Genetic and epigenetic alterations of the blood group ABO gene in oral squamous cell carcinoma

Abstract

Loss of histo-blood group A and B antigen expression is a frequent event in oral carcinomas and is associated with decreased activity of glycosyltransferases encoded by the ABO gene. We examined 30 oral squamous cell carcinomas for expression of A and B antigens and glycosyltransferases. We also examined DNA from these tumors for loss of heterozygosity (LOH) at markers surrounding the ABO locus at chromosome 9q34, for loss of specific ABO alleles, and for hypermethylation of the ABO promoters. Loss of A or B antigen expression was found in 21 of 25 tumors (84%) and was a consistent feature of tumors lacking expression of A/B glycosyltransferases. LOH at 9q34 was found in 7 of 27 cases (26%), and one case showed microsatellite instability. Key words: oral carcinoma; ABO gene; methylation; loss of heterozygosity; genotypingChanges in the glycosylation patterns of cell surface carbohydrates have been demonstrated in most human cancers. Many recent studies have indicated that aberrant glycosylation occurs early during oncogenic transformation and may represent a key event in invasion and metastasis. 1 The blood group ABH antigens are cell surface carbohydrates distributed abundantly in epithelial tissues. Loss or reduction of A and B epitopes in human cancers is well documented, and loss of A and B antigens is correlated with the degree of malignancy and metastatic potential in lung, bladder and oral carcinomas. [2][3][4][5][6][7] In vitro studies have demonstrated that loss or addition of a single glycosyl residue, for example, ␣Gal-NAc on A antigen or ␣Gal on B antigen, may affect tumor cell motility by altering glycosylation of ␣3 and ␣6 integrin receptors and their interaction with ␤1 integrin. This may explain the observed correlation between glycosylation and prognosis. 8 The A and B antigens are terminal carbohydrates synthesized step-by-step by the addition of single sugars catalyzed by a series of specific glycosyltransferases. The phenotypic difference between A and B antigens is due to differences in substrate specificity of A and B glycosyltransferases. Phenotypic O is characterized by the absence of A and B glycosyltransferases and presumably by the presence of an inert protein encoded by the O allele. 9 -15 Expression of A/B antigens in tumors is directly correlated with A and B glycosyltransferase activity. 16 It is, however, not clear how the activity of A and B glycosyltransferases is suppressed in carcinomas. In vitro studies have shown that A antigen negative tumors have reduced levels of ABO transcript as compared to A antigen positive tumors. 17 Loss of heterozygosity (LOH) studies of bladder carcinomas have suggested frequent deletion at chromosome 9q34, which contains the ABO gene. 18 Alternatively, in vitro studies have shown that A antigen negative tumor cell lines have a higher level of DNA methylation at the ABO promotor region compared to A antigen positive cell lines, indicating that ABO promotor hypermethylation could be responsible for transcriptional inactivation. 19,20 As lack of AB...

Loss of blood group A antigen expression in bladder cancer caused by allelic loss and/or methylation of the ABO gene

“…Loss of the A or B allele was found in 3/20 tumors (15%) heterozygous for the ABO locus and hypermethylation of the promoter region in 10 of 30 tumors (33.3%). 22 Furthermore, Habuchi et al 23 reported that the region 9q32-9q33, which is in the vicinity of the ABO gene locus at 9q34.1, is a frequent target of LOH and methylation in bladder cancer. These findings prompted us to hypothesize that deletion of blood-group A antigen expression in TCC of the bladder might be regulated by a combination of genetic and epigenetic mechanisms, that is, an LOH of the ABO gene locus and hypermethylation of the ABO gene promoter region.…”

Glycoprotein B7-H3 overexpression and aberrant glycosylation in oral cancer and immune response

“…Both Ca9-22 and OEC-M1 are gingival carcinoma and significant in the Asian population. According to the literature, besides erythrocytes, blood group antigen A, B, and H can be expressed in epithelial cells of many tissues including oral tissue, and their expression can be varied among degrees of differentiation, but decreased in tumor tissue of OSCC (41,42). The loss of blood group antigens in OSCC specimens correlates significantly with both the stage and histological grade of malignancy (42).…”

ABO Blood Group, Epstein-Barr virus Infection and Prognosis of Patients with Non-metastatic Nasopharyngeal Carcinoma

“…Links between ABO blood groups with benign or malignant diseases, such as gastric and pancreas cancers, have been observed for a long time (Wang et al, 2012;Wolpin et al, 2009). It was proved that ABO blood group antigen expression on cancer cells was modified by hypermethylation of ABO gene promoter (Gao et al, 2004), which might be related with the invasiveness or metastasis of tumor. A latest research suggested that blood type A or AB was associated with an increased risk of NPC compared with subjects with blood type O (Sheng et al, 2013).…”