Editorial

Molecular alterations in gallbladder cancer

Ruhi Dixit¹, Vijay K Shukla¹, Manoj Pandey²

• ¹Department of Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, India
• ²Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005, India

• Submitted: February 17, 2012;
• Accepted March 22, 2012
• Published: March 27, 2012

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gallbladder carcinoma, (GBC) first described by M deStoll in 1777 is the fifth commonest cancer of the digestive tract. In Eastern part of Uttar Pradesh, GBC is the third most common cancer of the digestive tract. Carcinoma of gallbladder is mostly found in females with a male to female ratio of 4-5:1. Mortality rate is also higher in females than males.

The carcinoma of the gallbladder shows a wide geographical variation. The highest incidences have been reported from Chile, Poland, Japan and India [1]. The variations are observed within the country as well. In India, a high incidence was observed in New Delhi (14/100,000) & Bhopal (10/100,000) cancer registries during 1988 and 1989, the incidence in the south India was low [2]. The cause of gallbladder cancer and its higher incidence in some parts of the world is still debated. Gallstones are the most common factor thought to be responsible for gallbladder carcinogenesis in 40-80 percent of cases in various series [3,4]. The evidence is also available to the contrary where the GBC occurs without cholelithiasis in up to 25% of the cases. Apart from gallstones, presence of chronic cholecystitis is also reported in 40-50 percent of the patients of GBC which ultimately led to the conclusion that chronic cholecystitis could also be a causative factor in pathogenesis [3].

GBC has a poor prognosis as it is mostly asymptomatic in nature in early course of the disease. Carcinoma of the gallbladder is difficult to diagnose in an early stage because of the non-specific symptoms and signs. The most common symptom is pain in the upper quadrant. GBC include symptoms like right upper quadrant pain, anorexia, weight loss and jaundice. [5]. More over the symptoms of GBC can’t be distinguished from those of cholecystitis, cholelithiasis, or other benign biliary tract diseases. Adenocarcinoma is the most common type of gallbladder neoplasm.

A number of studies have identified molecular and genetic defects underlying cancer of the gallbladder, one of such primary genetic abnormality is defective DNA nucleotide mismatch repair. Usually the carcinogenesis is caused due to accumulation of cumulative genetic and epigenetic alterations that include activation of oncogene and inactivation of tumor suppressor genes [6]. Alterations in several genes like K-ras, p53 and p16 have been described to play an important role in the carcinoma of gallbladder. Activation of mutations in p21, TP53 leads to the pathogenesis of usual gallbladder carcinogenesis. [7].

Tumor suppressor genes (TSGs) act as cell-cycle check points and therefore mutation in TSGs may lead to malignant transformation [8]. The most complex mechanism which are responsible for the inactivation of tumor suppressor genes is the mutation occurring in one allele and loss of the other allele [9]. Mutation occurring in one allele is the most complex mechanism which is responsible for the inactivation of tumor suppressor genes. The allelic loss can be detected as loss of heterozygosity (LOH) by using microsatellite markers. There are many tumor suppressor genes which are mutated however only few of them are described here.

p53 protein is a tumor suppressor gene product that in humans is encoded by the TP53 gene. It regulates the cell-cycle and is involved in preventing cancer, thus it functions as a tumor suppressor gene. It is located on short arm of chromosome 17 (17p13.1) in humans. Over expression of p53 gene has been reported in various human cancers including gallbladder cancer (GBC). p53 protein expression has been detected in GBC by using various techniques in various studies [8,10,11] but the relationship between p53 over expression and prognostic factors are still obscure.

p16 is a cyclin-dependent kinase 4 inhibitor and is linked to the regulation of cell-cycle in mammalian cells. The genes encoding these inhibitors are located at 9p21. The frequencies of p16 gene mutations were analyzed in 15 GBC, 5 dysplasia and 3 adenoma and a p16 mutation rate of 30.7 percent was observed in GBC. However, no mutations were found in dysplasia or adenoma. This gene is frequently mutated or deleted in a wide variety of tumors, and it is known to be an important tumor suppressor gene [12,13].

