Objective To investigate the association between tea drinking habits in Golestan province, northern Iran, and risk of oesophageal squamous cell carcinoma.
Design Population based case-control study. In addition, patterns of tea drinking and temperature at which tea was drunk were measured among healthy participants in a cohort study.
Setting Golestan province, northern Iran, an area with a high incidence of oesophageal squamous cell carcinoma.
Participants 300 histologically proved cases of oesophageal squamous cell carcinoma and 571 matched neighbourhood controls in the case-control study and 48 582 participants in the cohort study.
Main outcome measure Odds ratio of oesophageal squamous cell carcinoma associated with drinking hot tea.
Results Nearly all (98%) of the cohort participants drank black tea regularly, with a mean volume consumed of over one litre a day. 39.0% of participants drank their tea at temperatures less than 60°C, 38.9% at 60-64°C, and 22.0% at 65°C or higher. A moderate agreement was found between reported tea drinking temperature and actual temperature measurements (weighted κ 0.49). The results of the case-control study showed that compared with drinking lukewarm or warm tea, drinking hot tea (odds ratio 2.07, 95% confidence interval 1.28 to 3.35) or very hot tea (8.16, 3.93 to 16.9) was associated with an increased risk of oesophageal cancer. Likewise, compared with drinking tea four or more minutes after being poured, drinking tea 2-3 minutes after pouring (2.49, 1.62 to 3.83) or less than two minutes after pouring (5.41, 2.63 to 11.1) was associated with a significantly increased risk. A strong agreement was found between responses to the questions on temperature at which tea was drunk and interval from tea being poured to being drunk (weighted κ 0.68).
Conclusion Drinking hot tea, a habit common in Golestan province, was strongly associated with a higher risk of oesophageal cancer.
The very high incidence of oesophageal squamous cell carcinoma (ESCC) in Golestan Province in northeastern Iran was suggested by studies in the 1970s as partly due to opium use, which is not uncommon in this area, but based on limited numbers. From December 2003 to June 2007, we administered a validated structured questionnaire to 300 ESCC cases and 571 controls, matched on neighbourhood of residence, age (±2 years), and sex. We used conditional logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for potential confounders. Compared with those who used neither tobacco nor opium, risk of ESCC was increased in those who used tobacco only (OR, 95% CI: 1.70, 1.05–2.73), in those who used opium only (2.12, 1.21–3.74), and in those who used both tobacco and opium (2.35, 1.50–3.67). All forms of tobacco use (cigarettes, hookah, and nass) were associated with higher ESCC risk. Similarly, use of both crude opium and other forms of opium were associated with higher risk. Alcohol consumption was seen in only 2% of the cases and 2% of the controls, and was not associated with ESCC risk.
oesophageal cancer; Iran; opium; tobacco; alcohol
Gastric fundal atrophy has been hypothesised to increase the risk of oesophageal squamous cell carcinoma (OSCC), but studies have shown inconsistent results.
We measured serum pepsinogen I (PGI) and pepsinogen II (PGII) among 293 incident cases and 524 matched neighbourhood controls in a high-risk area of Northern Iran. Conditional logistic regression model was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs).
After controlling for age, sex, residence area and other potential confounders, gastric atrophy (defined by a validated criterion, PGI <55 μg dl−1) was associated with a two-fold increased risk (OR=2.01, 95% CI: 1.18, 3.45) of OSCC in the absence of nonatrophic pangastritis (defined as PGII <11.8 μg dl−1). Stratification by PGII decreased the misclassification errors due to cancer-induced gastritis. Presence of both poor dental health, indicated by higher than median sum of decayed, missing, and filled teeth (DMFT score), and gastric atrophy further increased the risk of OSCC (OR=4.15, 95% CI: 2.04, 8.42) with relative excess risk due to interaction (RERI) of 1.47 (95% CI: −1.15, 4.1). Coexistence of poor oral hygiene habit with gastric atrophy elevated OSCC risk eight times (OR=8.65, 95% CI: 3.65, 20.46) and the additive interaction index was marginally statistically significant (RERI=4.34, 95% CI: −1.07, 9.76).
Gastric atrophy is a risk factor for OSCC, and poor dental health and oral hygiene habit may act synergistically in increasing the risk.
atrophic gastritis; oesophageal neoplasm; relative risk; dental health; oral hygiene; pepsinogen
Polymorphisms in the Glutathione S-transferase genes are associated with altered risks in many cancers, but their role in oesophageal cancer is unclear. Recently a 37-kb deletion polymorphism of GSTT2B that reduces expression of GSTT2 has been described. We evaluated the influence of the GSTT1 and GSTT2B deletion polymorphisms, and the GSTP1 Ile105Val polymorphism (rs1695) on susceptibility to oesophageal squamous cell carcinoma (OSCC) in the Black and Mixed Ancestry populations of South Africa.
