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Correlation of HLA-A02* genotype and HLA class I antigen down-regulation with the prognosis of epithelial ovarian cancer

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Abstract

Background

In recent years, evidence is accumulating that cancer cells develop strategies to escape immune recognition. HLA class I HC down-regulation is one of the most investigated. In addition, different HLA haplotypes are known to correlate to both risk of acquiring diseases and also prognosis in survival of disease or cancer. We have previously shown that patients with serous adenocarcinoma of the ovary in advanced surgical stage disease have a particularly poor prognosis if they carry the HLA-A02* genotype. We aimed to study the relationship between HLA-A02* genotype in these patients and the subsequent HLA class I HC protein product defects in the tumour tissue.

Materials and methods

One hundred and sixty-two paraffin-embedded tumour lesions obtained from Swedish women with epithelial ovarian cancer were stained with HLA class I heavy chain (HC) and β2-microglobulin (β2-m)-specific monoclonal antibodies (mAb). Healthy ovary and tonsil tissue served as a control. The HLA genotype of these patients was determined by PCR/sequence-specific primer method. The probability of survival was calculated using the Kaplan–Meier method, and the hazard ratio (HR) was estimated using proportional hazard regression.

Results

Immunohistochemical staining of ovarian cancer lesions with mAb showed a significantly higher frequency of HLA class I HC and β2-m down-regulation in patients with worse prognosis (WP) than in those with better prognosis. In univariate analysis, both HLA class I HC down-regulation in ovarian cancer lesions and WP were associated with poor survival. In multivariate Cox-analysis, the WP group (all with an HLA-A02* genotype) had a significant higher HR to HLA class I HC down-regulation.

Conclusions

HLA-A02* is a valuable prognostic biomarker in epithelial ovarian cancer. HLA class I HC loss and/or down-regulation was significantly more frequent in tumour tissues from HLA-A02* positive patients with serous adenocarcinoma surgical stage III–IV. In multivariate analysis, we show that the prognostic impact is reasonably correlated to the HLA genetic rather than to the expression of its protein products.

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Abbreviations

APM:

Antigen processing machinery

BP:

Better prognosis

β2-m:

β2-microglobulin

BSA:

Bovine serum albumin

CTL:

Cytotoxic T lymphocyte

EOC:

Epithelial ovarian cancer

FFPE:

Formalin fixed paraffin-embedded

HF:

Haplotype frequency

HFS:

High frequency stained

The constitutional allele characteristics:

HLA genotype

HR:

Hazard ratio

KIR:

Killer cell immunoglobulin-like receptors

HLA:

Human leucocyte antigen

IHC:

Immunohistochemistry

FIGO:

International federation of gynaecology and obstetrics

LD:

Linkage disequilibrium

LFS:

Low frequency stained

MHC:

Major histocompatibility complex

HC:

Heavy chain

Mab:

Monoclonal antibody

NK:

Natural killer

HLA-otherwise:

Non-HLA-A02*

PLC:

Peptide loading complex

PCR:

Polymerase chain reaction

tpn:

Tapasin

TAP:

Transporter associated with antigen processing

TBS:

Tris-buffered saline

TA:

Tumour antigen

WP:

Worst prognosis

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Acknowledgments

The statistics was performed under the supervision of Dr. Henning Johansson, Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden: hemming.johansson@karolinska.se. We thank Dr. Anders Höög, Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, SE-171 76 Stockholm, Sweden, anders.hoog@karolinska.se as third pathologist consultant in the diagnosis and read out of immunohistochemistry. This study was supported by grants from the Cancer Society in Stockholm and the King Gustaf V Jubilee Fund and the Swedish Cancer Society, the Karolinska Institute/Stockholm County ALF grant and the Deutsche Forschungsgemeinschaft (DFG) Se-585-10-1 (Barbara Seliger). We gratefully acknowledge the motility grant #040226# from “NordForsk, Holbergs gate 1, NO-0166 Oslo, Norway” to the NCV (Emilia Andersson, HH, Lisa Villabona, Kjell Bergfeldt, Barbara Seliger, Rolf Kiessling) network project. We thank: Dr. Elisabeth Åvall-Lundqvist for her suggestions; Mrs. Liss Garber, Mrs. Gunilla Hagberg and the personnel at the Pathology Unit for assistance with the histological samples.

Conflict of interest

The authors have no conflicts of interest.

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Authors and Affiliations

  1. Department of Oncology-Pathology, Karolinska Institute, Radiumhemmet, Karolinska University Hospital, 171 76, Stockholm, Sweden

    Emilia Andersson, Lisa Villabona, Kjell Bergfeldt, Joseph W. Carlson, Rolf Kiessling & Giuseppe V. Masucci

  2. Departments of Surgery, Immunology and Pathology, School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Soldano Ferrone

  3. Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany

    Barbara Seliger

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  1. Emilia Andersson
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Correspondence to Giuseppe V. Masucci.

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Andersson, E., Villabona, L., Bergfeldt, K. et al. Correlation of HLA-A02* genotype and HLA class I antigen down-regulation with the prognosis of epithelial ovarian cancer. Cancer Immunol Immunother 61, 1243–1253 (2012). https://doi.org/10.1007/s00262-012-1201-0

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