculated from the paper text, while major exclusion criteria were (1) case-only study, case reports, and review articles, (2) studies without the raw data of the HSP70 genotype, and (3) studies that compared the HSP70 variants in precancerous lesions.
The following information was extracted from each eligible publication: the first author’s name, year of publication, country of origin, ethnicity, cancer type, source of control, genotyping methods, number of cases and controls, and Hardy-Weinberg equilibrium (HWE) in controls (
The risk of cancer associated with the HSP70 polymorphisms was estimated for each study by odds ratio (OR) and 95% confidence interval (95% CI). Four different ORs were calculated: dominant model (the combined variant homozygote and heterozygote versus the wild-type homozygote), recessive model (the variant homozygote versus the combined heterozygote and wild-type homozygote), heterozygote comparison (heterozygote versus the wild-type homozygote), and homozygote comparison (variant homozygote versus the wild-type homozygote). A
All analyses were performed by the Cochrane Collaboration RevMan 5.2 and STATA package version 12.0 (Stata Corporation, College Station, Texas).
After an initial search, a total of 132 published articles relevant to the topic were identified. According to the inclusion criteria, 21 studies [
Characteristics of studies included in the meta-analysis.
Study | Year | Country | Ethnicity | Cancer type | Source of |
Genotype |
Genotype (case/control) | HWE | |||
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Total | WT Ho | Ht | VR Ho | ( |
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HSP70-2 | AA | AG | GG | ||||||||
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Chouchane et al. [ |
1997a | Tunisia | African | Non-Hodgkin’s lymphoma | PB | AFLP | 44/106 | 4/22 | 28/82 | 12/2 | 0 |
Chouchane et al. [ |
1997b | Tunisia | African | Breast | PB | AFLP | 40/106 | 4/22 | 26/82 | 10/2 | 0 |
Ferrer-Ferrer et al. [ |
2013 | Costa Rica | Mixed | Gastric | HB | RFLP | 39/79 | 7/30 | 26/32 | 6/17 | 0.137 |
Jalbout et al. [ |
2003 | Tunisia | African | Nasopharyngeal | PB | AFLP | 140/274 | 40/101 | 68/138 | 32/35 | 0.251 |
Jeng et al. [ |
2008 | Taiwan (China) | Asian | Hepatocellular | HB | AFLP | 150/150 | 28/70 | 55/65 | 67/15 | 0.987 |
Kádár et al. [ |
2008 | Hungary | European | Multiple myeloma | PB | PCR-RFLP | 94/141 | 34/65 | 60/76* | NA | |
Li et al. [ |
2010 | China | Asian | Hepatocellular | HB | PCR | 145/127 | 48/56 | 71/62 | 26/9 | 0.139 |
Medhi et al. [ |
2013 | India | Asian | Hepatocellular | PB | PCR-RFLP | 185/200 | 111/156 | 59/40 | 15/4 | 0.453 |
Mestiri et al. [ |
2001 | Tunisia | African | Breast | PB | PCR | 243/174 | 52/35 | 123/130 | 68/9 | 0 |
Rehman et al. [ |
2009 | India | Aisian | Kangri cancer | PB | PCR-RFLP | 118/95 | 10/24 | 103/70 | 5/1 | 0 |
Shibata et al. [ |
2009 | Japan | Asian | Gastric | HB | PCR-RFLP | 225/200 | 46/33 | 173/155 | 6/12 | 0 |
Srivastava et al. [ |
2012 | India | Asian | Pancreatic | PB | PCR-RFLP | 50/50 | 13/33 | 29/15 | 8/2 | 0.858 |
Tóth et al. [ |
2007 | Hungary | European | Colorectal | PB | PCR-RFLP | 183/141 | 69/65 | 87/57 | 27/19 | 0.258 |
Ucisik-Akkaya et al. [ |
