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Biological and Clinical Implications of Functional Promoter Polymorphism of CASPASE 9 Gene in Non Small Cell Lung Cancer Patients

Jamsheed Javid1, Rashid Mir1, Masroor M1, Shazia Farooq1, Imtiyaz Ahamad1, Mariyam Zuberi1, Prasant Yadav1, AA Bhat2, Ishfaq Ah Sheikh3, Tanveer Ah Khatlani3, Julka PK4, Anant Mohan5, Maqbool Lone6, Ray PC1 and Alpana Saxena1*

1Cancer Genetics Lab, Department of Biochemistry, Maulana Azad Medical College and Associated hospitals, New Delhi, India

2Division of Surgical Oncology, Vanderbilt University, Nashville, TN, USA

3King Fahd Medical Research Center, King Abdulaziz University, Kingdom of Saudi Arabia

4Department of Radiotherapy, All India Institute of Medical Sciences, New Delhi, India

5Department of Medicine, All India Institute of Medical Sciences, New Delhi, India

6Department of Radiation Oncology, SKIMS, Srinagar, India

*Corresponding Author:
Alpana Saxena
Director, Professor and Head
Department of Biochemistry
Maulana Azad Medical College and Associated Hospitals
New Delhi, India
Tel: +91-9968584601
E-mail: [email protected]

Received date: April 15, 2013; Accepted date: June 17, 2013; Published date: June 19, 2013

Citation: Javid J, Mir R, Masroor M, Farooq S, Ahamad I, et al. (2013) Biological and Clinical Implications of Functional Promoter Polymorphism of CASPASE 9 Gene in Non Small Cell Lung Cancer Patients. J Mol Biomarkers Diagn S8:007. doi:10.4172/2155-9929.S8-007

Copyright: © 2013 Javid J, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Purpose: The study was conducted to determine the impact of promoter polymorphism in CASP9 gene on
susceptibility and prognosis of Non Small Cell Lung Cancer patients of Indian origin.
Patients and methods: Present case control study includes newly diagnosed 160 NSCLC patients and 160
healthy controls. Promoter polymorphism (-712C>T, rs4645981) in CASP9 gene was investigated using PCR-RFLP
technique.
Results: Our findings reveal that a statistically significant increased risk of about 2.6 fold was associated with
homozygous TT genotype of CASP9 (-712C>T) promoter polymorphism (OR 4.3, 95%CI 2.2-8.3, p=0.0000) in Indian
population .In addition smokers were at high risk for NSCLC which was more predominant in heavy smokers with
pack-year >40 and in cigarette or beedi smokers. Compared to males, females were at high risk; about 2.3 fold more
in association with homozygous TT genotype [OR, 3.9(1.9-8.2) in males vs. 6.2(1.4-27.1) in females]. Significant
association was observed between advanced TNM stage (p<0.0001) and distant metastasis status (p<0.0001) of
NSCLC patients with the polymorphism. Patients homozygous for T allele exhibited a significant poor overall survival
compared with patients displaying CT+TT or CT or CC genotype (Median survival 6.0 vs. 9.0, 11.0, and 30.0, months
respectively, p<0.0001). Also advanced stage patients with TT genotype showed lower median survival time than
early stage NSCLC patients (Median 5.0 vs. 9.0 months respectively).
Conclusion: The functional polymorphism (-712C>T) in the promoter region of CASP9 gene is associated with
risk and susceptibility to NSCLC in north Indian population, and also is an important factor for poor prognosis in
patients with NSCLC.

Keywords

NSCLC; CASP9 promoter polymorphism; PCR-RFLP; Prognosis

Abbreviations

NSCLC: Non Small Cell Lung Cancer; ADC: Adenocarcinoma; SCC: Squamous Cell Carcinoma; CASP9: Caspase-9 gene

Introduction

Lung cancer is the most common cause of cancer mortality throughout the world including India among both men and women of every ethnic group, comprising 17% of the total new cancer cases and 23% of the total cancer deaths [1-4]. Cancer mortality rates varied greatly in different states of India, including mortality of lung cancer, the most common cancer in men in cities like Calcutta, Mumbai and New Delhi, accounting for more than 11% mortality in men aged 30–69 years [4]. NSCLC is the major type of lung cancer, accounts for 85% of lung cancer cases with 5-year survival rate of 11 to 15 percent overall, and less than 5 percent at stage IIIB/IV [5].