Methods and Results
The GSTT1, GSTT2B and GSTP1 variants were genotyped in 562 OSCC cases and 907 controls, and tested for association with OSCC and for interaction with smoking and alcohol consumption. Linkage disequilibrium (LD) between the deletions at GSTT1 and GSTT2B was determined, and the haplotypes tested for association with OSCC. Neither the GSTT1 deletion nor the GSTP1 Ile105Val polymorphism was associated with OSCC risk in the Black or Mixed Ancestry populations. The GSTT2B deletion was not associated with OSCC risk in the Black population, but was associated with reduced risk of OSCC in the Mixed Ancestry population (OR = 0.71; 95% CI 0.57–0.90, p = 0.004). Case-only analysis showed no interaction between the GST polymorphisms and smoking or alcohol consumption. LD between the neighboring GSTT1 and GSTT2B deletions was low in both populations (r2Black = 0.04; r2MxA = 0.07), thus these deletions should be assessed independently for effects on disease risk.
Although there was no association between the GSTT1 deletion polymorphism or the GSTP1 Ile105Val polymorphism with OSCC, our results suggest that the presence of the recently described GSTT2B deletion may have a protective effect on the risk of OSCC in the Mixed Ancestry South African population. This is the first report of the contribution of the GSTT2B deletion to cancer risk.
Oesophageal cancers rank as the eighth most common cancer and the sixth most common cause of cancer death, worldwide. Gastric atrophy, as determined by a low serum pepsinogen I/II ratio, may be associated with an increased risk of oesophageal squamous cell carcinoma (OSCC). Ghrelin, a hormone which, like pepsinogen, is produced in the fundic glands of the stomach, may be a sensitive and specific marker of gastric atrophy, but its association with OSCC is not known.
To examine the relationship between baseline serum ghrelin concentration and subsequent risk of OSCC, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. 82 cases of OSCC were matched (1:1) by age and date of blood draw to controls from the ATBC study. Serum ghrelin was measured by radioimmunoassay. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression with adjustment for potential confounders.
For those individuals in the lowest quartile of serum ghrelin, compared to those in the highest, the multivariate odds ratio of subsequent OSCC was 6.83 (95% CI: 1.46, 31.84). These associations were dose dependent (P for trend = 0.005 for both), and independent of the effects of low pepsinogen I/II ratio (a marker of gastric fundic atrophy) and Helicobacter pylori infection. The significance of these associations remained even for individuals developing OSCC up to 10 years after baseline ghrelin measurement, though they become attenuated after 10 years.
Lower baseline concentrations of serum ghrelin were associated with an increase in risk of OSCC. Further studies are needed to confirm this finding in other populations and to explore the role of ghrelin in the aetiology of OSCC.
ghrelin; oesophageal squamous cell carcinoma; atrophy
Oesophageal squamous cell carcinoma (OSCC) often arises from preceding dysplastic lesions in the oesophageal epithelium. However, the molecular changes occurring in premalignant lesions are not well understood. An epigenetic change is an example of OSCC that may occur within the epithelium.
To investigate the methylation status of multiple promoters in cancer‐derived DNA, as well as in the background epithelium of OSCC, including dysplastic lesions and non‐neoplastic mucosa. The normal epithelium from patients without cancer was also examined. The findings were correlated with the mutational status of p53.
Patients and methods
56 patients with advanced OSCC, 21 patients with intraepithelial neoplasia (IEN), 56 patients with a background of non‐neoplastic epithelium, adjacent to the OSCC, and 42 normal control epithelia from healthy volunteers were studied. The promoter methylation status of SFRP1, SFRP2, DCC, APC, p16INK4a, p14ARF, MINT1, MINT2, MINT31, CACNA1G, COX2, DAPK, hMLH1 and MGMT was examined by methylation‐specific single polymerase chain reaction or combined bisulphite restriction analysis. The mutation of p53 by direct sequencing was assessed.
DNA methylation was observed in OSCC and in its background epithelium. The frequency of CpG island methylation increased from a baseline level in the background non‐neoplastic epithelium, through IEN, to advanced OSCC. However, mutations in p53 were almost exclusively observed in IEN and OSCC. More extensive DNA methylation was seen in the neoplastic lesions (OSCC or IEN) having a p53 mutation than in those with wild‐type p53.