2010a | UK | European | Childhood ALL | PB | PCR-RFLP | 114/414 | 58/139 | 47/199 | 9/76 | 0.747 |
Ucisik-Akkaya et al. [ |
2010b | Mexico | Mixed | Childhood ALL | PB | PCR-RFLP | 92/235 | 27/61 | 51/111 | 14/63 | 0.397 |
Wang et al. [ |
2010 | China | Asian | Lung | HB | PCR-RFLP | 159/202 | 57/56 | 72/100 | 30/46 | 0.915 |
Zagouri et al. [ |
2012 | Greece | European | Breast | HB | PCR | 113/124 | 24/32 | 82/76 | 7/16 | 0.006 |
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HSP70-hom | TT | TC | CC | ||||||||
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Chouchane et al. [ |
1997a | Tunisia | African | Non-Hodgkin’s lymphoma | PB | AFLP | 44/106 | 31/98 | 10/8 | 3/0 | 0.686 |
Chouchane et al. [ |
1997b | Tunisia | African | Breast | PB | AFLP | 40/106 | 31/98 | 8/8 | 1/0 | 0.686 |
Ferrer-Ferrer et al. [ |
2013 | Costa Rica | Mixed | Gastric | HB | RFLP | 39/79 | 34/55 | 5/23 | 0/1 | 0.409 |
Guo et al. [ |
2011 | China | Asian | Lung | PB | TaqMan | 1152/1152 | 674/695 | 412/411 | 66/46 | 0.124 |
Medhi et al. [ |
2013 | India | Asian | Hepatocellular | PB | PCR-RFLP | 185/200 | 178/144 | 7/42 | 0/14 | 0.0001 |
Rehman et al. [ |
2009 | India | Aisian | Kangri cancer | PB | PCR-RFLP | 118/95 | 60/28 | 56/60 | 2/7 | 0.001 |
Sfar et al. [ |
2010 | Tunisia | African | Prostate | PB | PCR-RFLP | 101/105 | 77/65 | 20/32 | 4/8 | 0.164 |
Ucisik-Akkaya et al. [ |
2010a | UK | European | Childhood ALL | PB | TaqMan | 105/371 | 67/246 | 30/103 | 8/22 | 0.015 |
Ucisik-Akkaya et al. [ |
2010b | Mexico | Mixed | Childhood ALL | PB | TaqMan | 99/245 | 87/214 | 11/27 | 1/4 | 0.008 |
Wang et al. [ |
2010 | China | Asian | Lung | HB | PCR-RFLP | 159/202 | 95/141 | 56/59 | 8/2 | 0.120 |
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HSP70-1 | GG | GC | CC | ||||||||
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Guo et al. [ |
2011 | China | Asian | Lung | PB | TaqMan | 1152/1152 | 589/564 | 457/486 | 106/102 | 0.853 |
Partida-Rodríguez et al. [ |
2010 | Mexico | Mixed | Gastric | HB | PCR-RFLP | 42/106 | 4/59 | 37/41 | 1/6 | 0.746 |
Ucisik-Akkaya et al. [ |
2010a | UK | European | Childhood ALL | PB | TaqMan | 106/365 | 47/137 | 45/162 | 14/66 | 0.139 |
Ucisik-Akkaya et al. [ |
2010b | Mexico | Mixed | Childhood ALL | PB | TaqMan | 99/250 | 62/127 | 32/98 | 5/25 | 0.347 |
Wang et al. [ |
2010 | China | Asian | Lung | HB | PCR-RFLP | 159/202 | 57/104 | 65/82 | 37/16 | 0.977 |
HWE, Hardy-Weinberg equilibrium;
Flow chart showing study selection procedure.
For HSP70-2 polymorphism, 17 studies with 2134 cases and 2818 controls were identified. Overall, a significant association was found (dominant model: OR = 1.53, 95% CI: 1.11–2.09; recessive model: OR = 1.91, 95% CI: 1.06–3.45; AG versus AA: OR = 1.38, 95% CI: 1.03–1.84; GG versus AA: OR = 2.34, 95% CI: 1.21–4.54) (Figure
Summary of ORs of the HSP70 polymorphism and cancer risk.
Variables |
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Dominant model | Recessive model | Ht versus WT Ho | VR Ho versus WT Ho | ||||||||
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OR (95% CI) |
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OR (95% CI) |
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|
