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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 1  |  Page : 97-101
HLA class I and II antigens expression in patients with renal cell carcinoma


Department of Urology, Turkey Yuksek Ihtisas Education and Training Hospital, Ankara, Turkey

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   Abstract 

An optimal antitumoral immune response requires the activation of both CD8(+) and CD4(+) T lymphocytes by the peptide antigen presentation via the human leukocyte antigen (HLA) class I and class II molecules, respectively. The frequency of A1, A26, DR11 alleles are signifi­cantly elevated and seem to be the predisposing alleles in RCC, while HLA A29 and DQ1 are the protective alleles and are found more frequently in the healthy group. To investigate the association between renal cell carcinoma (RCC) and the host's immune system, we immunohistochemically examined RCCs in 44 Turkish patients for the expression of class I and class II antigens. We found a significantly higher frequency of the alleles HLA-A1 (p= 0.001), HLA-A26 (p=0.047) and HLA­DR11 (p= 0.03) in RCC patients compared to the control group. The most frequent alleles in the control population were A29, DQ1 (p= 0.004 and 0.002 respectively). We observed no significant difference between patients and controls in HLA-B and HLA-C allele frequency. We conclude that our study found an association between HLA antigens and RCC in Turkish patients. We found a significantly higher frequency of the alleles HLA-A1, HLA-A26 and HLA-DR11in RCC patients compared to the control group. Larger studies are required to confirm these results.

Keywords: Human leukocyte antigens, Renal cell carcinoma, Turkish

How to cite this article:
Ozgur B C, Gonenc F, Yazicioglu AH. HLA class I and II antigens expression in patients with renal cell carcinoma. Saudi J Kidney Dis Transpl 2009;20:97-101

How to cite this URL:
Ozgur B C, Gonenc F, Yazicioglu AH. HLA class I and II antigens expression in patients with renal cell carcinoma. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2019 Nov 22];20:97-101. Available from: http://www.sjkdt.org/text.asp?2009/20/1/97/44713

   Introduction Top


Renal cell carcinoma (RCC) accounts for ap­proximately 3% of adult malignancies and 90­95% of neoplasms arising from the kidney. [1] It is characterized by lack of early warning signs, diverse clinical manifestations, and resistance to radiation and chemotherapy. A number of cellular, environmental, genetic and hormonal factors have been studied as possible causal factors for renal cell carcinoma. Although to­bacco and industrial carcinogens have been im­plicated, the cause of renal cell carcinoma is still unknown. [2]

The human leukocyte antigen system (some­times human lymphocyte antigen) (HLA) encodes the cell-surface antigen-presenting proteins that are (effectively) unique to every person. [3] RCC is most likely affected by a genetic predispo­sition that can be uncovered through population studies. It is believed to be triggered by an intri­cate combination of environmental and genetic factors.

Furthermore, novel vaccines produce specific immune responses and objective clinical res­ponses with minimal toxicity in phase I/II trials. Advances in gene transfer technology, tumour immunology and better methods of monitoring specific antitumour immune responses allow the hope that tumour vaccines will be introduced into the clinic, at least in some malignancies resistant to systemic therapy so far such as renal cell carcinoma. [4]

A variety of malignancies have been linked to HLA genes, also the association of certain anti­gens with renal cell carcinoma (RCC) has been both claimed and disclaimed. [5] To determine whether HLA genotypes are associated with RCC, several genotyping methods have been used. It was therefore, of obvious interest to study to what extend the malignant human tumors are associated with suppression of MHC gene expression.

The aim of this study was to investigate HLA class 1(A-B-C) and 2(D) expression in RCC pa­tients and have a database for future vaccine studies.


   Subjects and Methods Top


We studied the HLA frequencies in 44 Turkish patients with histopathologically confirmed RCC in the Ankara Yuksek Ihtisas Training Hospital from 2000 to 2005. All the patients had under­gone radical nephrectomy for the primary lesion, and none of them developed distant metastases at the time of their first admission. The mean age at the onset of the disease was 61.3 years (range 40-80 years); 23 patients were men and 21 were women. The tumors were staged accor­ding to Tumor Node Metastasis (TNM) classifi­cation. [6] Six patients were classified as T1stage, 33 as T2, 5 as T3a, and 38 as N0M0 and 6 N1M0.

As controls we used genetic frequencies of HLA in 44 healthy Turkish results (living renal donors protocol). [7],[8]

HLA typing of peripheral blood samples from the patients and controls was performed using a standard microlymphocytotoxicity assay as pre­viously described. [9],[10] HLA typing was per­formed using the Biologische Analysensystem Histo Tray ABC 72 and Histo Tray DR 72 (BAG GmbH, Lich, Germany).


   Statistical Analysis Top


The chi-square test using a standard 2 × 2 con­tingency table was used to measure the diffe­rence between the RCC patients and healthy individuals, and the Fisher's exact test was applied in cases where the number of subjects in a group was less than five. P values less than 0.05 were considered to indicate statistical sig­nificance. Analyses were carried out with SPSS (version 13) software.


