IntroductionThe A, B, and H antigens (hereafter referred to as ABH antigens) are complex carbohydrate structures found on glycoproteins and glycolipids present on the surface of erythrocytes, endothelial cells, and on most epithelial cells. Alleles of the ABO gene code for glycosyltransferases that act on the precursor H antigen. 1,2 In red blood cells, the H antigen is determined by a fucosyltransferase coded for by the FUT1 gene. If the H antigen is absent, there is no substrate for the ABO glycosyltransferases to modify. Homozygous deficiency of FUT1 gives rise to the Bombay phenotype where there are no A or B antigens on the red cell due to lack of the H precursor. The major alleles of the ABO gene are A, which adds N-acetylgalactosamine to give the A antigen; B, which adds galactose to give the B antigen; and O, which is a null allele coding for an inactive transferase incapable of modifying the H antigen. The most frequent of the minor A and B alleles is the A 2 allele, which gives rise to a lower density of A antigen. Weaker alleles such as A 3 and A x show progressively less A antigen. 3 Alteration of ABH antigens in hematologic malignancy was first reported by van Loghem et al, 4 who described very weak A antigen expression on the red cells of a patient with acute myeloid leukemia (AML), who had previously shown normal A antigen expression. Loss of A, B, or H antigens from the surface of red blood cells is now recognized as a recurrent observation in hematologic malignancy. 5,6 In a healthy individual of type A, B, or AB, complete agglutination of the red blood cells is observed after incubation with antibodies reactive against their blood group. In patients with loss of ABH antigens, a varying proportion of red blood cells do not agglutinate, giving a characteristic mixed-field reaction. Mixed-field reactions can also occur in healthy individuals where the reactions are associated with rare alleles of the ABO gene such as A 3 and B 3 .Loss of ABH antigens is also seen in the tumor cells of many types of carcinoma, including bladder, lung, head and neck, cervical, and thyroid, where it has been associated with tumor grade, metastatic potential, and poor prognosis. 7-13 Furthermore, laboratory studies have shown that tumorigenicity is reduced when A or B antigens are expressed. 14,15 Whether the mechanisms of loss of ABH antigens in epithelial tumors and hematologic malignancies are truly analogous to each other remains to be determined.Unlike epithelial malignancies where the loss of ABH antigens is seen in dedifferentiated tumor cells, loss of ABH antigens in myeloid malignancies is only seen on red cells as most hematopoietic cells and precursors do not express ABH antigens. However, malignant stem cells often retain the potential to differentiate along the erythroid lineage. [16][17][18] Thus, loss of ABO expression in the population of red cells derived from a malignant stem cell is an indicator of genetic changes that have occurred in the malignant stem cell. Consistent with this, Salmon et al 19 s...

The role of BRCA1 in sporadic breast and ovarian cancers remains elusive. Direct involvement of BRCA1 in the development of breast and ovarian cancer is suggested by the finding that the BRCA1 promoter region CpG island is methylated in a proportion of breast and ovarian cancers. The aim of this study was to compare the incidence of BRCA1 promoter region methylation in tumours in which loss of BRCA1 has been shown to play a role in pathogenesis (breast and ovarian carcinomas) with the incidence in tumours in which BRCA1 is unlikely to play a role in pathogenesis. Promoter region hypermethylation was significantly more common (P < 0.008) in breast and ovarian cancer (6/38 tumours methylated) than in colon cancer (0/35 tumours methylated) or in leukaemias (0/19 samples methylated). The restriction of BRCA1 promoter region hypermethylation to breast and ovarian cancer is consistent with a pathogenetic role of BRCA1 promoter methylation in these tumours. We suggest that the rarity of observed BRCA1 mutations in sporadic breast and ovarian cancer is due to the greater likelihood of BRCA1 inactivation by non-mutational mechanisms such as methylation.

Intercellular communication via gap junctions is a mechanism for tumor suppression. Connexin 26 (Cx26) is a structural component of gap junctions expressed by breast epithelial cells. Expression levels of Cx26 are reduced in many breast tumors. Methylation-sensitive single-stranded conformation analysis showed variable methylation in the promoter region CpG island in 11 out of 20 (55%) breast cancer patients. Heterogeneity in methylation patterns was observed both between and within tumors. The degree of methylation ranged from a few CpG dinucleotides to almost all the CpG dinucleotides in the analyzed region. The most frequently methylated CpG was in an Sp1 site known to be important for Cx26 gene expression. One of eight breast cancer cell lines (MD-MBA-453) was methylated in the promoter region and did not express Cx26. Treatment of MDA-MB-453 with 5-aza-2'-deoxycytidine resulted in the re-expression of Cx26 mRNA. Methylation of the promoter region is likely to be an important mechanism in modulating the expression of Cx26 in breast cancer.

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