Annals of Oncology Advance Access originally published online on February 23, 2006
Annals of Oncology 2006 17(4):657-662; doi:10.1093/annonc/mdl018
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© 2006 European Society for Medical Oncology
Promoter methylation of helicase-like transcription factor is associated with the early stages of gastric cancer with family history
1 Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine; 2 Seoul Science High School; 3 Center for Genome Research, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine; 4 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine; 5 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine; 6 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea
* Correspondence to: Dr D-H. Kim, Center for Genome Research, Samsung Biomedical Research Institute, Rm B155, #50 Ilwon-dong, Kangnam-Ku, Seoul, Korea, 135–710. Tel: +82 (02) 3410–3632; Fax: +82 (02) 3410–3649; E-mail: dukhwan.kim{at}samsung.com
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Abstract |
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Background: To investigate the clinicopathological significance of promoter methylation of the helicase-like transcription factor (HLTF) in primary gastric cancer.
Patients and methods: Two-hundred fifty six patients participated in this study. Methylation status of HLTF gene was evaluated in fresh-frozen tissues by the methylation-specific polymerase chain reaction. All statistical analyses were two-sided, with a 5% type I error rate.
Results: Aberrant methylation of HLTF was found in 98 (38%) of 256 gastric cancer patients. HLTF methylation was significantly associated with a family history in the early stages of gastric cancer, regardless of histologic types. In intestinal-type cases, HLTF methylation occurred in 15 (56%) of 27 patients with family histories, and in 26 (31%) of 85 patients without family histories (P = 0.02). In diffuse-type cases, patients with family histories were also found to exhibit a higher prevalence of HLTF methylation than those without family histories (61% vs. 34%; P = 0.009). HLTF methylation in both of the histologic types occurred in about 70–90% of the early stage cases in which the patient had a family history and in 15–30% of cases in which the patient did not have a family history. In our multivariate logistic regression analysis, the stage 1–2 cases with family histories were determined to carry a higher risk of HLTF methylation than did the stage 3–4 cases without family histories in both the intestinal-type (OR = 6.01, 95% CI = 1.20–30.01, P = 0.02) and the diffuse-type cancers (OR = 8.25, 95% CI = 1.67–40.86, P = 0.009).
Conclusions: These results suggest that HLTF methylation may play a crucial role in the early stages of gastric carcinogenesis in patients with family histories and may be a valuable susceptible marker for the risk of gastric cancer in individuals with family histories.
Key words: HLTF, methylation, gastric cancer, family history, early stage
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introduction |
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Despite the apparent decline in gastric cancer incidence in some countries, it still remains a major cause of worldwide cancer morbidity and mortality. Gastric cancer tends to emerge via a multi-step process, which involves the progressive accumulation of both genetic and epigenetic alterations [1
]. Pathologically, gastric cancers are classified according to the histomorphological classifications, established by Lauren [2], into two major types: intestinal-type and diffuse-type. The intestinal-types are usually exophytic and are often associated with intestinal metaplasia of the stomach. The diffuse-types are poorly differentiated infiltrating lesions, and tend to manifest marked scattered cell growth, with fairly loose intercellular adhesion. A series of epidemiological studies have demonstrated that a variable, but significant, proportion of cases strongly point to a familial history of gastric cancer [3]. However, the pathogenesis of these familial gastric cancers has yet to be defined clearly.
The SWI/SNF (mating type switching/sucrose nonfermenting) chromatin-remodeling complex is known to harbor a large helicase-like domain, which functions as a DNA-dependent ATPase and contributes to the regulation of gene expression via its modulation of nucleosome positioning and spacing [4–5]. The results of recent studies have indicated that subunits of the SWI/SNF complex may be linked to the development of human cancer, and may function as tumor suppressors [6–8]. The loss of expression of the helicase-like transcription factor (HLTF), a member of the SWI/SNF family protein, has been reported in patients who suffer from gastric cancers [9–10].
The aberrant methylation of CpG islands is an epigenetic change which has been shown to induce the transcriptional silencing of tumor suppressor genes [11–12]. The CpG island methylation of HLTF gene has recently been detected in cancers of the colon, esophagus, and stomach, but has not been detected in breast or lung cancers [7, 9–10, 13], thereby suggesting that HLTF may play a distinct role in carcinogenesis of the gastrointestinal epithelia. The aberrant methylation of the CpG island at the promoter region of the HLTF gene has been detected in approximately 20–50% of primary gastric cancers, suggesting that HLTF methylation is a frequently-encountered feature of tumorigenesis in the stomach [9–10, 13]. However, the relationship of HLTF methylation with clinicopathologic characteristics was not consistent due to probably a very small number of sample size, about 45–65 patients [9–10, 13]. Therefore, we have attempted to delineate the relationship of HLTF methylation to a series of clinicopathological parameters in a large sample, in order to gain more insight into the role of HLTF with regard to the pathogenesis of gastric cancer.
