HLA‐G polymorphism and transitional cell carcinoma of the bladder in a Brazilian population

Abstract

The morphologic appearance and clinical behavior of the human urinary bladder papillary transitional cell carcinoma (TCC) probably result from a complex interaction between carcinogenic insults and host resistance during the patient's life. While the main recognized risk factors are of environmental origin (e.g. smoking), relatively little information exists about the susceptibility to TCC development. The human leukocyte antigen G (HLA-G) molecule plays an important role in immune response regulation and has been implicated in the inhibition of the cytolytic function of natural killer and cytotoxic T cells. Several lines of evidence indicate that HLA-G polymorphisms influence the expression level and production of different HLA-G isoforms. The aim of this study was to explore a possible influence of the HLA-G polymorphism on the susceptibility to urinary bladder TCC development and progression in smokers and nonsmokers Brazilian subjects. The HLA-G locus was found to be associated with susceptibility to TCC development and progression. The G*0104 allelic group (specially the G*010404 allele) and the G*0103 allele were associated with a tobacco-dependent influence on TCC development. The G*0104 group was associated with progression to high-grade tumors, irrespective of smoking habit, while the G*0103 allele was associated to high-grade tumor only in smoking patients. Our results are an evidence that the HLA-G locus itself, or as part of an extended haplotype encompassing this chromosome region (particularly the HLA-A given the high linkage disequilibrium observed between them in this data series), may be associated with TCC susceptibility and tumor progression, suggesting a tobacco-dependent influence of these polymorphisms.

Tumor-specific upregulation of human leukocyte antigen–G expression in bladder transitional cell carcinoma

“…Recently susceptibility for certain kinds of malignancies such bladder transitional cell carcinoma with HLA-G polymorphism was examined [35]. In that study, the G*0104 group was associated with progression to high-grade tumors irrespective of smoking habit, whereas the G‫3010ء‬ allele conferred high-grade tumor susceptibility only to smoking patients once the tumor was established.…”

Absence of the HLA-G*0113N allele in Amerindian populations from the Brazilian Amazon region

“…To further explore the existence of the G*0113N allele in South America, the reexamination of HLA-G exon 2 sequence data [6,30] from 295 admixed individuals (590 alleles) sampled from different places in the State of SÄo Paulo, Southeastern Brazil, confirmed the absence of such null allele in a highly diverse population. Following the same rationale described earlier in the text, it may be inferred that the frequency of the G*0113N allele is not higher than 0.5% in the Brazilian urban population.…”

“…It should be emphasized that Brazilians represent one of the most heterogeneous populations in the world, which is the result of five centuries of genetic admixture between people from three continents: the European colonizers mainly represented by the Portuguese, the African slaves, and the autochthonous Amerindians [31]. Therefore, the Brazilian urban population has presented the largest HLA-G variability already detected [6,30,32]. Therefore, the present observation suggests that G*0113N is a Ghanaian private mutation rather than a worldwide polymorphic allele.…”

“…Additionally, sequence data from 295 admixed individuals from the State of SÄo Paulo, Southeastern Brazil, previously genotyped for HLA-G exon two [6,30], were reexamined for the G*0113N mutation.…”

“…The G*0113N allele is defined by a C ¡ T transition at the first base of codon 54 in exon 2 that determines the presence of a premature TAG stop codon. The presence of such deletion was investigated according to a previously described method [6,30]: exon 2 was individually amplified yielding polymerase chain reaction (PCR) products of 361 bp, which were directly sequenced. The obtained sequences were aligned with the genomic sequences of the official alleles (recognized by the IMGT), and the existence of the G*0113N allele was carefully verified.…”