   Results Top


We found a significantly higher frequency of the alleles HLA-A1 (p= 0.001), HLA-A26 (p= 0.047) and HLA-DR11 (p= 0.03) in RCC pa­tients compared to the control group. The most frequent alleles in the control population were A29, DQ1 (p= 0.004 and 0.002, respectively). We observed no significant difference between patients and controls in HLA-B and HLA-C allele frequency [Table 1], [Table 2].


   Discussion Top


The results of our study suggest the existence of HLA predisposing and specific protective markers, but do not support previous reports of a primary association between HLA polymor­phism and development of RCC. Over the last 2 decades many reports of HLA expression in different populations have been published in an effort to further our understanding of the immu­nological and genetic features of the disease. [10],[11],[12],[13] Although a clear association between HLA ty­ping and RCC is still disputed, there is nonethe­less general agreement that some HLA haplo­types are related to phenotypic variations of the disease. [14],[15],[16] HLA molecules may be responsible for an altered effectiveness of the immune res­ponse against tumor associated antigens expressed by RCC. [18]

In the present study the association between HLA antigens and RCC was investigated in Turkish patients. Of the HLA class 1 antigen A1 and A26, and of the class 2 DR11 were found to be significantly increased in our pa­tients, whereas the frequencies of A29 and DQ1 were significantly lower in these patients com­pared to the control group. These results are consistent with those found by Cekmen et al in a similar study of the same population sample. [19]

Previous work on the relationship of RCC to HLA has produced different results, however. The most common RCC association has been found to be with the HLA-DR1 allele in Japa­nese patients. [20]

Buszello et al reported that in RCC, a com­plete loss of HLA class I expression is a rare phenomenon observed in 0/48 primary tumors and in 1/12 metastases. Reduced expression of HLA class I antigens occurred in about 15% of primary tumors but was more frequent (50%) in case of metastases; however, if this is relevant to cytotoxicity by T lymphocytes is still un­known. [21] Consistent with the findings of Bus­zello et al, we found increased frequency of HLA-A29 expression.

Our results also revealed that the HLA-A1 and A-26 expression was significantly high in renal cell carcinomas (p= 0.033 and 0.47 respectively). This is in contrast to the report by Atkins et al who found low incidence of class 1 expression in kidney tumors. [22] However, similar findings to ours have been reported by Ibrahim et al. [23]

It is possible that an association between HLA and disease is only a marker for an undisco­vered polymorphism in a linked gene. There are at least 120 additional genes in the MHC re­gion. Most of these additional genes in the HLA class II region are involved in immunological functions that relate to the HLA class I and II genes [24],[25] Because of the high density of poten­tially important genes in the MHC region, lin­kage disequilibrium around this region makes it difficult to identify the exact susceptibility gene for a disease. [26]

Finally, the results obtained from this study will be useful as basic data on Turks for anthro­pology, organ transplantation and disease asso­ciation studies. In the future, further studies are required in the same population to confirm these results as it is well known that there are large differences in the frequencies of the HLA polymorphisms in different populations.