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study population
A total of 256 patients who suffered from gastric cancer participated in this study, all of whom had undergone curative surgical resection for gastric cancers between February 2001 and July 2004 at the Department of Surgery, at the Samsung Medical Center, in Seoul, Korea, participated in this study. Written informed consent for the use of surgically removed tumor tissues, according to protocols previously approved by the Institutional Review Board at the Samsung Medical Center, was provided by all gastric cancer patients prior to operation.
Information regarding family histories of gastric cancer, as well as demographics and lifestyle factors, were obtained via an interviewer-administered questionnaire. Family history of gastric cancer was defined as when the patient had at least one first-degree relative with a story of gastric cancer. Postoperative follow-up examinations were scheduled at 1 month, and then again every 3 months for the first 2 years after gastrectomy, and then every 6 months for the next 2 years, and then annually thereafter or more frequently if required. The 256 patients included in this study were aged between 21–87 years.
DNA extraction from fresh tissues
Gastric cancer tissues and the corresponding non-neoplastic tissues far from tumor tissues were surgically removed, immediately snap-frozen in liquid nitrogen, then stored at –80°C until use. Histological grades were classified in accordance with the criteria of Lauren [2] and the World Health Organization [14]. The tumors were staged at the time of surgery, using the standard criteria for TNM staging established by the American Joint Committee on Cancer [15]. The fresh-frozen tissues were sectioned with a microtome, and the serial sections were placed on slides prior to DNA extraction, then stained with hematoxylin-eosin in order to evaluate the admixture of tumorous and nontumorous tissues. Areas corresponding to the tumors were carefully microdissected. Tissues containing at least 75% neoplastic cells were used in this study. The microdissected tissues were digested with proteinase K, then resuspended in lysis buffer ATL (DNeasy Tissue kit, Qiagen, Valencia, CA), after which the genomic DNA was isolated according to the instructions provided by the manufacturer.
methylation-specific polymerase chain reaction
The methylation status of the CpG island at the promoter region of the HLTF gene was determined by methylation-specific PCR (MSP) (Figure 1), as was described by Herman et al. [16] (Figure 1). Two pairs of primers were used, one specific for the methylated promoter and the other specific for the unmethylated promoter, which was an internal control for the validity of MSP. The primer sequences for the methylated and unmethylated HLTF promoter have been previously described by Moinova et al. [7]. The primer sequences for the amplification of the methylated HLTF promoter were as follows: 5'-TGGGGGTTTCGTGGTTTTTTCGCGC-3' (sense) and 5'-CCGCGAATCCAATCAAACGTCGACG-3' (antisense), and the primer sequences for the unmethylated HLTF were 5'-ATTTTTGGGGTTTTGTGGTTTTTTTGTGT-3' (sense) and 5'-ATCACCACAAATCCAATCAAACAT-3' (antisense). One microgram of genomic DNA from the fresh-frozen tissues was then denatured via 10 min of incubation with 0.3M NaOH for 10 min at 37°C, and was then modified with 3M sodium bisulfite (pH 5.0). The bisulfite modified DNA was then purified with WizardTM DNA purification resin according to the manufacturer's instructions (Promega Corp., Madison, WI), desulphonated with 3M NaOH, precipitated with ethanol, and finally dissolved in 20 µl of 5 mM Tris (pH 8.0). Forty microliters of DNA extracted from the plasma was also bisulfite-modified, using a CpGenomeTM DNA modification kit (Chemicon, Temecula, CA) in accordance with the manufacturer's recommendations, then dissolved in 20 µl of TE (10 mM Tris, 1 mM EDTA, pH 8.0). The PCR mixture consisted of 1x PCR buffer (50 mM KCl, 67 mM Tris, pH 8.8, 1.5 mM MgCl2), deoxynucleotide triphosphates (each 0.25 µM), primers (300 ng of each per reaction), 2.5 units of Taq polymerase, and bisulfite-modified DNA (50 ng of modified DNA from fresh-frozen tissue, or 1 µl of modified plasma DNA) as a template for MSP. The PCR was conducted using a hot start for 5 min at 95°C and then the following cycles: 35 amplification cycles (95°C for 30s, 66°C for 45s, and 72°C for 30s) and a final, 10-min extension at 72°C.
