Comparison of human leukocyte antigen DR-DQ disease associations found with cervical dysplasia and invasive cervical carcinoma

Background: Human leukocyte antigen (HLA) molecules, whose biological role is in the regulation of immune responses to foreign antigens and in discrimination of self from non-self antigens, are encoded by a series of closely linked genetic loci found on chromosome 6. Although the evidence for a link between HLA and cervical cancer has been controversial, it has been recently reported that certain HLA class II haplotypes (linked class II alleles) are positively associated with invasive cervical cancer, while other class II haplotypes are negatively associated or protective. Since HLA associations between human papillomavirus type 16 (HPV16)-mediated cancer cases and non-HPV16-mediated cancer cases have been found to be different, this suggests that specific HLA class II haplotypes may influence the immune response to HPV infection and may affect the risk of acquiring invasive cervical carcinoma. Purpose: This study was conducted to determine if the same HLA class II haplotypes that are associated with invasive cervical carcinoma are also associated with cervical dysplasia (pre-sumed precursors of invasive cervical cancer). Methods: We have examined HLA DR-DQ haplotypes among 128 Hispanic women from New Mexico with biopsy-confirmed cervical dysplasia in a case-control study using sensitive DNA-based polymerase chain reaction amplification and sequence-specific oligonucleotide probe hybridization methods to detect the presence and type of HPV and to detect allelic polymorphism in the HLA DRB1 and DQB1 loci. Results: Dysplasia cases were divided into two groups for comparison to controls: severe dysplasia/carcinoma in situ (CIS), and slight/moderate dysplasia. The frequency distribution of HLA class II haplotypes among the HPV16-positive severe dysplasia/CIS cases had a statistically significant (two-tailed P<.005) difference compared with controls, whereas haplotypes among the severe dysplasia/CIS cases containing HPV types other than HPV16 did not show statistically significant frequency differences. DR-DQ haplotypes previously found to be associated with HPV16-invasive cervical carcinomas were also associated with HPV16-positive severe dysplasia/CIS. However, no statistically significant haplotype frequency difference was observed between slight/moderate dysplasia cases and controls. In addition, we noted a DQA1-DQB1 haplotype negatively associated with severe dysplasia/CIS but not with invasive cervical cancers. Conclusions: Our results strongly suggest that certain HLA haplotypes confer an increased risk for severe cervical dysplasia and invasive cervical carcinoma following HPV16 infection. Implications: Further molecular studies are needed to identify HLA alleles or haplotypes that may provide increased susceptibility to HPV-associated cervical disease. [J Natl Cancer Inst 87: 427-436, 1995]