Apoptosis plays a crucial role in the prevention of uncontrolled cell growth and any deviation in its regulation may lead to many human disorders including cancer [6,7]. NSCLC has a devastating prognosis and markers enabling a precise prediction of the clinical outcome have long remained scarce. It has been demonstrated that genotype distribution of single nucleotide polymorphisms in genes that modulate apoptosis can serve as helpful predictive parameters in various carcinomas including lung cancer. One of the most important

mediators of apoptotic process is the cysteine-dependent aspartatespecific proteases known as caspases. Particularly caspase-9 plays a central role in the initiation of intrinsic apoptotic pathway, forming a large multi-protein complex with Apaf1 and cytochrome c, known as apoptosome for its self-activation and the activation of other effector caspases such as 3 and 7 to bring about the process of apoptosis [8].

CASP9 gene, located at chromosome 1p34-1p3.1 contains 9 exons with 8 introns and encodes 4.6 kDa pro-caspase proteins of 416 amino acids [9], which have been reported to play an important role in controlling tumor development [10]. Downregulation of caspase-9 is a frequent event in patients with different cancers [11,12]. Various polymorphisms in the promoter region of CASP9 gene have been found to regulate its expression both in-vivo as well as in vitro [13-15] and one of the most well studied promoter polymorphism of CASP9 at-712C>T (rs4645981)was reported to be associated with risk of diverse types of carcinomas including lung cancer [16-19]. Presently we aimed to find out the impact of the promoter polymorphism in CASP9 gene (-712C>T) on susceptibility and prognosis of non-small cell lung cancer patients among north Indian population.

Materials and Methods

Study population

Present study was approved and annually reviewed by Institutional ethics committee of Maulana Azad Medical College & associated hospitals, New Delhi. Peripheral blood samples from newly diagnosed 160 NSCLC patients and 160 cancer free healthy controls were included. Both cases as well as controls belonging to north India were enrolled between 2010-2013. All subjects received a detailed description of this study and provided written informed consent. Patient follow-up was obtained through hospital records as well as by direct patient contact in order to obtain the patient survival time from the date of diagnosis to the date of cancer related death or the date of completion of follow-up.

The distribution of the selected characteristics for patients with NSCLC and the healthy controls are summarized in Table 1. Tumor staging and grading of NSCLC patients was determined using 7th edition Lung cancer staging system [20] and similarities between cases and controls were maintained with respect to characteristics such as age (± 5 years), gender and smoking history.

Variable NSCLC patients (%) Healthy Controls (%)
Total No. 160 160
Gender
Males 124(77.5) 124(77.5)
Females 36(22.5) 36(22.5)
Age at diagnosis (Years)
<45 32(20.0) 32(20.0)
>45 128(80.0) 128(80.0)
Mean ± SD age (Y) 57.32 ± 11.9
(range, 30–85 Years)
56.02 ± 10.6
(range,32–80 Years)
Smoking Status
Non Smoker 47(29.4) 47(29.4)
Smokers 113(70.6) 113(70.6)
Current smokers 48(42.5) 48(42.5)
Ex–smokers 65 (57.5) 65 (57.5)
Smoking Level (Pack Year)
Mild (≤ 10) 18(15.9) 18(15.9)
Moderate (≤ 40) 49(43.4) 49(43.4)
Heavy (> 40) 46(40.7) 46(40.7)
Smoking Type
Cigarette 53(46.9) 53(46.9)
Beedi 23(20.4) 23(20.4)
Hooka 37(32.7) 37(32.7)
Histological Type.
SCC 79(49.4)  
ADC 81(50.6)  
TNM Stage
Early ( I & II) 60(37.5)  
Advanced ( III & IV ) 100(62.5)  
Distant Metastasis
Positive 42(26.2)  
Negative 118(73.8)  
Family History of any cancer
Significant 19(11.9)  
Non Significant 141(88.1)  
SCC Grade
Well differentiated 43(54.4)  
Moderately differentiated 22(27.8)  
Poorly differentiated 14(17.7)  
ADC Grade
Well differentiated 14(17.3)  
Moderately differentiated 22(27.2)  
Poorly differentiated 45(55.5)  

Table 1: Distribution of Selected Characteristics among the study population.

