Human leukocyte antigen G polymorphism is associated with an increased risk of invasive cancer of the uterine cervix

Abstract

Human leukocyte antigen (HLA)-G acts as negative regulator of the immune responses and its expression in tumor cells may enable them to escape immunosurveillance. The purpose of this study was to investigate the influence of HLA-G polymorphism on risk of high-grade cervical intraepithelial neoplasia (HG-CIN) and cervical cancer in a Canadian population. The authors have analyzed 1,372 women from participants recruited between 2001 and 2009 in the ongoing Biomarkers of Cervical Cancer Risk case-control study. A total of 539 women with histologically confirmed HG-CIN and invasive cancer formed the case series, and 833 women with normal cytology served as controls. Cervical specimens were tested for human papillomavirus (HPV) DNA using the MY09/11 PCR protocol and HLA-G alleles where determined using a direct DNA sequencing procedures. HLA-G polymorphisms were not associated with HG-CIN or HPV infection. However, the risk for invasive cancer was significantly increased with the homozygous genotypes HLA-G*01:01:02 [odds ratio (OR) 5 3.52, 95% confidence interval (CI): 1.43-8.61, p 5 0.006], 2G*01:06 (OR 5 19.1, 95% CI: 2.29-159, p 5 0.005) and 2G* 3 0 UTR 14-bp insertion (OR 5 2.17, 95% CI: 1.10-4.27, p 5 0.020), whereas, the heterozygotic form of the G*01:01:01 wild-type allele was significantly associated with a reduced risk of invasive cancer (OR 5 0.31, 95% CI: 0.16-0.59, p < 0.0001) after adjusting for age, HPV infection and ethnicity. These associations were also observed with progression of disease from HG-CIN to invasive cancer among HPV-positive women. These results suggest that HLA-G polymorphism is an independent risk factor for the development of invasive cervical cancer.

Determinants of Human Papillomavirus Coinfections among Montreal University Students: The Influence of Behavioral and Biologic Factors

“…Another previous study in this cohort also found the HLA-G Ã 01:01:02 allele to be associated with both increased cumulative risk and persistence of HPV16 (28), and this allele was also recently linked to invasive cervical cancer (32). Both the HLA-G Ã 01:01:03 and HLA-G Ã 01:01:05 alleles associated with coinfections here were also previously found to be associated with increased odds of certain low-risk HPV infections in this cohort, but not among women purported to be highly exposed to HPV (28).…”

“…HLA alleles were typed from purified DNA obtained from cervical specimens collected at enrollment, using PCR amplification of sequence-specific primers for HLA-B (27,28). These HLA types were chosen a priori based on consistent published evidence to support their role in susceptibility to both HPV infection (27)(28)(29)(30) and cervical cancer (24,26,31,32).…”

“…Through their role in antigen presentation, HLA molecules are thought to be critically involved in cell-mediated immune recognition and viral clearance (25,26), and as such, there is strong biologic plausibility for the HLA system to be involved in the acquisition of HPV coinfections. Indeed, although HLA alleles have been implicated in HPV acquisition (27)(28)(29), persistence (28,30), and carcinogenic progression (24,26,31,32), no studies to date have looked at the impact of specific HLA alleles on the risk of developing HPV coinfections.…”

Association of the programmed cell death-1 PD1.5 C>T polymorphism with cervical cancer risk in a Chinese population

“…A few risk-modulating variants for cervical cancer have been identified by a candidate gene association study. The genes that are associated with cervical cancer susceptibility are involved in DNA repair, cell cycle and apoptosis, cell proliferation and differentiation, the human leukocyte antigen system, and various immune responses (Ferguson et al, 2012;Safaeian et al, 2012).…”

Polimorfismo do HLA-G nas lesões cervicais em mulheres portadoras ou não da infecção pelo HIV - 1

“…Corroborando com estes achados, um importante estudo com a participação de 1.372 mulheres, sendo 833 controles saudáveis, 395 com HSIL e aumentado para desenvolvimento de ICC (P = 0,020) e o genótipo ins/ins está associado com a progressão de HSIL para ICC (OR = 2,0; IC = 1,01 -3,98; P = 0,048) (FERGUSON et al, 2012). Bertolotti e colaboradores sugerem que este mesmo genótipo possua associação com a progressão das lesões cervicais devido à ausência de ins/ins entre os casos de condiloma e sua presença aumentada entre as participantes com LSIL ou ICC (P = 0,011) (BERTOLOTTI et al, 2014).…”