Antigen structure and genetic basis of histo-blood groups A, B and O: their changes associated with human cancer

Three areas of research involved in blood group (or histo-blood group) ABO antigens and their genes, developed by our research group, are reviewed: (1 ) Antigen structures. The structural basis of A and H, A(1) and A(2), i and I antigens expressed in erythrocyte membranes. Major carriers of A and H d eterminants in erythrocytes are type 2 chain poly-LacNAc, short vs. long an d unbranched vs. branched structures termed A(a), A(b), A(c), A(d) and H-1, H-2, H-3, H-4 Regular A (A(1)) and weak A (A(2)) were identified respectiv ely as repetitive A (type 3 chain A) and A-associated H. A(1)- and A(2)-spe cific type 3 chain A and H, type 1 chain (representing Lewis blood group an tigens), and type 4 chain (globo-series antigen; an extremely minor compone nt in erythrocytes) are all glycosphingolipids. A and H determinants in fet al and newborn erythrocytes are carried by unbranched poly-LacNAc, whereas these determinants in adult erythrocytes are carried by branched poly-LacNA c. (2) ABO genes. A few cDNAs encoding A enzyme (UDP-GalNAc: H-a-GalNAc tra nsferase) were cloned based on the amino acid sequence of purified A enzyme and their structures were compared with those of homologous cDNA from bloo d cells of B and O individuals (genotype BE, OO). Four nucleotide substitut ions and four corresponding amino acid sequences essential for expression o f A(1) allele and B allele, and differences between A and B enzymes, were i dentified. Amino acids 266 and 268, i.e. Leu and Gly for A enzyme vs. Met a nd Ala for B enzyme, were dominant in determining A vs. B activity (presuma bly recognizing UDP-GalNAc vs. UDP-Gal). The A(2) allele was characterized by deletion of the termination codon, extending nucleotides up to 1128 and thus encoding 21 extra amino acids at the C terminus, which may affect (dim inish) the dominant function of amino acids 266 and 268. Typical O allele ( O-1) is characterized by deletion of nucleotide 261 G, causing frame shift and encoding of an entirely different, short polypeptide, due to appearance of early termination codon at nucleotide 354. Structures of other O allele s (O-1 (v), O-2) and other weak A alleles (A(3), A(el)) are also described. The genomic structure of ABO genes consists of seven exons which span simi lar to 19 kb of genomic DNA on chromosome 9, band q34. Most of the coding s equence is located in exon 7. Analysis of the 5' upstream region revealed t he presence of the binding site for transcription factors and enhancer elem ent. (3) Antigens and genes ii? cancer. A and B phenotypes aberrantly expre ssed in various types of human cancer, and their genetic basis, have been s tudied. One widely-occurring change observed in a large variety of human ca ncers is deletion of A or B epitope, associated with accumulation of their precursor H (Le(y), Le(b)), which causes enhanced malignancy. A less-common ly observed change is expression of incompatible A, identified as real type 1 chain A, in tumors of O or B individuals. A possible molecular genetic m echanism leading to such phenotypic changes is discussed. (C) 1999 Elsevier Science B.V. All rights reserved.