Genotype analysis

Peripheral blood sample (3-5 mL) from each participant was drawn into an EDTA vial and genomic DNA was extracted by following manufacturer´s protocol of DNA sure blood mini kit (Nucleo-pore Genetix brand). PCR-RFLP was performed to determine the (-712C>T, rs4645981) polymorphism in the promoter region of CASP 9 gene. PCR was performed in a final volume of 50 microliters containing 5 microliters of 50 nanogram genomic DNA, 3.0 microliters of 20 mM MgCl2, 5 microliters of 10 mM dNTPs, 0.5 microliters of 5 U/microliter Taq polymerase (Genei, Bangalore) with 2.5 microliters of 10X Taq Buffer (200 mM Tris-HCl, pH 8.0; 500 mM KCl),0.50 microliters of 25 pmol/L of forward primer 5´-AGTCGCGGAGGTGCCGCCTT-3´ and reverse primer 5´-AGGGCTAGCCTCGTGCCAGC-3´ [17] and the final volume was adjusted by nuclease free ddH2O. PCR program was started with an initial denaturation at 95°C for 5 minutes, followed by 40 cycles of denaturation at 95°C for 30s, annealing at 60°C for 45s, extension at 72°C for 45s, and completed with a final elongation step at 72°C for 5 minutes. The expected 194 bp product was then digested by the fast digest restriction enzyme HaeII (Fermentas) at 37°C for 15 min. The genotypes were assessed as follows: a single 194 bp fragment for homozygous CC genotype, two fragments of 174 bp and 20 bp for homozygous TT genotype and three fragments of 194 bp, 174 bp and 20 bp for the heterozygous CT genotype (Figure 1). Negative control with ddH2O instead of DNA template was included in each PCR run. A blind case/control analysis was performed with approximately more than 10% random samples were selected for confirmation and the results were 100% concordant.

molecular-biomarkers-diagnosis-PCR-amplification

Figure 1: (A) PCR amplification of CASP9 (-712C>T) showing amplified size of 194 bp (P1-P6) (B) HaeII restriction digestion of the PCR product with CASP9 (-712C>T) polymorphic sites: P1, P6- homozygous CC genotype, P2, P5-homozygous TT genotype, P3, P4- heterozygous CT genotype and NC –Negative control. L-100 bp molecular weight marker.*20 bp fragment not visible due to overrun.

Statistical analysis

Survival was calculated from the time of diagnosis to date of last follow-up and survival analysis was done by using Kaplan–Meier plots and log–rank (Mantel–Cox) test. Statistical analysis was performed using the Graph Pad Prism 6.0 or SPSS 16.0 software. Assessment of the correlations between genetic carrier status and CASP 9 polymorphism was carried out using the Chi-Square or Fisher Exact test. CASP 9 variants and risk of NSCLC were estimated by computing the odds ratios (OR), risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs) from multivariate logistic regression analysis. Kolmogorov-Smirnov test (KS-test) was used to calculate Mean ± SD and allele frequencies among cases as well as controls were evaluated by using Hardy-Weinberg equilibrium test. A p value <0.05 was considered significant.

Results

Case-control genotype distribution

The observed genotype frequencies of CASP9 (TT, CT and CC) were statistically different among NSCLC patients and healthy controls (Chi square 20.1, p< 0.0001). NSCLC cases represented with higher T allele frequency (fT= 0.56 vs. 0.38) whereas among cancer free healthy controls C allele frequency shows the dominance (fC= 0.62 vs. 0.44), however the heterozygous genotype (CT) was almost similar among both cases and controls Table 2.