DNA methylation is present at low levels in the non‐neoplastic oesophageal epithelium and appears to contribute to the progression of the dysplasia–carcinoma sequence in OSCC carcinogenesis.
Background and Objectives:
Early diagnosis and appropriate management are of prime importance for oral squamous cell carcinoma (OSCC) in the present scenario. Molecular changes in OSCC are well documented with the occurrence of a wide range of genetic damage. Identification of the genetic damage in OSCC using various diagnostic aids is mandatory, and one of the important advances in this field is cytogenetics using fluorescence in-situ hybridization (FISH). The aim of the present study is to analyze the genetic alteration in OSCC using FISH as a diagnostic aid.
Materials and Methods:
Peripheral blood was analyzed in 20 clinically and histopathologically proven OSCC cases and 10 healthy controls for chromosomal alteration under standardized conditions.
Of the 20 OSCC cases, 7 (35%) cases showed chromosomal alterations. No cases from the control group showed any chromosomal changes. Of the positive cases in OSCC, 30% cases showed increased copy number of cyclin D1 gene and 1 (5%) case showed positivity indicating extra copy of chromosome 11p11.11-q11 region.
Interpretation and Conclusion:
Increased genetic damage in OSCC which is a prominent feature can be identified by the use of FISH as seen from the present study. The findings suggest that FISH can be used as a diagnostic aid in the detection of genetic changes occurring in OSCC. The present study also suggests the importance of peripheral blood as a medium for assessing cytogenetic damage in OSCC.
Fluorescence in-situ hybridization; oral squamous cell carcinoma; peripheral blood; cyclin D1
Aberrant promoter methylation is an important mechanism for gene silencing.
To evaluate the promoter methylation status of p300 gene in patients with oesophageal squamous cell carcinoma (OSCC).
The methylation status of p300 promoter was analysed by methylation‐specific PCR (MSP) in 50 OSCC tissues and the matching non‐cancerous tissues. Oesophageal cancer cell lines (ECa‐109 and TE‐10) were treated with the demethylation agent 5‐aza‐2′‐deoxycytidine (5‐Aza‐CdR), and p300 mRNA expression was detected by RT‐PCR.
p300 methylation was found in 42% (21/50) of the OSCC tissues, but in only 20% (10/50) of the corresponding non‐cancerous tissues (p = 0.017). In OSCC samples, 65% of those with deep tumour invasion (adventitia) and 63% samples with metastasis revealed p300 promoter methylation (p<0.05). p300 mRNA expression was observed in 19.0% (4/21) of methylated tumours and 58.6% (17/29) of unmethylated tumours (p = 0.005). In addition, p300 mRNA expression was observed in 40% (4/10) of methylated non‐neoplastic tissues and 87.5% (35/40) of unmethylated non‐tumours (p = 0.001). The demethylation caused by 5‐Aza‐CdR increased the p300 mRNA expression levels in oesophageal cancer cell lines.
p300 transcription silenced by promoter hypermethylation could play a role in the pathogenesis of oesophageal squamous cell carcinoma.
The aetiological role of human papillomavirus (HPV) in oesophageal squamous cell carcinoma (OSCC) has been widely researched for more than three decades, with conflicting findings. In the absence of a large, adequately powered single case-control study, a meta-analysis of all available case-control studies is the most rigorous way of identifying any potential association between HPV and OSCC. We present the first global meta-analysis of case-control studies investigating the role of HPV in OSCC.
Case-control studies investigating OSCC tissue for presence of HPV DNA were identified. 21 case-control studies analyzing a total of 1223 cases and 1415 controls, met our inclusion criteria. HPV detection rates were tabulated for each study and all studies were assessed for quality. The random effects method was used to pool the odds ratios (OR).
From all OSCC specimens included in this meta-analysis, 35% (426/1223) were positive for HPV DNA. The pooled OR for an HPV-OSCC association was 3.04 (95% CI 2.20 to 4.20). Meta-regression analysis did not find a significant association between OR and any of the quality domains. Influence analysis was non-significant for the effect of individual studies on the pooled estimate. Studies conducted in countries with low to medium OSCC incidence showed a stronger relationship (OR 4.65, 95% CI 2.47 to 8.76) than regions of high OSCC incidence (OR 2.65, 95% CI 1.80 to 3.91).
Uncertainty around the aetiological role of HPV in OSCC is due largely to the small number and scale of appropriately designed studies. Our meta-analysis of these studies suggests that HPV increases the risk of OSCC three-fold. This study provides the strongest evidence to date of an HPV-OSCC association. The importance of these findings is that prophylactic vaccination could be of public health benefit in prevention of OSCC in countries with high OSCC incidence.
