Significance of Microsatellite Instability and Gene Methylation as Prognostic Biomarkers during Gallbladder Cancer Progression: A Review Yogesh D Walawalkar, Kanishka Tiwary, Tannishtha Saha and Vijayashree Nayak * Department of Biological Sciences, Birla Institute of Technology & Science, Goa, India * Corresponding author: Vijayashree Nayak, Department of Biological sciences, Birla Institute of Technology & Science, KK Birla Goa Campus Zuarinagar, Goa-403 726, India, Tel: +91 832 2258161; Fax: +91-832-2557-033; E-mail: yo.genetech@gmail.com Rec date: Jan 25, 2015; Acc date: Feb 18, 2015; Pub date: Feb 20, 2015 Copyright: © 2015 Walawalkar YD, 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. Abstract Gallbladder cancer is a common malignancy of the biliary tract with increasing incidences seen in Chile and Northern India. The disease is aggressive with poor prognosis and a median survival rate of less than 6 months following diagnosis. The aetiology of the tumour is complex with early lymph node metastasis and direct invasion into the liver and peritoneal cavity. Diagnosis is usually incidental during pathological review of cholecystectomy due to non-specific symptoms. Chemotherapy has no significant impact on gallbladder carcinoma as seen in other solid gastrointestinal malignancies. Various pre-disposing factors underlie the progression towards gallbladder cancer, but a strong correlation exists with chronic cholelithtiasis and inflammation. A number of molecular alterations have been reported during gallbladder disease progression which may be associated with prognosis and certain risk factors. But the mechanisms contributing to gallbladder cancer are poorly understood. Various studies report the importance of DNA methylation and microsatellite instability in pathogenesis of gallbladder carcinogenesis. Their involvement in cell cycle pathways and DNA repair mechanisms respectively could make them potential candidates for biomarkers in early detection, diagnosis and therapeutics. Further elucidation of molecular and pathological events during gallbladder disease progression would help to identify novel targets for diagnosis and disease management. This review summarizes significant data related to microsatellite instability and specific gene methylation patterns, and concludes their importance as possible molecular markers of gallbladder cancer. Keywords: Microsatellite instability; Gene methylation; Gallbladder cancer; Chronic cholelithiasis Introduction Gallbladder disease and progression Gallbladder carcinoma is the cancer of gallbladder epithelium with low incidence rates compared to other cancer types. Among populations at highest risk, about 1% deaths occur because of gallbladder cancer due to poor survival rates. During 2008, the cases of gallbladder cancer incidence at the global level were 145, 662 with an Age-Standardized Rate (ASR) of 2.0 per 105 person years. Incidence varies geographically with higher rates in certain areas of Latin America (Colombia, Peru, and Ecuador), Japan, and Eastern Europe (Poland, the Czech Republic, Slovakia, Hungary, and the former East Germany). High rates of gallbladder cancer have been noted in Hispanic and American Indian populations in North America. The incidence among women is approximately double than that of men in high-risk populations [1,2]. In India, during 2001, the estimated number of gallbladder cancer was 14,986 and is likely to increase to 23,750 by 2016 as a result of aging and increase in size of the population. The GBC incidence rates have been reported to be highest in women from India (21.5 out of 100,000), Chile (18.1 out of 100,000), Pakistan (13.8 out of 100,000) and Ecuador (12.9 out of 100,000) [3,4]. Thus with ever-increasing incidence and poor prognosis, early diagnosis and treatment of gallbladder carcinoma is essential. Various markers according to the stages of gallbladder cancer are yet to be experimentally documented and thus still require extensive research. The advancement of cancer up to the stage of gallbladder carcinoma is a lengthy process. There are many risk factors currently proposed to be involved in progression of gallbladder cancer. One of the main causes is chronic cholecystisis (CC) which may lead to various molecular changes (like continuous release of inflammatory factors), therefore resulting in the progression from inflammation to malignancy. The staging towards gallbladder cancer is usually characterized by chronic cholelithiasis with inflammation, metaplasia, dysplasia, carcinoma in situ and then finally invasive carcinoma [1,2]. Based on these observations researchers propose the period for progression from dysplasia to advanced gallbladder carcinoma to be approximately 15 years. Studies examining various tumor-related genes and gene products have shown great promise as possible prognostic and diagnostic markers, which are yet to be explored and well-understood in gallbladder cancers [5]. Genetic Alterations in Gallbladder Cancer There are a number of reasons for GBC which include a) mutation b) loss of heterozygosity c) microsatellite instability (MSI) and d) promoter methylation. GBC could be the result of any of these phenomena or due to the cumulative effect of these phenomena [6]. Identifying these alterations and mapping their regulation is of utmost importance for improved prognosis and diagnosis of gallbladder carcinoma. In this study we focus on two such parameters (i.e. MSI Journal of Cell Science & Therapy Walawalkar, et al., J Cell Sci Ther 2015, 6:1 http://dx.doi.org/10.4172/2157-7013.1000196 Review Article Open Access J Cell Sci Ther ISSN:2157-7013 JCEST, an open access Journal Volume 6 • Issue 1 • 1000196