Cervical carcinoma: human papillomavirus infection and HLA-associated risk factors in the Spanish population

Abstract

There is evidence for a link between MHC and squamous cell carcinoma of the cervix (SCCC), and different patterns of association in different patient cohorts have been reported. To investigate this subject in the Spanish population, HLA class I, -II serotypings and HLA-DQB1 oligogenotypings of 142 patients and 138 healthy sex-age-matched controls were performed. Comparative analysis of the DR2-DQ3-stratified phenotypes demonstrated a strong association between DR2 and DQ3 in SCCC (Pc9 < 7 x 10(-8)). However, no interaction was observed between the two HLA factors, which seem to confer two weak and independent risks. Thus, phenotypes with DR2 and/or DQ3 (patients, 79%, controls, 60%; P < 5 x 10(-4)) were over-represented, while the less common DR2/DQ3-negative phenotypes with the HLA class I A2 antigen were found to confer the highest risk (EF = 62%, Pc84 < 1 x 10(-2)) of SCCC. Comparative analysis of allele frequencies revealed two weakly significant increases, one for DQB1*0301 (P < 1 x 10(-2)) in low-moderate dysplasias (CINI,II), and the other for DQB1*0402 (P < 3 x 10(-2)) in severe dysplasia in situ (CINIII/CIS), and a trend for an increase of DQB1*0302 among CINIII/CIS and invasive SCCC (ISCCC). With regard to DQB1 genes encoding the DR2-associated DQ serotypes, there was no significant deviation in patients. In contrast, the frequency of DQB1*0603 was found to be weakly decreased in CINI,II (P < 5 x 10(-2)) and ISCCC (P < 3 x 10(-2)), indicating a protective effect for this DR13 serotype-associated allele. No significant association could be shown between HLA and HPV infective status. However, there is circumstantial evidence that HPV-infected lesions may have been misassigned in some cases, and the sample size was small, so a role for DQB alleles in modifying the course of HPV-induced diseases cannot be excluded. The observations in this study suggest A2, DR2, DQB1*0301, DQB1*0402 and DQB1*0603 as independent factors associated with SCCC and as relevant targets in HLA-restricted peptide presentation. Our results are consistent with the theory that HLA loci may have different contributions in susceptibility and resistance to low-moderate dysplasias, CIS and invasive SCCC.

Association between HLA-DQB1 and cervical dysplasia in Vietnamese women

“…Likewise, HLA‐DQB1*0601 has been found associated with cervical carcinoma in Iranian women (26) . Strikingly, HLA‐DQB1*0301 has been found to be associated with cervical carcinoma in several populations (17,20,22–24,27,28,44,48,57,58) ; however, our results point toward a protective role among Vietnamese, as has been reported also among African American women (14) .…”

“…Moreover, HLA‐DQB1*0301 was more common in women without cervical dysplasia (Fisher’s exact P = 0.0152). The association of HLA‐DQB1*0302 with cervical dysplasia has been previously reported in other populations (13,16,23) . Likewise, HLA‐DQB1*0601 has been found associated with cervical carcinoma in Iranian women (26) .…”

“…For this reason, the absence or presence of particular HLA alleles may constitute an important factor of cervical carcinogenesis. The importance of HLA‐DQB1 alleles in cervical dysplasia and/or cervical cancer has been reported among populations of different ethnicity: American (13) , African American (14) , Brazilian (15) , Costa Ricans (16) , Honduran (17) , Venezuelan (18) , Belgian (19) , British (20) , French (21) , Norwegian (22) , Spanish (23) , Swedish (24) , Japanese (25) , Iranian (26) , Senegalese (27) , and Tanzanian (28) women.…”

HLA‐DRB1, ‐DQB1 alleles in head and neck carcinoma patients

“…However, the associated alleles and haplotypes seem to differ depending on the origin of the population of the patients. The strongest protective association in cervical cancer thus far is with DRB1*13 or DQB1*0603 or both (4, 12, 13), and increased cervical cancer risk has been linked to DQB1*0301‐3 (9, 14, 15), and DRB1*1501; DQB1*0602 (15, 16, 17). Certain haplotypes have also been linked to prevention of pre‐malignant cervical intraepithelial lesions progressing to invasive carcinoma (18).…”

Analysis of HLA‐DRB1*0901‐binding HPV‐16 E7 helper T cell epitope†

“…In addition, French women carrying HLA‐DRB1*1301 or DRB1*1302 alleles were resistant to the development of cervical carcinoma 10 . Although cytotoxic T cell responses to cancer antigens depend upon expression of MHC class I molecules, it is interesting to note that the emerging molecular epidemiological data supports an almost exclusive association of cervical carcinoma with MHC class II genotype rather than MHC class I type 8–12 . Therefore, MHC class II molecules should play an important role in the immune responses that cervical cancer patients make to HPV antigens.…”