Risk of invasive cervical cancer associated with polymorphic HLA DR/DQ haplotypes

Abstract

The genes encoding human leukocyte antigens (HLA) have shown to be associated with cervical neoplasia. To obtain reliable data on HLA associations with cervical tumors, the study should be performed within a strictly defined cohort. To investigate the population attributable risk of cervical cancer associated with the HLA class II haplotypes DR15 and DQ6 (DQA1*0102 and DQB1*0602), we performed a nested case-control study of 85 women who developed invasive cervical cancer and 120 healthy women from a population-based cohort of Swedish women. The relative risks of cervical cancer among DR15 and DQ6-positive women were 3.73 [confidence interval (CI): 1. Susceptibility to viral infections is partly controlled by the human leukocyte antigens (HLA). Certain HLA specificities are associated with efficient virus elimination while others are associated with a tendency towards long lasting, persistent virus infections. [1][2][3][4][5] Infection with oncogenic human papillomaviruses (HPV), particularly type 16 and 18, is the major cause of cervical intraepithelial neoplasia (CIN) and cervical cancer 6 -8 Although over 90% of cervical cancers harbor HPV genomes, 9 only a small fraction of women infected with high-risk papillomaviruses develop cancer, suggesting that other environmental and/or genetic factors contribute to cervical carcinogenesis. Both studies of monozygotic and dizygotic twins 10 and family studies 11 have found evidence of a genetic component in cervical cancer. Several studies have reported HLA as one genetic factor that is associated with CIN and cervical cancer. 12-14 However, a link between HLA polymorphisms and cervical neoplasia has not been consistently reported. 15 Varying results could be due to the fact that many studies did not use epidemiologically defined study designs. For valid results, acceptable response rates are required.Two previous studies, a population-based cohort study and a population-based case-control study with high attendance rate, both identified HLA-DQ6 and HLA-DR15 as a susceptibility marker for high grade CIN in Scandinavia. 16,17 The aim of our study was to test the hypothesis that HLADR15-DQ6 association demonstrated in our earlier CIN study is also true for the invasive cervical cancer study. We performed a populationbased cohort study of the risk of invasive cervical cancer in relation to these HLA haplotypes and to HPV infection. METHODS Study baseIn the Västerbotten County in Northern Sweden [population, 260,472; women, 130,651 (1995)], a population-based invitational cervical screening program started in 1969 with invitations issued at 4-year intervals. The attendance rate was Ͼ80 percent during the follow-up. All cytological diagnoses in this county, both on Papsmears taken in the organized program and on spontaneously taken smears, are made and the smears stored at the Cytology Laboratory, Umeå University Hospital since 1969. Similarly, all histological specimens from the Västerbotten population have been examined and stored at the Pathology laboratory of the same...

MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP2

“…Previous studies of Swedish patient cohorts have indicated that these four alleles affect susceptibility to cervical cancer, but only *0602 reached statistical significance. [6][7][8] Smaller studies of other populations have also indicated a protective effect of DQB1*0501. 35-38 DQB1*0603, which is in strong LD with DRB1*1301 and DQA1* 0103, has been associated with reduced risk in many populations, 5,38 but not in Sweden.…”

“…The DQB1 alleles analyzed in the current study were selected on the basis of previous work pointing toward an association with cervical cancer susceptibility [6][7][8]38 DQB1 association results were therefore not corrected for multiple testing and Po0.05 was considered significant. In the analysis of SNPs, uncorrected P-values were calculated for all loci as a first step.…”

“…[6][7][8]38 Samples were classified as carriers (all individuals at least heterozygous for an allele) or non-carriers of each DQB1 allele. A total of 11 polymorphisms in 4 other candidate genes of the MHC were also analyzed ( Table 7).…”

“…This allele has been associated with cervical intraepithelial neoplasia 6 and cancer in situ in HPV16-positive women 7 as well as with invasive cervical cancer. 8 Apart from the HLA genes, polymorphisms in genes encoding the two cytokines tumor necrosis factor (TNF, also called TNFa or cachectin) and lymphotoxin-alpha (LTA, also known as TNFb), both located in the MHC class III region, and the transporter associated with antigen processing 1 and 2 (TAP1 and TAP2) have been associated with cervical cancer susceptibility. Both tumor and stromal cells in the microenvironment of many tumors chronically produce low levels of TNF.…”

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

“…[4][5][6] Certain HLA class II alleles, such as DRB1*1501 and DQB1*0602, have been shown to increase the risk for cervical carcinoma, most strongly in HPV 16-positive carcinomas. [7][8][9][10][11][12][13] We have previously shown that the increased carcinoma risk primarily depends on that the alleles render carriers more susceptible to HPV16 infections. 12 In addition, carriers of these HLA susceptibility alleles had higher HPV 16 load in their cervical smears compared to HPV 16-positive noncarriers.…”