| 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 2020 Oct 30];20:97-101. Available from: https://www.sjkdt.org/text.asp?2009/20/1/97/44713
| Introduction|| |
Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 9095% of neoplasms arising from the kidney.  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. 
The human leukocyte antigen system (sometimes human lymphocyte antigen) (HLA) encodes the cell-surface antigen-presenting proteins that are (effectively) unique to every person.  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. 
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.  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|| |
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.  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). ,
HLA typing of peripheral blood samples from the patients and controls was performed using a standard microlymphocytotoxicity assay as previously described. , HLA typing was performed using the Biologische Analysensystem Histo Tray ABC 72 and Histo Tray DR 72 (BAG GmbH, Lich, Germany).
| Statistical Analysis|| |
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|| |
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|| |
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. ,,, 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. ,, HLA molecules may be responsible for an altered effectiveness of the immune response against tumor associated antigens expressed by RCC. 
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. 
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. 
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.  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.  However, similar findings to ours have been reported by Ibrahim et al. 
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 , 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. 
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|| |
|1.||Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999; 49(1):8-31. |
|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. |
|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. [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. |
|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. [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. |
|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. |
|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. |
|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. |
|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. |
|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. |
|12.||Fleiss JL. Statistical methods for rates and proportions. 2nd ed. New York: John Wiley and Sons, 1981; p. 61-4. |
|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. |
|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. |
|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. [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. |
|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. |
|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. |
|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. |
|20.||Kojima Y, Takahara S, Nonomura N, et al. HLA-DRB genotypes in Japanese patients with renal cell carcinoma. Oncology 2000;59:57-62. [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. [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. |
|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. [PUBMED] [FULLTEXT]|
|24.||Marsh SG, Parham P, Barber LD. THE HLA Facts Book. San Diego, Academic Press; 2000:1-398. |
|25.||Beck S, Trowsdale J. The human major histocompatability complex: Lessons from the DNA sequence. Annu Rev Genomics Hum Genet 2000;1:117-37. [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. [PUBMED] [FULLTEXT]|
B Cem Ozgur
Libya Street 62\17 06650 Kocatepe, Ankara
[Table 1], [Table 2]