Integrative genomics and pathway analysis identified prevalent FA-BRCA pathway alterations in arsenic-associated urinary bladder carcinoma chronic arsenic accumulation in cancer tissues hampers the FA-BRCA pathway.

Arsenic in drinking water is one of the major etiological factors in urinary bladder carcinoma (BlCa). Here, high-resolution CGH-SNP microarray analyses in arsenic accumulated BlCa tissues showed significant (p < 0. 05) association of chromosomal alterations with high arsenic (≥112 ng/g) accumulation as corroborated by high γH2AX nuclear expression. Cytobands 5q11-35, 9p24.3-21.5, 18q11.1-25, etc. showed deletion, whereas 12q was amplified in high arsenic samples (AsH). Consecutively, IPA® found FA-BRCA pathway to be exclusively altered in AsH group. Validation of several key regulatory genes (RAD50, BRIP1, UIMC1, FANCD2, BRCA2 and BRCA1) of the pathway, were performed in independent BlCa cases (n = 81). UIMC1, RAD50 and BRIP1 were differentially deleted and associated with poor survival of AsH samples. Moreover, reduced nuclear expression with diffused cytoplasmic expression of FANCD2 was higher in AsH samples. Collectively, frequent deregulation of RAD50, UIMC1 and BRIP1 may result in reduced translocation of FANCD2, which may cause more chromosomal aberrations among AsH samples.

Genomics. 2020 Sep 10 [Epub ahead of print]

Mukta Basu, Sabnam Ghosh, Anirban Roychowdhury, Sudip Samadder, Pijush Das, Sankar Addya, Anup Roy, Dilip Kumar Pal, Susanta Roychoudhury, Amlan Ghosh, Chinmay Kumar Panda

Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37 SPM Road, Kolkata 700026, India., Department of Life Science, Presidency University, 86/1, College Street, Kolkata 700073, India., Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata, West Bengal 700032, India., Department of Cancer Biology, Sidney Kimmel Cancer Centre, Thomas Jefferson University, Philadelphia, PA, USA., Nil Ratan Sarkar Medical College and Hospital, West Bengal, India., Department of Urology, IPGMER, SSKM, 244 A.J.C. Bose Road, Kolkata 700020, India., Molecular Biology and Basic Research Division, Saroj Gupta Cancer Centre and Research Institute, Thakurpukur, Kolkata 700 063, India., Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37 SPM Road, Kolkata 700026, India. Electronic address: .