Role of BCL2 (ala43thr), CCND1 (G870A) and FAS (A-670G) polymorphisms in modulating the risk of developing esophageal cancer
Introduction
According to the Population Based Cancer Registry of the Indian Council of Medical Research, esophageal cancer is the second most common cancer in males (crude rate of 4.08/100,000) and the fifth most common cancer in females (crude rate of 3.79/100,000) [1]. The 5-year survival in patients with early stage disease who undergo resection is of the order of 20%, but for others, with more advanced disease, who receive radiotherapy with or without chemotherapy, the prognosis is more dismal with close to 10% of patients surviving a similar period [2].
Nutritional deficiency coupled with alcohol and tobacco abuse (both smoked and smokeless forms) and occupational exposure and human papillomavirus (HPV) infection has been shown to be associated with the development of esophageal cancer [3], [4]. It is known to induce chromosomal aberrations, telomeric shortening and telomerase activity, and expression of certain genes such as c-myc, ras, bcl-2 and p53 resulting in loss of cell growth control and apoptosis, causing cellular transformation [5]. Studies have suggested that genes involved in apoptosis (BCL2, FAS), cell cycle regulation (CCND1) and their interaction with environmental exposure may play a significant role in neoplastic transformations [6], [7]. Emerging data from epidemiological and clinical studies suggest that tobacco exposure, treatment modality and prognosis vary as a function of location of disease within the esophagus, i.e. upper, middle or lower segments [8], [9], [10]. However, site-wise incidence of esophageal cancer is not available from the National Cancer Registry of India [1]. Further alterations in apoptotic and cell cycle regulatory genes may influence site-specific genetic alterations as has been pointed out [11], [12]. It has been hypothesized that polymorphisms in these genes may be an important determinant of site-specific phenotype [12].
However, in esophageal cancer, to the best of our knowledge, no study has been reported with regard to genotype–phenotype association of BCL2, CCND1 and FAS genotypes with tumor location, histopathology and spread to lymph nodes.
BCL2 gene (B cell lymphoma leukemia 2) encode protein which is localized on intracellular membranes prevents programmed cell death in response to various death inducing stimuli. Over expression and elevated levels of bcl-2 have been shown to promote cell survival [13], [14]. An in vitro study of ala43thr (G128A) polymorphism in BCL2 anti-apoptotic gene showed that ala43ala genotype increases the survival of cells, while the threonine variant acts as a suppressed haplotype for the anti-apoptotic factor [15]. To the best of our knowledge, till date, there is no reported study of BCL2 ala43thr polymorphism in esophageal cancer. The CCND1 gene encodes cell cycle regulatory proteins that regulate abnormal cell proliferation. The splice donor site CCND1 polymorphism G870A in exon 4 (codon 242) affects splicing of mRNA [16]. The variant A allele has aberrant functions with increased activity for cellular transformation [17]. Several association studies show CCND1 870AA genotype to be at an increased risk for several malignancies, e.g. upper aero-digestive tract, larynx and colon [18], [19], [20]. Only a few studies have analysed the association of CCND1 A870G polymorphism and risk of tumor induction, factoring in the site of tumor [12].
FAS/Apo1 (CD95) gene expressed on epithelial cell surfaces mediates apoptosis and is involved in cell turnover in many tissues [21]. FAS A-670G polymorphism in the promoter region affects the transcription factor binding site, hence modulates expression levels of the gene. A previous study has shown FAS -670GG genotype to be associated with risk of esophageal cancer [22].
This case–control study reports the role, if any, of BCL2 (ala43thr) CCND1 (G870A) and FAS (A-670G) polymorphisms in influencing the risk of developing esophageal cancer and their association with certain tumor characteristics as these polymorphisms have only been studied individually as far as could be ascertained. In addition, a case-only analysis was used to analyze the influence of gene–environment interaction on the risk of developing esophageal cancer.
Section snippets
Patients and controls
Between January 2003 and September 2005, 151 histologically confirmed esophageal cancer patients of squamous or adenocarcinoma were inducted into this study. They had been referred to the Departments of Gastroenterology and Radiotherapy of the Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGI), a tertiary referral hospital in North India. Patients with Barrett's esophagus or with any pre-cancerous condition were excluded. During the same period, blood samples of 201 unrelated
Results
The study population included 151 patients with esophageal carcinoma and 201 control subjects. Their mean age (S.D.) (in years) was similar, 56.4 (12.3) vs. 56.6 (9.1) as was their gender distribution with 75.5 and 71% males, respectively. Other characteristics are summarized in Table 1. Following a history and examination, patients underwent routine blood tests along with an endoscopic biopsy to ascertain histology. A contrast enhanced CT scan of the thorax and abdomen was performed to
Discussion
It is now well known that both cancer initiation and neoplastic events are influenced by genetic background. Control of cell proliferation is achieved by a precarious balance between regulation of apoptosis and cell cycle genes. BCL2 was one of the first genes discovered that regulate apoptosis [28], [29]. In esophageal carcinoma, expression studies on bcl-2 suggest its role in regulating carcinoma growth, especially in the early stage of tumorigenesis [30]. It has been positively associated
Conflict of interest
None.
Acknowledgements
The study was sponsored by research grants from Department of Science and Technology and Indian Council of Medical Research. One of the authors (MJ) thanks the University Grants Commission, New Delhi, India for providing Senior Research Fellowship. We gratefully acknowledge the assistance of Dr. Sandeep Bhattacharya, King George Medical University, Lucknow. Grant sponsor: Department of Science and Technology, Government of India and the Indian Council of Medical Research, New Delhi, India.
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