Influence of the major histocompatibility complex on age at onset of chronic lymphoid leukaemia

Abstract

The major histocompatibility complex is one of the interactive factors in the multifactorial model of carcinogenesis. Its main influence in experimental models is on the age at onset of malignancies. We have previously shown a similar effect of homozygosity for HLA-DR53 in CML. In the present study, we investigated 79 patients with CLL and 329 local controls from Germany. In addition to full serotyping, all patients and I I 6 of controls were also typed by HU-DR6 PCR analysis. The homozygosity rates for DR53 in patients under and over the median age (60 years) were 18.6% and 2.9%, respectively ( p = 0.03). In experimental models, the major histocompatibility complex (MHC) has an interactive influence on the development of spontaneous, virally or chemically-induced malignancies (Lilly et al., 1964; Boyse et al., 1972;Faraldo et al., 1979;Oomen et al., 1988;Vasmel et al., 1988). Particular alleles of this polymorphic system influence the incidence and phenotype, as well as the age at onset of malignancies (Vasmel et al., 1988;Miyazawa et al., 1992). The interaction of the MHC is not exerted on transformation of a neoplastic clone but occurs during the pre-leukaemic stage (Chesebro, 1981;Lonai et al., 1982). Thus, it does not contain essential susceptibility genes but influences the rate of progression to overt malignancy. More than one MHC gene is involved in the complex, multifactorial development of malignancies (Oomen et al., 1988;Zijlstra and Melief, 1986). Eight of theThe findings in animal models stimulated similar studies investigating the role of the human MHC (HLA complex) in malignancies. The initial serological studies uncovered some associations but did not establish a strong and consistent influence of HLA antigens on the development of neoplasms (Tiwari and Terasaki, 1985). The haemopoietic malignancies have been the most extensively studied ones (Seremetis et al., 1985;Bortin et al., 1987;Caruso et al., 1987;Richter et al., 1973;Nunez-Roldan et al., 1982; Kilpatrick et al., 1984;Dyer et al., 1986;Cuttner et al., 1994). In leukaemia and lymphoma also, no consistent HLA association has been shown by serology.With the advent of molecular typing methods, this issue has been revisited. Recent studies have shown stronger allelic associations, although genotypes, age and gender effect have usually been overlooked (Apple et al., 1994;Klitz et al., 1994). The first DNA-based study investigating the role of the HLA complex in the development of leukaemia showed a strong influence of several independent genotypes on the age at onset of chronic myeloid leukaemia (CML), the strongest one being homozygosity for the supertypic specificity HLA-DR53 (Dorak et al., 1994a). A second molecular study confirmed the role of this homozygous genotype in increased susceptibility to childhood acute lymphoblastic leukaemia (ALL) and also showed a gender effect (Dorak et al., 1995).In the present study, the same association and its influence on the age at onset of chronic lymphoid leukaemia (CLL) were investigated by DNA analy...

Association of chronic lymphocytic leukemia with specific alleles of the HLA-DR4:DR53:DQ8 haplotype in German patients

“…For the haplotype HLA-DRB1*0401:DRB4*0103, a CLL-specific linkage disequilibrium together with an increased haplotype frequency were observed. In accordance with the observation of Dorak et al, 16 these findings can be interpreted as a positive association of CLL with the HLA-DR4:DR53 haplotype.…”

“…An association of HLA-DRB1*0401 and -DRB4(DR53) with CLL had been suggested in a previous study based on PCR-SSO and serologic typing. 16 Due to the different typing techniques compared with our present study, these results did not represent an a priori hypothesis, and correction with the total number of alleles was necessary. With the large number of known HLA alleles, a lack of significance after correction is a common problem of studies investigating disease association of polymorphic genes.…”

“…A positive association of HLA-DRB1*0401 with CLL and an accelerating effect of HLA-DR53 homozygosity on the onset of CLL have been reported. 16 The results suggest a susceptibility factor for CLL within the MHC class II region. To our knowledge, no study has completely investigated HLA-A, -B, -Cw, -DRB1/3/4/5, -DQB1 and -DPB1 alleles in a group of CLL patients.…”

Human leukocyte antigen class II allele association to disease progression in Iranian patients with chronic lymphocytic leukemia

“…These polymorphic antigens could also influence the pathogenesis of B-cell or T-cell malignancies through continuous clonal stimulation of antigen-specific lymphocytes [16]. Many studies examined the possible association of the HLA system with lymphoproliferative disorders, but few reported HLA frequencies in CLL [17][18][19][20][21][22][23][24]. Furthermore, the frequency of HLA alleles has not been well determined in Asian CLL patients.…”

“…Whereas some studies indicated no association of CLL with HLA molecules [24], others demonstrated association with a variety of HLA alleles [17][18][19][20][21][22][23].…”