OR (95% CI) |
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OR (95% CI) |
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Total | 17 | 1.53 (1.11, 2.09) | <0.00001 | 81 | 1.91 (1.06, 3.45) | <0.00001 | 87 | 1.38 (1.03, 1.84) | <0.00001 | 74 | 2.34 (1.21, 4.54) | <0.00001 | 88 |
Ethnicity | |||||||||||||
Asian | 7 | 1.96 (1.10, 3.51) | <0.00001 | 87 | 2.34 (0.94, 5.85) | <0.00001 | 86 | 1.67 (1.03, 2.71) | <0.0001 | 80 | 3.12 (0.99, 9.77) | <0.00001 | 89 |
European | 4 | 1.06 (0.59, 1.89) | 0.0009 | 82 | 0.59 (0.29, 1.22) | 0.06 | 64 | 1.04 (0.54, 1.99) | 0.007 | 80 | 0.61 (0.23, 1.66) | 0.01 | 78 |
African | 4 | 1.34 (1.00, 1.80) | 0.19 | 37 | 7.06 (2.33, 21.41) | 0.0009 | 82 | 1.09 (0.66, 1.82) | 0.11 | 51 | 7.56 (2.44, 23.39) | 0.005 | 77 |
Mixed | 2 | 1.44 (0.45, 4.65) | 0.03 | 79 | 0.53 (0.31, 0.91) | 0.62 | 0 | 1.78 (0.55, 5.78) | 0.03 | 78 | 0.77 (0.27, 2.23) | 0.13 | 55 |
Cancer type | |||||||||||||
Hepatocellular | 3 | 2.41 (1.50, 3.87) | 0.06 | 65 | 4.98 (3.18, 7.79) | 0.19 | 40 | 1.80 (1.34, 2.42) | 0.38 | 0 | 6.07 (2.79, 13.19) | 0.10 | 57 |
Breast | 3 | 1.16 (0.81, 1.64) | 0.29 | 19 | 3.61 (0.43, 30.28) | <0.00001 | 92 | 1.06 (0.55, 2.05) | 0.07 | 62 | 3.86 (0.56, 26.43) | 0.0002 | 88 |
Others | 11 | 1.39 (0.93, 2.07) | <0.00001 | 82 | 1.13 (0.64, 2.00) | <0.00001 | 78 | 1.37 (0.92, 2.06) | <0.00001 | 78 | 1.43 (0.70, 2.93) | <0.00001 | 83 |
Source of control | |||||||||||||
PB | 11 | 1.57 (1.06, 2.34) | <0.00001 | 81 | 2.69 (1.21, 5.97) | <0.00001 | 87 | 1.44 (0.95, 2.16) | <0.00001 | 78 | 3.27 (1.36, 7.83) | <0.00001 | 87 |
HB | 6 | 1.46 (0.83, 2.57) | <0.00001 | 84 | 1.17 (0.44, 3.09) | <0.00001 | 90 | 1.31 (0.86, 2.00) | 0.006 | 69 | 1.43 (0.46, 4.47) | <0.00001 | 90 |
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Total | 10 | 0.85 (0.53, 1.37) | <0.00001 | 87 | 1.05 (0.50, 2.18) | 0.008 | 60 | 0.84 (0.55, 1.29) | <0.00001 | 83 | 0.98 (0.43, 2.24) | 0.001 | 68 |
Ethnicity | |||||||||||||
Asian | 4 | 0.55 (0.24, 1.28) | <0.00001 | 93 | 0.68 (0.14, 3.32) | 0.001 | 81 | 0.59 (0.28, 1.23) | <0.00001 | 91 | 0.57 (0.09, 3.42) | 0.0002 | 85 |
European | 1 | 1.12 (0.71, 1.75) | NA | NA | 1.31 (0.56, 3.03) | NA | NA | 1.07 (0.66, 1.74) | NA | NA | 1.34 (0.57, 3.13) | NA | NA |
African | 3 | 2.02 (0.41, 9.94) | <0.0001 | 90 | 3.03 (0.24, 38.65) | 0.04 | 70 | 1.79 (0.44, 7.29) | 0.0006 | 86 | 3.33 (0.20, 55.83) | 0.02 | 75 |
Mixed | 2 | 0.61 (0.22, 1.68) | 0.11 | 61 | 0.63 (0.10, 3.88) | 0.97 | 0 | 0.64 (0.23, 1.77) | 0.11 | 61 | 0.59 (0.10, 3.64) | 0.95 | 0 |
Source of control | |||||||||||||
PB | 8 | 0.86 (0.49, 1.52) | <0.00001 | 89 | 0.87 (0.39, 1.94) | 0.008 | 63 | 0.85 (0.51, 1.42) | <0.00001 | 85 | 0.79 (0.32, 1.98) | 0.001 | 71 |
HB | 2 | 0.78 (0.18, 3.50) | 0.008 | 86 | 3.58 (0.99, 12.93) | 0.26 | 23 | 0.77 (0.20, 2.97) | 0.02 | 82 | 3.66 (1.03, 13.02) | 0.19 | 42 |
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Total | 5 | 1.30 (0.75, 2.24) | <0.00001 | 89 | 1.02 (0.52, 2.00) | 0.0008 | 79 | 1.26 (0.75, 2.12) | <0.0001 | 86 | 1.13 (0.52, 2.45) | 0.0001 | 83 |
Meta-analysis of the association between HSP70-2 polymorphism and susceptibility to cancer. ((a) dominant model; (b) recessive model; (c) AG versus AA; (d) GG versus AA.)