Patients with oral premalignant lesions (OPL) present with oral squamous cell carcinomas (OSCC) at a much higher rate than the general population. There are currently no useful markers that indicate specifically which OPLs are most likely to progress. Three SIBLING family proteins, bone sialoprotein (BSP), osteopontin (OPN), and dentin sialophosphoprotein (DSPP), have been shown to be up-regulated in many cancers, including OSCC. The status of SIBLING expression in OPLs and their correlation to transition to oral cancer are unknown.
Sixty archival surgical biopsies of dysplastic OPLs were evaluated by immunohistochemistry for expression of BSP, DSPP and OPN and correlated with local transformation to OSCC at sites adjacent to surgically removed dysplastic OPL
The OPL patient population was representative of previous studies with 20% progressing to OSCC, and no correlation between degree of dysplasia and progression. 87% were positive for at least one SIBLING protein. OPN expression had no correlation with progression. The BSP+/DSPP− expression pattern however correlated with decreased transformation to OSCC (Point Prevalence=0%, 95%CI=0–20.6%) while the BSP−/DSPP+ pattern was associated with more frequent progression (Point Prevalence=77.8%, 95%CI=47.8–95.4%). Incrementally higher expression scores (0 to 3+) of BSP and DSPP were also associated with increased predictive values (OR=25.53, 95%CI=2.14–304.7 and 10.13, 95%CI=2.0–50.0, respectively, for each increment).
BSP and DSPP are excellent candidate markers for successful OPL surgical intervention and may be predictors of OPL-OSCC progression.
SIBLINGs; Oral-cance; Oral Premalignant Lesions; Dysplasia; Biomarkers; BSP; DSPP; OPN; Transition
Previous studies indicated that oral squamous cell carcinomas (OSCC) might be related to human papilloma virus (HPV) infection. However, up to now, there still lacks a large sample study to analyze the relationship between OSCC in a Chinese population and oral HPV infection. In the present study, we used a meta-analysis to evaluate the relationship of OSCC with HPV infection in a Chinese population.
The reports on HPV and OSCC in a Chinese population published between January, 1994, and September, 2011 were retrieved via CNKI/WANFANG/OVID/MEDLINE databases. According to the inclusion criteria, we selected 18 eligible case-control studies. After testing the heterogeneity of the studies by the Cochran Q test, the meta-analyses for HPV and HPV16 were performed using the fixed effects model.
The overall positive rates of HPV and HPV16 in OSCC were 58.0% (354/610; 95% confidence interval [CI], 54.1–61.9) and 47.47% (169/356; 95% CI: 42.3–52.7), respectively; which were significantly higher than those in normal controls 10.44% (26/249; 95% CI: 7.2–14.7) and 7.1% (13/182; 95% CI: 4.2–11.8). Quantitative meta-analysis revealed that, compared with normal controls, the combined odds ratios of OSCC with HPV or HPV16 infection were 12.7 (95% CI: 8.0–20.0) and 9.0 (95% CI: 5.1–15.6), respectively. Both Begg's test and funnel plots revealed that no publication bias was found in this present study (P>0.05).
High incidences of HPV infection (mainly involving HPV16) were found in the samples of Chinese OSCC. For the Chinese population, HPV infection elevates the risk of OSCC tumorigenesis. Prophylactic HPV-vaccination may reduce the burden of HPV-related OSCC in China.
High incidence rates of gastrointestinal tract cancers have been reported in the Caspian region of Iran. This study aimed to: 1) describe the geographical spatial patterns of gastrointestinal tract cancer incidence based on cancer registry data and, 2) determine whether geographical clusters of statistical significance exist.
The Babol Cancer Registry, which covers the two major northern Iranian provinces of Mazandaran and Golestan (total population = 4,484,622) was used to identify new gastrointestinal tract cancer cases during 2001 to 2005. Age-specific cancer incidence rates were calculated for 7 gastrointestinal tract cancer sites in 26 wards of the Mazandaran and Golestan provinces. Spatial autocorrelation indices, hierarchical Bayesian Poisson models, and spatial scan statistics were used in measuring the geographic pattern and clusters.
There were non-random spatial patterns in esophageal and stomach cancers that were similar for both sexes. Clusters of high incidence were identified in esophageal, stomach, colorectal and liver cancer for both sexes, as well as a possible cluster of pancreas cancer in males.
Gastrointestinal tract cancers exhibit significant spatial clustering of risk in northern Iran. Further work is needed to relate these geographical patterns to information on potential life-style and environmental factors.
