HLA and KIR Associations of Cervical Neoplasia.

Background: Cervical cancer is the fourth most common cancer in women, and we recently reported human leukocyte antigen (HLA) alleles showing strong associations with cervical neoplasia risk and protection. HLA ligands are recognized by killer immunoglobulin-like receptors (KIRs) expressed on a range of immune cell subsets, governing their proinflammatory activity. We hypothesized that the inheritance of particular HLA-KIR combinations would increase cervical neoplasia risk. Methods: Here, we used HLA and KIR dosages imputed from single-nucleotide polymorphism genotype data from 2143 cervical neoplasia cases and 13858 healthy controls of European decent. Results: The following 4 novel HLA alleles were identified in association with cervical neoplasia, owing to their linkage disequilibrium with known cervical neoplasia-associated HLA-DRB1 alleles: HLA-DRB3*9901 (odds ratio [OR], 1.24; P = 2.49 × 10-9), HLA-DRB5*0101 (OR, 1.29; P = 2.26 × 10-8), HLA-DRB5*9901 (OR, 0.77; P = 1.90 × 10-9), and HLA-DRB3*0301 (OR, 0.63; P = 4.06 × 10-5). We also found that homozygosity of HLA-C1 group alleles is a protective factor for human papillomavirus type 16 (HPV16)-related cervical neoplasia (C1/C1; OR, 0.79; P = .005). This protective association was restricted to carriers of either KIR2DL2 (OR, 0.67; P = .00045) or KIR2DS2 (OR, 0.69; P = .0006). Conclusions: Our findings suggest that HLA-C1 group alleles play a role in protecting against HPV16-related cervical neoplasia, mainly through a KIR-mediated mechanism.

Correction: Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study.

[This corrects the article DOI: 10.1371/journal.pgen.1006866.].

Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study.

A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods.

Determination of the diagnostic accuracy of testing for high-risk (HR) human papillomavirus (HPV) types 16, 18 and 45 in precancerous cervical lesions: preliminary data.

AIMS: In Germany, cervical cancer screening is regulated by the German Federal Ministry of Health and Social Security and is available for all women from the age of 20 on the basis of the Papanicolaou (PAP) smear. The purpose of this study was to determine the positive predictive value of HR-HPV testing for precancerous lesions of the cervix uteri. Therefore, this study especially focused on the diagnostic accuracy of testing for one or more of the HPV types 16, 18 and 45 for all HR-HPV positive women, since HR-HPV infections with subtypes 16, 18 and 45 have demonstrated a higher risk of developing cervical cancer [Bulk S, et al. Br J Cancer 2006; 94:171-5]. METHODS: Between 2007 and 2008 a total of 586 women were recruited: a group of 477 women with a history of known cervical lesions and/or HPV infections (eligibility criterion: HR-HPV DNA positive test result with HC2T) and a group of 109 women who were examined as part of their routine cervical cancer screening. Baseline HR-HPV status was measured at enrollment with the FDA-approved Hybrid Capture(R) 2 HPV DNA Test and the HR-HPV 16/18/45 Probe Set Test (HC2T, PST; QIAGEN, Hilden, Germany). Both tests use hybrid capture hybridization genotyping technology. Cervical smears were classified according to the Second Munich Nomenclature (1989). The results were converted to the nearest equivalent in the Bethesda system. In general, study subjects were followed up semiannually for a period of 1(1/2) years. The histopathological endpoint of CIN 2-3 lesion was used as a surrogate endpoint. RESULTS: Preliminary data for 194 women of the risk group (43.5%) and for the complete control group were available. To date, CIN 2-3 was confirmed in 77 HR-HPV DNA positive women. 85.7% of these lesions were positive for one or more of the HR-HPV types 16, 18 and 45 (PST+). 88.2% (60/68) of the histologically confirmed CIN 3 lesions and six out of nine (66.6%) CIN 2 lesions were positive PST+. Furthermore, all women with a histologically confirmed squamous cell carcinoma (n = 4) were PST+. Besides, three (50%) out of six detected CIN 1 lesions were PST+. Nonetheless, histology confirmed no malignancy in three cases. Two of them were PST+. CONCLUSION: These preliminary results demonstrate that starting cervical cancer screening at the age of 20 years remains important as seventeen (25%) of the 68 histologically verified CIN 3 lesions arose in women who were younger than 30 years. Furthermore, our data suggest that adding an HR-HPV test that detects one or more of the HR-HPV types 16, 18 and 45 in conjunction with cytology could help to identify women with an underlying cervical lesion who have an elevated risk of developing severe cervical lesions. This might offer the opportunity of a decrease in incidence and mortality rates that are related with invasive cervical cancer.

Genomic amplification of the human telomerase gene (TERC) in pap smears predicts the development of cervical cancer.

Invasive cervical carcinomas almost invariably carry extra copies of chromosome arm 3q, resulting in a gain of the human telomerase gene (TERC). This provided the rationale for the development of a multicolor fluorescence in situ hybridization (FISH) probe set as a diagnostic tool for the direct detection of TERC gains in Pap smears. We previously used this probe set to show that cervical intraepithelial neoplasia (CIN) 2 and CIN3 lesions could be distinguished from normal samples, atypical squamous cell of undetermined significance (ASCUS) and CIN1, with a sensitivity and specificity exceeding 90%, independent of the cytomorphological assessment. In the current study, we explored whether gain of 3q and amplification of TERC could predict progression from CIN1/CIN2 to CIN3 and invasive carcinoma. We applied our probe set to a series of 59 previously stained Pap smears for which repeat Pap smears and clinical follow-up were available. The samples included CIN1/CIN2 lesions that progressed to CIN3 (progressors), CIN1/CIN2 lesions that regressed spontaneously (regressors), and normal Pap smears from women who subsequently developed CIN3 or cervical cancer. Here, we show that progressors displayed a gain of 3q whereas none of the regressors showed this genetic aberration. These data suggest that 3q gain is required for the transition from CIN1/CIN2 to CIN3 and that it predicts progression. Of note, 3q gain was found in 33% of cytologically normal Pap smears from women who were diagnosed with CIN3 or invasive cervical carcinoma after a short latency. The sensitivity of our test for predicting progression from CIN1/CIN2 to CIN3 was 100% and the specificity, ie, the prediction of regression, was 70%. We conclude that the detection of 3q gain and amplification of TERC in routinely collected Pap smears can assist in identifying low-grade lesions with a high progression risk and in decreasing false-negative cytological screenings.