Retinoblastoma gene (Rb) encodes a protein that acts by altering the activity of transcription factors [14]. It was the first tumor-suppressor protein to be discovered in human retinoblastoma. The Rb gene is mutated in many types of cancer. Two different forms of mutations in retinoblastoma gene have been described:

Sporadic & Familial

• Sporadic: It can affect anyone and is dependent on genetic changes (mutations) acquired during the lifetime of the affected individual
• Familial: It results when affected individuals inherit a defective copy of the gene from one of their parents. [15]

Retinoblastoma is a gene which has been found to be present in 100% of the patients with cholecystitis and adenoma; however, it is deleted in carcinoma of the gallbladder in 18-67% of the patients [16,17,18]. The expression of the pRb has been found to correlate with stage, grade and overall survival.

Wnt’s belong to a family of secreted glycoproteins. Wnt proteins can be characterized into two classes on the basis of their activity in cell lines or in vivo assays i.e. canonical and non-canonical. Canonical wnts are responsible for stabilization of β-catenin which activates transcription of TEF/LEF target genes [19]. Wnt/Wingless (Wg) family involves in development processes, cell proliferation to cell migration and cell polarity [20]. Wnts are important for regulation, development and formation of a heterodimer which contain β-catenin and a member of the LEF/TCF family of transcriptional regulators. Liang in their study reported that deregulation of wnt signaling pathway may lead to cancer [20].

Wnts bind to their receptors which activates a downstream component known as disheveled (Dsh) in Wnt/β-catenin signaling pathway. Dsh inhibits glycogen synthase kinase (GSK)-3β in the β-catenin destruction complex, which mainly consists of axin, GSK-3β, adenomatous polyposis coli (APC) and β-catenin (20). It has also been studied that mutations in the pathway leads to up-regulation of β-catenin signaling and it may cause numerous human cancers [21,22,23]. Polakis in his review article reported that wnt signaling can cause cancer and a number of genetic defects in this pathway results in tumor progression but the exact mechanism regarding defects in the wnt signaling regulation is still obscure [23].

The Hh signaling pathway is responsible for foregut development [24]. Hh comprised of secreted protein which influence morphogenesis by providing positional information. It also functions in tissue regeneration of adult tissue stem cells after damage in adults.

Wang in his study reported that Shh might be a potential diagnostic biomarker and therapeutic target as it is found to be a link between chronic tissue injury and cancer. Shh basically involved in the growth, differentiation and function of many organ in embryos and adults [24]. Shuhong suggested in his work that Shh activity is higher in liver cancers. Further, they discussed that Shh may be useful for the prognosis/detection of liver cancers [25,26]. A review on Shh concluded that Hh signaling promotes tumor growth and it might take part in the proliferation of tumor stem cells (27). Hh signaling may be described as important oncogenic pathway [27]. So, we presume that Shh expression might be higher in case of carcinoma gallbladder also.

In an earlier study in biliary tract carcinoma using gene expression and comparative genomic hybridization a number of genes were found to be up or down regulated [28]. This study included both extra and intra hepatic bile duct cancers and was not exclusive for gallbladder. Gallbladder cancer constituted a very small part of this study and hence the results cannot be applied to gallbladder cancer without some skepticism.

The biggest drawback of the above studies are the use of no controls or use of disease controls or the normal bile duct as control and extrapolation of the gallbladder data from it. Absence of normal or disease gallbladder control, makes the results of this study a little unreliable as we do not know that the expression pattern in normal bile duct is same as in gallbladder. The dilemma of molecular alteration in gallbladder cancer continues as more and more work and evidence pours in. However, the pathways of carcinogenesis are still speculative and gallbladder cancer remains an orphan cancer in absence of major studies.

Authors' Contribution

RD: conducted the literature search and prepared the draft manuscript
VKS: conceived and designed the study, edited the manuscript.Mbr
MP: Conceived and designed the study, literature review and interpretation, preparation of manuscript.

Conflict of interests

The authors declare that there are no conflicts of interests

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