Head and neck squamous cell carcinoma, including oral squamous cell carcinoma (OSCC) is the sixth most common cancer in the human population. Despite significant efforts committed in treatment of OSCC the overall survival rate of OSCC has not improved significantly. Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) genes are responsible for some human cancers, including bladder and cervical carcinoma. Despite a high frequency in some benign skin disorders, FGFR3 mutations have not been reported in cutaneous malignancies. Therefore, FGFR3 gene may play a role in epithelial biology and mutations of FGFR3 gene may contribute to the development of OSCC.
Materials and Methods:
In this cross-sectional study, DNA was extracted and purified from snap frozen tissue biopsy sections of 20 OSCC cases. Exons 7 and 15 were amplified by polymerase chain reaction (PCR) and sequenced in both directions.
In three cases silent mutations were identified in exon 7 (882 T to C) which may be introduced as Single Nucleotide Polymorphism (SNP) and no mutation was identified in exon 15.
FGFR3 gene mutation in exon 7 and 15 has no significant role in the development and progression of OSCC. Analyzing other exons or considering other advanced gene mutation assessment techniques may clarify the role of this receptor mutation in OSCC pathogenesis.
FGFR3; Oral Squamous Cell Carcinoma; PCR; Mutation
Genetic variants in multiple cellular pathways have been associated with an altered risk of oesophageal cancer. In this study, eight genes previously associated with an altered risk of oesophageal squamous cell carcinoma (OSCC) in European or Asian populations were investigated in two South African populations. We genotyped 12 single-nucleotide polymorphisms and one insertion/deletion variant in 1463 individuals from the Black and Mixed Ancestry populations. No polymorphisms were associated with OSCC in the Black population. In the Mixed Ancestry population, ALDH2 +82 G > A (rs886205) was significantly associated with a reduced risk of OSCC (odds ratio = 0.70, 95% confidence interval = 0.55–0.89; P = 0.0038). Several other polymorphisms showed a suggestive association (P < 0.05), including ADH1B Arg48His (rs1229984), COX-2 −1195G > A (rs689466), CASP8 Asp302His (rs1045485) and MGMT Leu84Phe (rs12917). Haplotype analysis indicated that the FAS polymorphisms −670 A > G (rs1800682) and −1377 G > A (rs2234767) were both associated with OSCC in the Mixed Ancestry population (P = 0.006 and P = 0.004, respectively), as well as the CASP8 (−652 6Ndel:302His) haplotype (P = 0.0013). This study indicates several instances of population-specific differences in the genetic etiology of OSCC between these two South African populations and between them and other high-risk populations, which may reflect differences in their ancestry and environmental exposures.
Background: Oesophageal squamous cell carcinoma (OSCC) is a common cancer worldwide and has a very high mortality rate. Squamous dysplasia is the precursor lesion for OSCC and it can be seen during routine endoscopy with Lugol’s iodine staining. We aimed to examine the risk factors for squamous dysplasia and determine if a risk model could be constructed which would be useful in selecting apparently healthy subjects for endoscopic screening in a high risk population in Linzhou, People’s Republic of China.
Subjects and methods: In this cross sectional study, 724 adult volunteers aged 40–65 years were enrolled. All subjects completed a questionnaire regarding potential environmental exposures, received physical and dental examinations, and underwent upper endoscopy with Lugol’s iodine staining and biopsy. Subjects were categorised as having or not having histologically proven squamous dysplasia/early cancer. Risk factors for dysplasia were examined using univariate and multivariate logistic regression. The utility of the final multivariate model as a screening tool was assessed using a receiver operating characteristics curve.
Results: We found that 230 of 720 subjects (32%) with complete data had prevalent squamous dysplasia. In the final multivariate model, more household members (odds ratio (OR) 1.12/member (95% confidence interval (CI) 0.99, 1.25)), a family history of cancer (OR 1.57 (95% CI 1.13-2.18)), higher systolic blood pressure OR 1.11/10 mm Hg (95% CI 1.03-1.19)), heating the home without a chimney (OR 2.22 (95% CI 1.27–3.86)), and having lost more but not all of your teeth (OR 1.91 for 12–31 teeth lost (95% CI 1.17–3.15)) were associated with higher odds of having dysplasia. Higher household income (OR 0.96/100 RMB (95% CI 0.91–1.00)) was associated with a lower odds of having dysplasia. Although we found several statistically significant associations, the final model had little ability to accurately predict dysplasia status, with maximum simultaneous sensitivity and specificity values of 57% and 54%, respectively.
