Identification of candidate tumor suppressor genes loci on chromosome 9 associated with the development of arsenic induced urinary bladder cancer in West Bengal India

Abstract

The etiological link of arsenic with bladder cancer (BC) is well established across the globe. The molecular pathogenesis of arsenic induced BC should be explored to identify potential markers of clinical importance for better disease management. Arsenic toxicity is a burning health issue along Gangetic belt of West Bengal and higher BC incidence was recorded in affected areas of the state than safe areas. On this background, present hospital-based study aimed to analyse the association of arsenic with development/progression/prognosis of BC in West Bengal and, explore molecular pathogenesis of arsenic-induced BC targeting candidate tumor suppressor genes (TSGs) of chromosome-9 due to previous reports of alteration of the chromosome in BC. In this hospital-based study, majority of BC patients were documented from arsenic affected areas of the state and in these patients, concordantly high tumor arsenic level (AsH, gt100 ppb) was detected. High tumor arsenic level was found to be associated with higher proliferation potential (assessed by immunohistochemically analysis of ki67) and pathological stages of tumor and poor patient survival. Thus, in exposed individuals, arsenic accumulates in bladder tissue to influence tumorigenesis and favour acquisition of aggressive tumor phenotypes that affect disease outcome. To explore molecular pathogenesis, 9p22-21 and 9q22.3 were selected based on previous report and candidate TSGs deleted in these regions in AsH tumors were detected by analysing whole genome CGH+SNP array data of our previous study. In 9p22 region, SH3GL2 (SH3 domain containing GRB2 like 2) showed molecular alteration (deletion and promoter methylation) preferably in AsH tumors similar to array based data and, concordant reduced expression. SH3GL2 inactivation seemed to affect receptor mediated endocytosis of active EGFR as evident from overexpression of the later without any amplification of gene in same sample set. SH3GL2 inactivation and associated dysregulation in negative regulation of ERBB signalling pa