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DNA obtained from peripheral blood lymphocytes of healthy volunteers was treated with SssI methyltransferase (New England Biolabs, Inc., Beverly, MA), subjected to bisulfite modification, and used as a positive-control for the methylated alleles. Bisulfite-modified DNA obtained from normal lymphocytes was used as a positive control for the unmethylated alleles, and unconverted DNA acquired from normal lymphocytes was used as a negative control for the methylated alleles. Negative control samples without DNA were included in each of the PCR. The PCR products were visualized on 2% agarose gel stained with ethidium bromide. Reactions were performed in duplicate with each of the samples, in order to ensure the reproducibility and consistency of the results.
statistical analysis
The continuous variables were assessed for normality via the Shapiro-Wilk test. The Wilcoxon rank sum test (or t-test) and Fisher's exact test (or the chi-square test) were used in the univariate analysis of continuous and categorical variables, respectively. Multivariate logistic regression was conducted to determine the relationship between HLTF methylation and any of the covariates found to be statistically significant in the univariate analysis, and also to calculate the Odds Ratios (ORs). All of the covariates with P-values less then 0.25 on the univariate analysis were subjected to multivariate analyses. All statistical analyses were two-sided with a 5% type I error rate.
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clinicopathological characteristics
The associations determined to exist between HLTF methylation in the 256 gastric cancer patients and the clinicopathological features of these patients are shown in Table 1. Aberrant methylation of HLTF promoter was detected in 98 (38%) of the 256 cases with primary gastric cancer. The mean age of the patients were similar in the patients with and without HLTF methylation. HLTF methylation was determined to have occurred more prevalently in women than in men, but this was not a statistically significant difference (P = 0.64). Patients with neural invasion were found to exhibit a higher prevalence of HLTF methylation than those without (47% versus 36%; P = 0.09). Although not a statistically significant result (P = 0.70), HLTF methylation was also found to occur more frequently in patients whom lymphovascular invasion was observed than in those without. HLTF methylation was determined to occur at a higher prevalence in diffuse types of Lauren classification than in intestinal types (39% versus 37%), but the difference was not statistically significant (P = 0.86).
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We found no statistically significant associations between HLTF methylation and the pathologic stage of the patient. HLTF methylation was noted to occur in 29 (41%) of the 71 patients with stage I disease, 22 (36%) of the 61 with stage II disease, 26 (39%) of the 67 with stage III disease, and 21 (37%) of the 57 diagnosed with stage IV disease (P = 0.94). Gastric cancer recurrence was noted in 23 (10%) of the 232 patients in which recurrence data were available, but these recurrences were not associated with HLTF methylation (P = 0.47). With regard to family histories of gastric cancer, HLTF methylation was found in 66 (33%) of the 199 patients with no family history of gastric cancer, and in 32 (56%) of the 57 patients with family histories of gastric cancer (P = 0.002). This indicates that the hypermethylation of the HLTF promoter tends to be seen more frequently in patients with family histories of gastric cancer than in those without.
analysis of HLTF methylation according to the histological types
Gastric cancers have been histologically classified into either intestinal-type or diffuse-type cancers [2]. These two types exhibit different epidemiological and pathophysiological features, thereby suggesting that the effect of a gene inactivation on the carcinogenic process is different in both types. Therefore, our data were stratified according to histologic type in order to further study the relationship between HLTF methylation and clinocopathological parameters in more detail. Relationships between HLTF methylation and age, sex, neural invasion, lymphovascular invasion, and recurrence were not determined to be significant in the intestinal-type cancers, nor in the diffuse-type cancers (data not shown). However, we did note a significant relationship between family history and HLTF methylation in both the histological types (Table 2). In the intestinal-type cancers, HLTF methylation occurred in 15 (56%) of 27 patients with family histories and in 26 (31%) out of 85 patients without, and this difference was determined to be a statistically significant one (P = 0.02). In the diffuse-type cancers, patients with family histories were determined to exhibit HLTF methylation at a higher prevalence than those without (61% versus 34%; P = 0.009). These results suggest that HLTF methylation is strongly associated with family histories, regardless of histological types.