Conclusions: We found that risk factors for dysplasia were similar to those previously identified as risk factors for OSCC in this population. The final model did a poor job of identifying subjects who had squamous dysplasia. Other methods will need to be developed to triage individuals to endoscopy in this high risk population.
oesophageal cancer; dysplasia; tooth loss; cancer screening; China
Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC.
Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9%), including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 “hotspots” but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs). Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence.
ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis.
The Glutathione S-transferases (GSTs) comprise a group of enzymes that are critical in the detoxification of carcinogens. In this study the effects of polymorphisms in these genes on the risk of developing oesophageal squamous cell carcinoma (OSCC) were evaluated in a hospital-based case-control study in two South African population groups. Genetic polymorphisms in GSTs were investigated in 245 patients and 288 controls samples by PCR-RFLP analysis.
The GSTP1 341T variant was associated with significantly increased risk of developing OSCC as observed from the odds ratios for the GSTP1 341C/T and GSTP1 341T/T genotypes (OR = 4.98; 95%CI 3.05-8.11 and OR = 10.9; 95%CI 2.43-49.1, respectively) when compared to the homozygous GSTP1 341C/C genotype. The risk for OSCC in the combined GSTP1 341C/T and T/T genotypes was higher in tobacco smokers (OR = 7.51, 95% CI 3.82-14.7), alcohol consumers (OR = 15.3, 95% CI 1.81-12.9) and those using wood or charcoal for cooking and heating (OR = 12.1, 95% CI 3.26-49) when compared to those who did not smoke tobacco, or did not consume alcohol or user other forms of fuel for cooking and heating. Despite the close proximity of the two GSTP1 SNPs (313A>G and 341C>T), they were not in linkage disequilibrium in these two population groups (D':1.0, LOD: 0.52, r2: 0.225). The GSTP1 313A/G polymorphism on the other hand, did not display any association with OSSC. The homozygous GSTT1*0 genotype was associated with increased risk of OSCC (OR = 1.71, 95%CI 1.18-2.46) while the homozygous GSTM1*0 genotype was associated with significantly decreased risk of OSCC in the Mixed Ancestry subjects (OR= 0.39, 95%CI 0.25-0.62).
This study shows that the risk of developing OSCC in the South African population can be partly explained by genetic polymorphisms in GST coding genes and their interaction with environmental factors such as tobacco smoke and alcohol consumption.
Tumors require blood supply for their growth and dissemination. It is a well accepted paradigm that tumors recruit new blood vessels from the existing circulation (angiogenesis) and this participates in tumor invasion and metastasis. Studies in the literature provide evidence for expression of Vascular Endothelial Growth Factor (VEGF) by the tumor for neo-angiogenesis, which is not only required for the tumor growth but also its metastasis. Based on the literary evidences we carried out an Immuno-Histochemical (IHC) study for VEGF in Oral Squamous Cell Carcinoma (OSCC) tissues to provide a strong link between the factor and oral cancer.
To analyze the expression of VEGF in OSCC tissues of different histological grades, clinical sizes and lymph node status and to use this as an indicator for disease progression by helping in delineating a risk population, that may benefit from an attractive adjuvant therapeutic strategy for OSCC.
Settings and Design:
Studies published from 1990 till 2010 have only seen the association of VEGF with tumor angiogenesis and its possible role in metastasis. This is the first study that takes into account the clinical status of the lymph nodes and VEGF expressivity in a sample size of 30 cases.
Materials and Methods:
30 oral squamous cell carcinoma tissue slides were stained using Hematoxylin and Eosin stain (to confirm the diagnosis) and immunohistochemically using VEGF antibody. IHC stained slides were thereafter evaluated for the positivity and intensity.
The result was subjected to statistical analysis using Chi-square test
Results and Conclusion:
VEGF positivity was seen in approximately. 90% of cases which was independent of histological grade of OSCC. However the intensity increased with the clinical size of cancer and from palpable lymph node to a tender and hard lymph node.
Angiogenesis; VEGF; immunohistochemistry
The high rate of oesophageal cancer amongst southern African blacks has also been recorded amongst the Zulus. Data embracing a wide spectrum of factors pertaining to socio-economic status, nutrition, exposure to carcinogens, tobacco and alcohol usage and traditional health practices were obtained from 211 hospitalized oesophageal cancer patients and compared with hospital population controls matched for age and urban-rural background. Stepwise logistic regression analysis with adjustment for age effects showed that four of the many factors could adequately model the odds of being a cancer case. They were the daily consumption of purchased maize meal (relative risk (RR) 5.7) currently smoking commercial cigarettes (RR 2.6), pipe smoking (RR 2.1), and a reduction of risk in those using butter or margarine daily (RR 0.51). Further significant differences (P less than 0.05) in 12 other factors suggest that those with rural assets but an ability to earn a modest income external to the subsistence economy are at highest risk. They represent a transitional state of Westernisation which is characterised by excessive smoking habits and a diet having a low vitamin and mineral density. These results provide further evidence for the need to combat smoking and for a program of nutrient enrichment of maize meal.