 
   References Top

1.Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999; 49(1):8-31.  Back to cited text no. 1    
2.Hunt JD, Van der Hel OL, McMillan GP, Boffetta P, Brennan P. Renal cell carcinoma in relation to cigarette smoking: Meta-analysis of 24 studies. Int J Cancer 2005;114(1):101-8.  Back to cited text no. 2    
3.Fogdell A, Hillert J, Sachs C, Olerup O. The multiple sclerosis- and narcolepsy-associated HLA class II haplotype includes the DRB5*0101 allele. Tissue Antigens 1995;46:333-6.  Back to cited text no. 3  [PUBMED]  
4.Jocham D, Richter A, Hoffmann L, et al. Adju­vant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: Phase III, randomised controlled trial. Lancet 2004;363(9409):594-9.  Back to cited text no. 4    
5.Cordon-Cardo C, Fuks Z, Drobnjak M, Moreno C, Eisenbach L, Feldman M. Expression of HLA-A,B,C antigens on primary and metastatic tumor cell populations of human carcinomas. Cancer Res 1991;51:6372-8.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Ficarra V, Galfano A, Mancini M, Martignoni G, Artibani W. TNM staging system for renal­cell carcinoma: Current status and future perspectives. Lancet Oncol 2007;8(6):554-8.  Back to cited text no. 6    
7.Rastogi N, Sahani DV, Blake MA, Ko DC, Mueller PR. Evaluation of living renal donors: Accuracy of three-dimensional 16-section CT. Radiology 2006;240(1):136-44.  Back to cited text no. 7    
8.Rydberg J, Kopecky KK, Tann M, et al. Evaluation of prospective living renal donors for laparoscopic nephrectomy with multisection CT: The marriage of minimally invasive imaging with minimally invasive surgery. Radiographics 2001;21(Spec Issue):223-36.  Back to cited text no. 8    
9.Terasaki PI, Bernoco D, Park MS, Ozturk G, Iwaki Y. Microdroplet testing for HLA-A, -B, - C, and -D antigens. Am J Clin Pathol 1978;69:103-20.  Back to cited text no. 9    
10.Rydberg J, Kopecky KK, Tann M, et al. Evaluation of prospective living renal donors for laparoscopic nephrectomy with multisection CT: The marriage of minimally invasive imaging with minimally invasive surgery. Radiographics 2001;21(Spec Issue):223-36.  Back to cited text no. 10    
11.Ayed K, Jendoubi SA, Makhlouf M, Sfar I, Abdallah TB. Comparison of HLA Class I and II Molecular and Serological Typing within Clinical Laboratory. Saudi J Kidney Dis Transpl 2003;14(1):39- 42.  Back to cited text no. 11    
12.Fleiss JL. Statistical methods for rates and proportions. 2nd ed. New York: John Wiley and Sons, 1981; p. 61-4.  Back to cited text no. 12    
13.Atkins D, Ferrone S, Schmahl GE, Storkel S, Seliger B. Down-regulation of HLA class I antigen processing molecules: an immune escape mechanism of renal cell carcinoma? J Urol 2004;171:885-9.  Back to cited text no. 13    
14.Saito T, Kimura M, Kawasaki T, Sato S, Tomita Y. MHC class II antigen-associated invariant chain on renal cell cancer may contribute to the anti-tumor immune response of the host. Cancer Lett.1996;109:15-21.  Back to cited text no. 14    
15.Gastl G, Ebert T, Finstad CL, et al. Major histocompatibility complex class I and class II expression in renal cell carcinoma and modulation by interferon gamma. J Urol 1996;155:361-7.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Angus R, Collins CM, Symes MO. Expression of major histocompatibility complex (MHC) antigens and their loss on culture in renal carcinoma. Eur J Cancer 1993;29:2158-60.  Back to cited text no. 16    
17.Kruger T, Schoor O, Lemmel C, et al. Lessons to be learned from primary renal cell carcinomas: Novel tumor antigens and HLA ligands for immunotherapy. Cancer Immunol Immunother 2005;54:826-36.  Back to cited text no. 17    
18.Hildesheim A, Apple RJ, Chen CJ, et al. Association of HLA class I and II alleles and extended haplotypes with nasopharyngeal carcinoma in Taiwan. J Natl Cancer Inst 2002; 94:1780-9.  Back to cited text no. 18    
19.Cekmen A, Akkus E, Onal B, Yillmaz E, Ozalp AU, Solok V. The relationship between Human Leucocyte Antigens and renal cell carcinoma. Turkish J Urol 2002;28:383-9.  Back to cited text no. 19    
20.Kojima Y, Takahara S, Nonomura N, et al. HLA-DRB genotypes in Japanese patients with renal cell carcinoma. Oncology 2000;59:57-62.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]
21.Buszello H, Ackermann R. Immunohistochemical studies on the expression of HLA class I antigens in renal cell carcinoma: Comparison of primary and metastatic tumor tissue. Eur Urol 1994;25:158-63.  Back to cited text no. 21  [PUBMED]  
22.Atkins D, Ferrone S, Schmahl GE, Storkel S, Seliger B. Down-regulation of HLA class I antigen processing molecules: An immune escape mechanism of renal cell carcinoma? J Urol 2004;171:885-9.  Back to cited text no. 22    
23.Ibrahim EC, Allory Y, Commo F, Gattegno B, Callard P, Paul P. Altered pattern of major histocompatibility complex expression in renal carcinoma: Tumor-specific expression of the nonclassical human leukocyte antigen-G molecule is restricted to clear cell carcinoma while up-regulation of other major histocompa­tibility complex antigens is primarily distributed in all subtypes of renal carcinoma. Am J Pathol 2003;162:501-8.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Marsh SG, Parham P, Barber LD. THE HLA Facts Book. San Diego, Academic Press; 2000:1-398.  Back to cited text no. 24    
25.Beck S, Trowsdale J. The human major histo­compatability complex: Lessons from the DNA sequence. Annu Rev Genomics Hum Genet 2000;1:117-37.  Back to cited text no. 25  [PUBMED]  [FULLTEXT]
26.Ogata T, Gregoire L, Goddard KA, et al. Evidence for association between the HLA­DQA locus and abdominal aortic aneurysms in the Belgian population: A case control study. BMC Med Genet 2006;7:67.  Back to cited text no. 26  [PUBMED]  [FULLTEXT]

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Correspondence Address:
B Cem Ozgur
Libya Street 62\17 06650 Kocatepe, Ankara
Turkey
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PMID: 19112225

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    Abstract
    Introduction
    Subjects and Methods
    Statistical Analysis
    Results
    Discussion
    References
    Article Tables
 

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