CLONING OF THE HUMAN AFLATOXIN B-1-ALDEHYDE REDUCTASE GENE AT 1P35-1P36.1 IN A REGION FREQUENTLY ALTERED IN HUMAN TUMOR-CELLS

Alterations of the distal portion of the short arm of chromosome 1 (1p ) are among the earliest abnormalities of human colorectal tumors. Los s of heterozygosity analysis has previously revealed a smallest region of overlapping deletion (SRO) B, at 1p35-36.1, deleted in 48% of spor adic tumors. From this region we have now cloned a gene encoding a pro tein of 330 amino acids that is 78% identical with the Rattus norvegic us aflatoxin B-1 aldehyde reductase (Afar) and, therefore, likely repr esents its human homologue. In rat liver, Afar is strongly inducible b y the antioxidants ethoxyquin and butylated hydroxyanisole, which prot ect the rat against aflatoxin B-1-induced liver tumorigenesis by detox ifying its genotoxic and cytotoxic dialdehyde. Human AFAR is expressed in a broad range of tissues and, therefore, is likely involved in end ogenous detoxication pathways. Impaired detoxication of genotoxic alde hydes and ketones, which are involved in tumorigenesis of the colon an d breast, may he a crucial factor both for tumor initiation and progre ssion. We here provide a detailed contig of 1.5-2 Mbp/2.7 cM encompass ing part of SRO B, including known genes and previously unmapped expre ssed sequence tags. PLA2G2A (secretory type II phospholipase A(2)), de scribed previously as a candidate, is localized outside SRO B.