Matrix metalloproteinase (MMP) is known to be involved in the initial and progressive stages of cancer development, and in the aggressive phenotypes of cancer. This study examines the association of single nucleotide polymorphisms in promoter regions of MMP-1 and MMP-3 with susceptibility to oral squamous cell carcinoma (OSCC).
We compared 170 Japanese OSCC cases and 164 healthy controls for genotypes of MMP-1 and MMP-3.
The frequency of the MMP-1 2G allele was higher and that of the 1G homozygote was lower in the OSCC cases (p = 0.034). A multivariate logistic regression analysis revealed that subjects who were 45 years old or older had a significantly increased (2.47-fold) risk of OSCC (95%CI 1.47–4.14, p = 0.0006), and those carrying the MMP-1 2G allele had a 2.30-fold risk (95%CI 1.15–4.58, p = 0.018), indicating independent involvement of these factors in OSCC. One of the key discoveries of this research is the apparent reduction of the MMP-1 1G/1G and 1G/2G genotype distributions among the early onset OSCC cases under the ages of 45 years. It should be noted that the tongue was the primary site in 86.2% of these early onset cases. This could suggest the specific carcinogenic mechanisms, i.e. specific carcinogenic stimulations and/or genetic factors in the tongue.
Since the 2G allele is a majority of the MMP-1 genotype in the general population, it seems to act as a genetic pre-condition in OSCC development. However this report suggests a crucial impact of the MMP-1 2G allele in the early onset OSCC.
Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancer. The 5-year survival rate has remained below 50% over the last two decades, and new tools for early diagnosis are needed. Saliva has been used for diagnosis of several systemic diseases, and its use for diagnosis of OSCC has been sought extensively. Among the many salivary analytes for diagnosis of OSCC, accumulating evidences indicate the possibility of using salivary cytokines. Overproduction of proinflammatory, proangiogenic cytokines by OSCC cells has been reported, and their role in tumor progression and angiogenesis is well established. However, many inflammatory conditions and immunological diseases could affect the levels of cytokines in serum and saliva. This article has reviewed publications in this matter, and some strengths and weaknesses have been pointed out. Conclusively, large-scale investigations are required for validation of the use of salivary cytokines for diagnosis of OSCC, with consideration to the influential role of periodontal inflammation in their levels.
Cytokines; early diagnosis; interleukins; oral squamous cell carcinoma; saliva
Cancers of the upper gastrointestinal tract remain a significant cause of morbidity and mortality. Cysteine, known to be involved in a myriad of immuno-modulatory, anti-oxidant, and anti-carcinogenic pathways, has not been investigated in the aetiology of oesophageal or gastric cancers. To examine the relationship between serum cysteine concentration and risk of these cancers we conducted a nested case-cohort study within the General Population Nutrition Intervention Trial in Linxian, China.
498 oesophageal squamous cell carcinomas (OSCC) and 255 gastric cardia adenocarcinomas (GCA) were matched by age and sex to 947 individuals from the wider cohort. We calculated hazard ratios (HR) and 95% confidence intervals (95% CI) using the case-cohort estimator for the Cox proportional hazards models, stratified on age and sex, with adjustment for potential confounders.
Higher concentrations of serum cysteine were significantly associated with a lower risk of both OSCC and GCA. For those in the highest quartile of serum cysteine, compared to those in the lowest, the multivariate HRs were 0.70 for OSCC (95% CI: 0.51, 0.98) and 0.59 for GCA (95% CI: 0.38, 0.91). These associations were dose dependent (P for trend = 0.006 and 0.008, respectively). These inverse associations were not significantly modified by other risk factors, with the exception of age, where a stronger association was noted among persons in the older age strata.