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The relationship between HLTF methylation and pathological stage was also evaluated in order to determine the role of HLTF during the progression of gastric cancer. However, HLTF methylation was not significantly associated with pathological stage in either of the histological types (Figure 2). Our data was then further stratified according to family history, as HLTF methylation had been determined to be significantly associated with family history. The relationship between HLTF methylation and pathological stage was found to differ significantly according to family history (Figure 3). For patients without family histories of the disease, the prevalence of HLTF methylation was determined not to differ significantly between all stages of intestinal-type (P = 0.54) and of diffuse-type (P = 0.61). However, for patients with family histories, HLTF methylation was determined to occur with significantly different prevalences in the early and advanced stages. HLTF methylation was detected in approximately 70–90% of early stage cases in which family history was involved, and in 15–30% of the cases in which family history was not involved. The prevalence of HLTF methylation was determined to have significantly decreased in advanced cases in which family history was involved. These results suggest that HLTF plays a role in the early carcinogenesis of gastric cancer in patients with family histories of the disease.
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multivariate logistic regression analysis
Our data was stratified according to histological types, and we conducted stratified multivariate logistic regression with the 256 cases of gastric cancer in an attempt to determine the relationship occurring between HLTF methylation and any of the covariates which had been found to be statistically significant in the univariate analysis, and to calculate the Odds Ratios (ORs) (Table 3). Pathological stages were categorized into early (stages 1–2) and advanced (stages 3–4) stages. The stages 1–2 cases without family histories were used as a reference group, as those cases had been determined to exhibit the lowest prevalence of HLTF methylation in the univariate analysis. The coefficient for variable age was not determined to be statistically significant in our univariate analyses (P = 0.94), but age was considered to be a biologically important variable, and it was thus included in the multivariate analysis in order to better construct a parsimonious model. With regard to the intestinal-type cancers, the risk of HLTF methylation for stages 1–2 cases with family histories was determined to be 6.01 times as high as that of the reference group (95% CI = 1.20–30.01, P = 0.02). HLTF methylation in diffuse-type cases in stages 1–2 with family histories occurred at a 8.25 (95% CI = 1.67–40.86, P = 0.009) times higher prevalence than the reference group.
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discussion |
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Both epidemiological and genetic studies have clearly shown that a family history of gastric cancer is an important risk factor of gastric cancer. This study attempted to gain greater insight into the role of HLTF methylation in gastric cancer, especially with regard to histological subtypes and family history. The prevalence of HLTF methylation determined in the present study was fairly consistent with the findings of other groups [9
–10, 13]. In the present study, HLTF methylation was significantly associated with early pathological stages of gastric cancer in patients with family histories of the disease, regardless of the histological subtype. These observations indicate that HLTF methylation is a common event in both histological types of gastric cancer in patients with family histories, and may be one of the most important factors in the early stages of gastric carcinogenesis in patients with family histories.
Gastric cancer is characterized by a marked heterogeneity in both morphology and function. The scenario of multiple gene changes in gastric cancer is known to differ, depending on the two histologic types, indicating that the two types of gastric cancer may occur via different genetic pathways [17–18]. Intestinal-type cancers are more frequently encountered within the general population, are more likely to occur sporadically, and have also been more strongly associated with environmental factors. These factors include diet, particularly the ingestion of salted fish and meat and smoked foods, as well as cigarette smoking and the use of alcohol. However, diffuse-type cancers are more likely to have a primarily genetic etiology. The risk of gastric cancer in relatives of patients has also been shown to be dependent upon histology. Relatives of patients with intestinal-type cancer carry a 1.4-fold increase in the risk of developing gastric cancer, as compared with the 7.0-fold increase in risk carried by relatives of patients with diffuse-type disease [19]. This would appear to suggest that diffuse-type gastric cancer has a greater hereditary basis than intestinal-type gastric cancer. However, in the present study, we determined a family history of the disease to be a factor in 24% of the intestinal-type cases, and 21% of the diffuse-type cases (P = 0.74). This may result from the small number of patients with family histories or from the blurring of genetic effects by environmental factors.
It remains somewhat unclear as to what is ultimately responsible for the HLTF methylation seen in the early stages of cases in patients with family histories. One possibility is that shared environmental risk factors, acting independently or in conjunction with genetic factors, reinforce the aggregation of gastric cancer within families. Among the many environmental factors which have been implicated in gastric cancer, dietary factors tend not to differ significantly between the familial and sporadic forms of the disease [20]. Helicobacter pylori infection has been established fairly thoroughly as a risk factor for gastric carcinoma. H. pylori infection has been confidently associated with the risk of both intestinal and diffuse gastric cancers. In a recent meta-analysis conducted with 19 cohort or case-control studies, a summary odds ratio of 1.92 (95% CI = 1.32–2.78) for gastric carcinoma in the H. pylori-infected subjects was estimated in comparison with the uninfected subjects [21]. Although H. pylori infection can not account for a certain proportion of familial cases, many groups have reported a relationship between H. pylori infection and the familial aggregation of gastric cancers. Infection with CagA-positive H. pylori strains was determined to be more frequently observed among patients with family histories of gastric carcinoma (55%) than among other patients (31%) [22]. In addition, H. pylori-associated gastric cancers tend to exhibit higher levels of gene-specific methylation than do tumors which arise independently of exposure to the bacterium.