Genotype TT Genotype(%) CT Genotype(%) CC Genotype(%) T allele Frequency C allele Frequency Chi-Square P value
Patients
(n=160)
52
(32.5)
75
(46.9)
33
(20.6)
0.56 0.44 20.1 < 0.0001
Controls
(n=160)
22
(13.8)
78
(48.8)
60
(37.4)
0.38 0.62    

Table 2: Genotype frequencies of CASP9 (-712C>T) among NSCLC cases and controls.

Genotype and risk of NSCLC

By multivariate analysis based on logistic regression odds ratio, risk ratio and risk difference with 95% confidence intervals were calculated for each group to estimate the association between the CASP9 (-712C>T) genotypes and risk of NSCLC in Indian patients (Table 3 and 4). It was found that an increased risk of NSCLC was associated with the CASP9 (T) allele in an allele dosage-dependent manner. Compared to the CC genotype, odds ratio, risk ratio and risk difference for the heterozygous CT and homozygous TT genotypes were OR=1.7(1.0-3.0) RR=1.3(1.0-1.6) RD=13.5(1.0-26.1) and OR=4.3(2.2-8.3) RR=2.2(1.5- 3.2) RD=34.8(20.5-49.0) respectively, suggesting a possible dominant effect of this polymorphism with 2.6 fold increased risk associated with homozygous TT genotype. The increased risk associated with the CASP9 TT genotype appeared to be more pronounced in female cases with OR 6.2(1.4-27.1) vs 3.9(1.9-8.2) in males whereas both the age groups ≤45Yr and >45Yr presented with same risk of developing NSCLC with respect to CASP9 polymorphism (Table 6).

Genotypes Control(n=160) Cases (n=160) OR*(95% CI)
CC (ref) 60 33 1
TT 22 52 4.3(2.2-8.3)
CT 78 75 1.7(1.0-3.0)
CT+TT 100 127 2.3(1.4-3.8)

Table 3: Risk of NSCLC associated with the CASP9 (-712C>T) genotypes.

Genotypes Control
(n=160)
Cases (n=160) No of Cancer related Deaths* RR#(95% CI) RD^(95% CI) p value
CC (ref) 60 33 17 1    
CT 78 75 32 1.3(1.0-1.6) 13.5(1.0-26.1) 0.03
TT 22 52 38 2.2(1.5-3.2) 34.8(20.5-49.0) 0.0000

Table 4: Risk ratio and risk difference of NSCLC associated with the CASP9 (-712C>T) genotypes.

Genotype and clinical characteristics

Of the lung cancer patients, 81 (50.6%) were classified as adenocarcinoma and 79 (49.4%) as squamous-cell carcinoma. Majority of the cases were diagnosed in advanced TNM stage 100 (62.5%) including more than 26% of patients with metastasis to distant organs. Well differentiated SCC 43 (54.4%) and poorly differentiated ADC 45(55.5%) represented a major proportion in histological grade of NSCLC cases (Table 1).

Clinical characteristics including TNM Stage and distant metastasis status showed statistically significant associations with respect to CASP9 (-712C>T) genotypes (Table 5) with higher prevalence of f(T) among cases with advanced stage (0.68 vs. 0.37) as well as in cases with metastasis to distant organs (0.89 vs.0.44) like brain, bone or adrenal etc. ADC patients represented slightly higher T allele frequency (0.61) than SCC patients (0.51) and cytological differentiation among ADC showed a continuous increasing trend of CASP9 T allele frequency from well to poor grade differentiation (Table 5).

  Genotype Frequency    
Variables TT (%) CC (%) T allele C allele Chi-Square p value
Histological type            
SCC 22(27.8) 21(26.6) 0.51 0.49 2.9 0.09
ADC 30(37.0) 12(14.8) 0.61 0.39    
TNM Stage            
Early Stage (I&II) 10(16.7) 26(43.3) 0.37 0.63 26.9 <0.0001
Advanced Stage (III&IV) 42(42.0) 7(7.0) 0.68 0.32    
Distant Metastasis            
Positive 35(83.3) 2(4.8) 0.89 0.11 28.4 <0.0001
Negative 17(14.4) 31(26.3) 0.44 0.56    
Family History of any Cancer            
Significant 9(47.4) 5(26.3) 0.61 0.39 0 1.0
Non Significant 43(2.8) 28(19.9) 0.55 0.45    
SCC Grade            
Well differentiated 14(32.6) 8(18.6) 0.57 0.43 2.8 0.3
Moderately differentiated 5(22.7) 8(36.4) 0.43 0.57    
Poorly differentiated 3(21.4) 5(35.7) 0.43 0.57    
ADC Grade            
Well differentiated 2(14.3) 5(35.7) 0.39 0.69 12.1 0.002
Moderately differentiated 4(17.4) 4(17.4) 0.50 0.50    
Poorly differentiated 24(53.3) 3(6.7) 0.74 0.26    