For HSP70-hom polymorphism, 10 studies with 2042 cases and 2661 controls were identified. Overall, no significant association was found under all genetic models (dominant model: OR = 0.85, 95% CI: 0.53–1.37; recessive model: OR = 1.05, 95% CI: 0.50–2.18; TC versus TT: OR = 0.84, 95% CI: 0.55–1.29; CC versus TT: OR = 0.98, 95% CI: 0.43–2.24). When the analysis was stratified by ethnicity, similar results were observed among Asian, European, African, and mixed populations. While, in stratified analysis by source of controls, a significant association was found in the hospital-based subgroup (CC versus TT: OR = 3.66, 95% CI: 1.03–13.02) but not in the population-based subgroup (Table
For HSP70-1 polymorphism, 5 studies with 1558 cases and 2075 controls were identified. The pooled results suggested that no significant association was found in overall analysis (dominant model: OR = 1.30, 95% CI: 0.75–2.24; recessive model: OR = 1.02, 95% CI: 0.52–2.00; GC versus GG: OR = 1.26, 95% CI: 0.75–2.12; CC versus GG: OR = 1.13, 95% CI: 0.52–2.45) (Table
For all three polymorphisms, substantial heterogeneities were observed among overall studies in all four genetic models (HSP70-2: dominant model:
Begg’s funnel plot and Egger’s test were performed to assess the potential publication bias in the available literature. The shape of funnel plots did not reveal any evidence of funnel plot asymmetry (data not shown). Egger’s test also showed that there was no statistical significance for the evaluation of publication bias under dominant model (HSP70-2 polymorphism:
To our knowledge, this is the first meta-analysis which comprehensively assessed the associations between HSP70 polymorphisms and cancer risk. In this study, we found significant associations in the overall comparison for HSP70-2 polymorphism. Individuals with the AG/GG genotype could have an increased risk of cancer. However, we failed to detect any association for HSP70-1 and HSP70-hom polymorphisms. Moreover, in the stratified analyses by several variables, including ethnicity, cancer type, and source of the controls, significant association was detected among Asians, Africans, hepatocellular carcinoma, and population-based population for HSP70-2 polymorphism, while for HSP70-hom polymorphism, we observed a significant association in hospital-based population under homozygote comparison model.
The HSP70 family is the most important and best characterized family of stress proteins. It acts as a chaperone molecule for antigenic peptides derived from tumor cells, leading to an antitumor immune recognition by cytotoxic T lymphocytes [
In this meta-analysis, we found that individuals with AG/GG genotype had a higher risk of developing cancer under all four models in HSP70-2 polymorphism; besides, in the stratified analyses by ethnicity, cancer type, and source of control, we found that G allele carriers had a higher risk of cancer than AA genotype carriers in Asians, Africans, hepatocellular carcinoma, and population-based population. With regard to HSP70-hom and HSP70-1 polymorphisms, the genotype distribution between cancer and control was not of significant difference. The inconsistent results may be attributed to differences in genetic backgrounds, environmental factors, and other factors, such as small sample size or inadequate adjustment for confounding factors. For example, the distribution of the AA genotype is about twice as frequent in the Chinese Han population, and the frequency of the GG genotype is similar, slightly above 25%, in the Costa Rican, Mexican, and Chinese population, whereas it does not reach 10% in the Tunisian, Indian, and Japanese groups [
Two significant issues should be addressed in this study, that is, heterogeneity and publication bias, which may influence the results of meta-analysis. We do not detect a significant publication bias in this meta-analysis, suggesting the reliability of our results. With regard to heterogeneity, substantial heterogeneities were observed among overall studies in all four genetic models for all three polymorphisms, when stratified analysis by ethnicity, cancer type and source of the controls were conducted. For HSP70-2 polymorphism, we found that heterogeneity significantly reduced or removed among Africans, mixed populations, and hepatocellular and breast cancers but not among Asians, Europeans, other cancers, population-based, and hospital-based populations. For HSP70-hom polymorphism, heterogeneity significantly reduced or removed in mixed populations and hospital-based populations, but it still exists among Asians, Africans, and population-based populations. When excluded the study by Partida-Rodríguez et al. or Wang et al. in HSP70-1 polymorphism, the study by Medhi et al. in HSP70-hom polymorphism, the heterogeneity was effectively decreased. The results above suggest that different ethnicity, tumor types, control selection, and particular study may be the source of heterogeneity.
This meta-analysis has limitations that must be acknowledged. First, because of incomplete raw data or publication limitations, some relevant studies could not be included in our analysis. Second, the controls included in our analysis were selected variously either from populations or hospitals. Therefore, misclassification bias was possible because these studies may have included control groups who have different risks of developing cancer. Third, our results were based on unadjusted estimates, while lacking of the information (such as age, gender, family history and other risk factors) for the date analysis may cause serious confounding bias.
In summary, this meta-analysis suggested that the HSP70-2 polymorphism rather than HSP70-hom and HSP70-1 polymorphisms was associated with the risk of cancer. However, large and well-designed studies taking into consideration gene-gene and gene-environment interactions are warranted to validate our findings.
The authors have declared that no conflict of interests exists.