Higher serum concentrations of cysteine were associated with a significantly reduced risk of OSCC and GCA. Cysteine should be further investigated for its potential as a chemopreventive agent for upper gastrointestinal cancers.
oesophageal squamous cell carcinoma; gastric cardia cancer; hazard ratio; cysteine
Golestan Province in northern Iran is an area with a high incidence of esophageal squamous cell carcinoma (ESCC). We aimed to investigate prognostic factors for ESCC and survival of cases in Golestan, on which little data were available. We followed-up 426 ESCC cases participating in a population-based case-control study. Data were analyzed using the Kaplan–Meier method and the Cox proportional hazard models. Median survival was 7 months. Age at diagnosis was inversely associated with survival, but the association was disappeared with adjustment for treatment. Residing in urban areas (hazard ratio, HR = 0.70; 95% CI 0.54–0.90) and being of non-Turkmen ethnic groups (HR = 0.76; 95% CI 0.61–0.96) were associated with better prognosis. In contrast to other types of tobacco use, nass (a smokeless tobacco product) chewing was associated with a slightly poorer prognosis even in models adjusted for other factors including stage of disease and treatment (HR = 1.38; 95% CI 0.99–1.92). Opium use was associated with poorer prognosis in crude analyses but not in adjusted models. Almost all of potentially curative treatments were associated with longer survival. Prognosis of ESCC in Golestan is very poor. Easier access to treatment facilities may improve the prognosis of ESCC in Golestan. The observed association between nass chewing and poorer prognosis needs further investigations; this association may suggest a possible role for ingestion of nass constituents in prognosis of ESCC.
Background: Oesophageal squamous cell carcinoma (OSCC) has a very poor prognosis, which is largely due to late diagnosis. Successful early detection strategies will require identification of clinically relevant precursor lesions that can be targets for screening and treatment.
Aims: To identify the clinically relevant histological precursors of OSCC.
Subjects: A cohort of 682 endoscoped patients from a high risk rural population in Linxian, China.
Methods: Subjects were endoscoped and biopsied at baseline and followed for 13.5 years. We estimated the relative risk of developing OSCC for each of the initial histological diagnoses using Cox proportional hazards regression models.
Results: A total of 114 (16.7%) patients developed OSCC during the follow up period. After adjusting for potential confounding factors, relative risks (95% confidence intervals) for incidence of this tumour, by initial histological diagnosis, were: normal 1.0 (reference), oesophagitis 0.8 (0.2–3.2), basal cell hyperplasia 1.9 (0.8–4.5), mild dysplasia 2.9 (1.6–5.2), moderate dysplasia 9.8 (5.3–18.3), severe dysplasia 28.3 (15.3–52.3), and carcinoma in situ 34.4 (16.6–71.4).
Conclusions: In this study, squamous dysplasia and carcinoma in situ were the only histological lesions associated with a significantly increased risk of developing OSCC within 13.5 years after endoscopy. There was no evidence that oesophagitis predisposed to this tumour. Increasing grades of dysplasia were strongly associated with increasing risk, indicating that the histological grading was clinically meaningful. The follow up experience of severe dysplasia and carcinoma in situ was equivalent, suggesting that this distinction is not clinically relevant. Documenting these precursor lesions of OSCC should assist in the development of effective prevention, early detection, and treatment strategies for this disease.
oesophageal cancer; precursor lesions; squamous dysplasia; China; follow up study
Oral Squamous Cell Carcinoma (OSCC) is a major cause of cancer death worldwide, which is mainly due to recurrence leading to treatment failure and patient death. Histological status of surgical margins is a currently available assessment for recurrence risk in OSCC; however histological status does not predict recurrence, even in patients with histologically negative margins. Therefore, molecular analysis of histologically normal resection margins and the corresponding OSCC may aid in identifying a gene signature predictive of recurrence.
We used a meta-analysis of 199 samples (OSCCs and normal oral tissues) from five public microarray datasets, in addition to our microarray analysis of 96 OSCCs and histologically normal margins from 24 patients, to train a gene signature for recurrence. Validation was performed by quantitative real-time PCR using 136 samples from an independent cohort of 30 patients.
We identified 138 significantly over-expressed genes (> 2-fold, false discovery rate of 0.01) in OSCC. By penalized likelihood Cox regression, we identified a 4-gene signature with prognostic value for recurrence in our training set. This signature comprised the invasion-related genes MMP1, COL4A1, P4HA2, and THBS2. Over-expression of this 4-gene signature in histologically normal margins was associated with recurrence in our training cohort (p = 0.0003, logrank test) and in our independent validation cohort (p = 0.04, HR = 6.8, logrank test).
Gene expression alterations occur in histologically normal margins in OSCC. Over-expression of the 4-gene signature in histologically normal surgical margins was validated and highly predictive of recurrence in an independent patient cohort. Our findings may be applied to develop a molecular test, which would be clinically useful to help predict which patients are at a higher risk of local recurrence.
oral squamous cell carcinoma; surgical resection margins; global gene expression profiling; prognostic signature; recurrence