Table 5: Association and stratification analysis of CASP9 (-712C>T) polymorphism and NSCLC.

Gene-smoking interaction

Healthy controls with similar smoking history as those of patients were included in the study in order to find the genetic susceptibility and risk of NSCLC in relation to CASP9 promoter polymorphism. Smokers constituted more than 70 percent wherein Cigarette (46.9%) was the major smoking source and about 57% had left smoking from more than 6 months among both cases as well as controls (Table 1).

Although an increased risk of NSCLC cancer was observed to be associated with CASP9 TT genotype in both smokers and nonsmokers, however , the OR for the TT genotype in smokers was significantly higher OR 5.1 (95%CI 2.4-11.0, p=0.0000) than those of non-smokers OR 2.6 (0.7-9.4,p=0.25). Moreover, when the risk associated with the CASP9 polymorphism was further evaluated within the strata of pack-years smoked, risk of development of NSCLC was increasing as the number of pack-years increases (Mild; OR 2.8, Moderate; OR 4.6 and Heavy; OR 5.6). In addition interaction between susceptible genotypes and source of smoking was mostly evident among beedi (OR 8.3 (1.4- 47.6) smokers (Table 6).

Variables CCControls/Cases TTControls/Cases OR (95%CI) p value
Gender
Males 47/28 17/40 3.9(1.9-8.2) 0.0003
Females 13/5 5/12 6.2(1.4-27.1) 0.01
Age at diagnosis (Years)
≤ 45 15/5 8/13 4.8(1.3-18.6) 0.02
>45 45/28 14/39 4.5(2.1-9.8) 0.0001
Smoking Status
Non Smoker 12/10 6/13 2.6(0.7-9.4) 0.25
Smokers 48/23 16/39 5.1(2.4-11.0) 0.0000
Smoking Level ( Pack Year)
Mild (<10) 9/4 4/5 2.8(0.5-16.4) 0.47
Moderate (<40) 13/9 6/19 4.6(1.3-16.0) 0.03
Heavy (>40) 26/10 6/13 5.6(1.7-19.0) 0.008
Smoking Type
Cigarette 16/10 5/22 7.0(2.0-24.6) 0.003
Beedi 12/2 8/11 8.3(1.4-47.6) 0.03
Hooka 18/11 3/6 3.3(0.7-15-8) 0.26

Table 6: Risk of NSCLC associated with the CASP9 (-712C>T) polymorphism by potential risk factors in the Indian population.

CASP9 (-712C>T) polymorphism and survival outcome

Survival analyses were based on the population of 160 NSCLC patients from whom peripheral blood samples were collected between 2009 and 2012, since detailed and long-term follow-up data have been documented. The mean follow-up time of the patients was 11.95 months (median 10.50; range, 0.5-127.5 months) for the overall survival. Out of 160 NSCLC patients, 87 (54.4%) died with mean follow-up time of 10.46 months ( median 10.00; range, 0.5- 40.0 months) and for the patients who survived the follow-up period (censored patients), the follow-up time was 14.24 months (median 13.00; range, 0.5-127.5 months). Patients homozygous for TT allele exhibited a significant poor overall survival (p <0.0001) (Figure 2A and 2B). Median survival time for patients with CASP9 (-712) CC, CT, CT+TT and TT genotype were 30.0, 11.0, 9.0 and 6.0 months respectively. In addition patients in advanced stage with TT genotype showed lower median survival time than early stage NSCLC patients (Median 5.0 vs. 9.0 months respectively) (Figure 2C and 2D).

molecular-biomarkers-diagnosis-Kaplan-Meier

Figure 2: Kaplan-Meier survival analysis of NSCLC patients with respect to CASP 9 (-712C>T) polymorphism:(A-B) Overall survival (C) Survival in Early stage patients (D) Survival in advanced stage patients.