We observed no association between H. pylori infection and HLTF methylation in gastric cancers. However, this study was a retrospective analysis, and so we did not have information regarding prior H. pylori infection status for all our study cases. H. pylori infection is known to decline with the development of gastric cancer [23], and histological examinations alone do not accurately determine previous exposures to H. pylori infection. Therefore, the potential contribution of H. pylori infection to HLTF methylation may warrant further study.
The role of HLTF methylation in gastric carcinogenesis in patients with family histories also remains somewhat unclear. Recent data appear to suggest that the SWI/SNF superfamily may function as tumor suppressors. However, the significance of the reduced expression of the HLTF gene in the tumorigenesis of the gastric epithelia remains poorly understood. HLTF methylation has been detected in cancers of the colon, esophagus, and stomach, but has not been reported to be a factor in breast or lung cancers [7]. This suggests that HLTF may have a distinct role in carcinogenesis of the gastrointestinal epithelium. It has also been reported that the transfection of an HLTF expression vector into HLTF-deficient colon cancer cells suppresses the growth of the cells [7], thereby indicating that HLTF silencing may confer a growth advantage in some colon cancers, and that HLTF may function as a tumor suppressor in cases of colon cancer. Further research into the growth suppressive effects of HLTF in gastric carcinoma cells is clearly warranted.
HLTF may also contribute to gastric carcinogenesis via interactions with other cancer-associated proteins. The SWI/SNF complex is known to regulate transcription, by using the energy of ATP hydrolysis to mobilize nucleosomes, thereby remodeling the chromatin. The SWI/SNF complexes are also known to directly interact with tumor suppressors and oncogenes, including Rb [24–26], BRCA1 [27], c-Myc [28] and MLL [29]. The SWI/SNF complex may also be involved in such processes as DNA synthesis [30–31], mitotic gene regulation [32] and viral integration [33–34]. Accordingly, the interactions occurring between these cancer-related proteins and HLTF in the development of gastric cancer requires further elucidation.
HLTF has also been shown to be involved in the expression of the plasminogen activator inhibitor-1 (PAI-1) by binding to its B Box [35]. PAI-1 is known to control the activity of the urokinase-type plasminogen activator (uPA), and the inhibition of uPA activity results in the inhibition of invasion in several experimental systems [36–37]. HLTF over-expression induces a 3-fold induction of PAI-1 transcription in HeLa cells [35], thereby suggesting that the silencing of HLTF as the result of DNA methylation may attenuate the expression of PAI-1. Identification of the target genes of HLTF will be necessary to understand the mechanisms underlying the involvement of HLTF in the early stages of gastric carcinogenesis in patients with family histories.
Unfortunately, our study was severely limited by the lack of cases of familial gastric cancer, and the small number of available patients with family histories of the disease. In addition, it remains unclear whether functional inactivation of HLTF may play a role in early stage gastric cancers with family histories. Accordingly, further work with a large sample of familial gastric cancer cases will be necessary to elucidate clearly the pathogenetic significance of HLTF methylation in the early stages of gastric cancer in patients with family histories of the disease. The study of adjacent normal mucosal samples is also needed to detect a possible pre-existing alteration in normal tissue for patients with family histories of gastric cancer. Genetic linkage analysis may also facilitate the identification of the other genetic factors responsible for an individual's susceptibility to gastric cancer. In this study, there were unmethylated signals in tumor tissues and these may result from a contamination of stromal cells in tumor tissues. In conclusion, the results of our present study suggest that the methylation of HLTF gene may play a crucial role in the early stages of gastric carcinogenesis in patients with family histories. HLTF methylation may prove to be a susceptible marker for the risk of gastric cancer in individuals with family histories of the disease.
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Acknowledgements |
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The authors thank Hee-Jin Jo and Hyang-Suk Jung for their help in data collection and management, and Suh-Kyu Park for his help in sample collection. This work was supported by grants from the Samsung Biomedical Research Institute (B-A5-103) and the SRC/ERC program of MOST/KOSEF (R11-2005-017).
Received for publication October 9, 2005. Revision received January 1, 2006. Accepted for publication January 9, 2006.
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