Discussion

Present study provides evidence that a variation in the promoter region of the CASP9 gene is directly associated with the susceptibility to NSCLC in Indian patients. The major finding of the study was that the CASP9 rs4645981TT genotype was significantly associated with poor overall survival outcomes of NSCLC patients. In-vitro cell line analysis has demonstrated that the CASP9 (-712) T allele had significantly reduced the transcriptional activity of the CASP9 promoter than the corresponding (-712) C allele [13], which may result in decreased caspase-9 expression and ultimately may reduce the apoptosis capacity. CASP9 knockdown mice showed reduced apoptosis rate which had led to the perinatal death of the mice [21]. In addition resistance to apoptotic stimuli was observed in caspase-9 deficient thymocytes [22]. Several anticancer agents trigger apoptosis via caspase-9 activation and caspase-9 was found out to be critical for the death response of neuroblastoma cells to cisplatin [23-25]. Clinical studies on various carcinomas including lung cancer had revealed that low caspase-9 expression was associated with unfavorable clinical outcomes and poor survival [12,13], thus the CASP9 promoter polymorphism (-712C>T) may also play an important role in chemotherapy response in NSCLC patients.

Our study, the first report from Indian population, suggested that homozygous CASP9 (-712)T genotype is strongly associated with the risk of developing NSCLC with approximately 2.6 fold increase than homozygous CASP 9 (-712)C genotype. A meta-analysis study on CASP 9 polymorphism reported that CASP9 (-712) C allele offers protection against lung cancer development whereas CASP9 (-712) T allele confers increased susceptibility to lung cancer in Asian population [19]. Study on early stage NSCLC patients depicted significantly decreased overall and death free survival among patients carrying homozygous CASP9 (-712) TT genotype [18]. Our results also revealed that CASP9 (-712) T allele homology was an important prognostic marker for poor clinical outcome of NSCLC patients.

In the present study, CASP9 promoter polymorphism has been found to be significantly associated with advanced stage NSCLC patients with distant organ metastasis, which may be due to the reduced caspase-9 expression levels associated with (-712) T allele homology, ultimately leading to the advancement of tumors. Low expression levels of caspase-9 have been observed in advanced tumors [11]. When the caspase-9 promoter polymorphism data was stratified with other parameters like gender, females were at more than 2 fold increased risk of lung cancer than males, whereas it was almost similar in both younger and old age groups.

Tobacco smoke exposure is responsible for to 80–90% of lung cancers [22]. Present study showed a clear example of gene– environmental interaction, wherein risk of NSCLC was 2.5 fold more in smokers than nonsmokers .The risk of developing NSCLC was increasing as the smoking exposure (pack years) increases in a statically significant manner. In addition, patients smoking beedi, which is the most commonly used tobacco smoking source in India, showed the highest prevalence of CASP9 TT risk genotype. Recent study observed that the protective effect of the CASP9 rs4645981 C allele was significant in light smokers whereas there was no significant association in the heavy smokers [13].

Conclusion

In conclusion, present study demonstrates that the promoter (-712C>T) polymorphism of CASP9 gene may contribute to the risk of developing NSCLC in Indian population. Study further suggests that the polymorphism might be a useful genetic marker in peripheral blood to predict susceptibility to advanced stage with distant metastasis and poor survival outcome of NSCLC; thereby it may be helpful in therapeutic management for the treatment of NSCLC. However, because this is the first report concerning the CASP9 gene polymorphism and the risk of NSCLC in the Indian population, independent large population-based studies for more rigorous analyses of subgroups are needed to validate our findings.

Acknowledgements

The authors thank the patients and physicians from Regional Cancer Center SKIMS, Srinagar and All India Institute of Medical Sciences, New Delhi, for their cooperation and participation.

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