Skip to main content

Advertisement

SpringerLink
Log in

Frequent loss of heterozygosity in the β2-microglobulin region of chromosome 15 in primary human tumors

  • Original Paper
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

Downregulation or total loss of HLA class I expression on tumor cells is known as a mechanism of cancer immune escape. Alterations of the HLA phenotype are frequently due to mutations affecting genes encoding the HLA class I heavy chains located on chromosome 6p21 or the β2-microglobulin (β2m) gene encoding the light chain of the HLA complex located on chromosome 15q21. Frequently irreversible total loss of HLA class I molecules is due to the coincidence of two molecular events, the mutation of one β2m gene and the loss of the second copy. The latter is detectable as loss of heterozygosity (LOH) of microsatellite markers in the β2m region on chromosome 15q21 (LOH-15q21). Thus, LOH-15q21 might be an important event in the processes of HLA class I downregulation and total loss. Here we studied the frequency of LOH-15q21 in tumor tissues of different entities. By determining the status of heterozygosity of two microsatellite markers we detected LOH-15q21 in 44% of bladder carcinomas (n = 69), in 35% of colon carcinomas (n = 95), in 16% of melanomas (n = 70) but only in 7% of renal cancers (n = 45). Moreover, we observed a frequent coincidence of LOH-15q21 and LOH-6p21 in colorectal carcinoma, bladder carcinoma and melanoma, but not for renal carcinoma. We believe that the high incidence of LOH-15q21 in some malignancies and especially the coincidence of LOH-15q21 and LOH-6p21 might have a strong impact on tumor immunogenicity and on the efficiency of cancer immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Aptsiauri N, Cabrera T, Mendez R, Garcia-Lora A, Ruiz-Cabello F, Garrido F (2007a) Role of altered expression of HLA class I molecules in cancer progression. Adv Exp Med Biol 601:123–131

    Article  PubMed  Google Scholar 

  • Aptsiauri N, Cabrera T, Garcia-Lora A, Lopez-Nevot MA, Ruiz-Cabello F, Garrido F (2007b) MHC class I antigens and immune surveillance in transformed cells. Int Rev Cytol 256:139–189

    Article  CAS  PubMed  Google Scholar 

  • Aptsiauri N, Carretero R, Garcia-Lora A, Real LM, Cabrera T, Garrido F (2008) Regressing and progressing metastatic lesions: resistance to immunotherapy is predetermined by irreversible HLA class I antigen alterations. Cancer Immunol Immunother 57(11):1727–1733

    Article  CAS  PubMed  Google Scholar 

  • Benitez R, Godelain D, Lopez-Nevot MA, Brasseur F, Jiménez P, Marchand M, Oliva MR, van Baren N, Cabrera T, Andry G, Landry C, Ruiz-Cabello F, Boon T, Garrido F (1998) Mutations of the beta2-microglobulin gene result in a lack of HLA class I molecules on melanoma cells of two patients immunized with MAGE peptides. Tiss Antigens 52(6):520–529

    Article  CAS  Google Scholar 

  • Cabrera CM, Jiménez P, Cabrera T, Esparza C, Ruiz-Cabello F, Garrido F (2003a) Total loss of MHC class I in colorectal tumors can be explained by two molecular pathways: beta2-microglobulin inactivation in MSI-positive tumors and LMP7/TAP2 downregulation in MSI-negative tumors. Tiss Antigens 61(3):211–219

    Article  CAS  Google Scholar 

  • Cabrera T, Pedrajas G, Cozar JM, Garrido A, Vicente J, Tallada M, Garrido F (2003b) HLA class I expression in bladder carcinomas. Tiss Antigens 6(4):324–327

    Article  Google Scholar 

  • Cabrera T, Lara E, Romero JM, Maleno I, Real LM, Ruiz-Cabello F, Valero P, Camacho FM, Garrido F (2007) HLA class I expression in metastatic melanoma correlates with tumor development during autologous vaccination. Cancer Immunol Immunother 56(5):709–717

    Article  CAS  PubMed  Google Scholar 

  • Carretero R, Romero JM, Ruiz-Cabello F, Maleno I, Rodriguez F, Camacho FM, Real LM, Garrido F, Cabrera T (2008) Analysis of HLA class I expression in progressing and regressing metastatic melanoma lesions after immunotherapy. Immunogenetics 60(8):439–447

    Article  CAS  PubMed  Google Scholar 

  • Chang CC, Campoli M, Restifo NP, Wang X, Ferrone S (2005) Immune selection of hot-spot beta 2-microglobulin gene mutations, HLA-A2 allospecificity loss, and antigen-processing machinery component down-regulation in melanoma cells derived from recurrent metastases following immunotherapy. J Immunol 174(3):1462–1471

    CAS  PubMed  Google Scholar 

  • Cliby W, Ritland S, Hartmann L, Dodson M, Halling KC, Keeney G, Podratz KC, Jenkins RB (1993) Human epithelial ovarian cancer allelotype. Cancer Res 53(10 Suppl):2393–2398

    CAS  PubMed  Google Scholar 

  • De Rienzo A, Balsara BR, Apostolou S, Jhanwar SC, Testa JR (2001) Loss of heterozygosity analysis defines a 3-cM region of 15q commonly deleted in human malignant mesothelioma. Oncogene 20(43):6245–6249

    Article  PubMed  Google Scholar 

  • del Campo AB, Aptsiauri N, Méndez R, Zinchenko S, Vales A, Paschen A, Ward S, Ruiz-Cabello F, González-Aseguinolaza G, Garrido F (2009) Efficient recovery of HLA class I expression in human tumor cells after beta2-microglobulin gene transfer using adenoviral vector: implications for cancer immunotherapy. Scand J Immunol 70(2):125–135

    Article  PubMed  Google Scholar 

  • Feenstra M, Veltkamp M, van Kuik J, Wiertsema S, Slootweg P, van den Tweel J, de Weger R, Tilanus M (1999) HLA class I expression and chromosomal deletions at 6p and 15q in head and neck squamous cell carcinomas. Tiss Antigens 54(3):235–245

    Article  CAS  Google Scholar 

  • García-Lora A, Algarra I, Collado A, Garrido F (2003) Tumour immunology, vaccination and escape strategies. Eur J Immunogenet 30(3):177–183

    Article  PubMed  Google Scholar 

  • Garrido F, Algarra I (2001) MHC antigens and tumor escape from immune surveillance. Adv Cancer Res 83:117–158

    Article  CAS  PubMed  Google Scholar 

  • Garrido F, Cabrera T, Concha A, Glew S, Ruiz-Cabello F, Stern PL (1993) Natural history of HLA expression during tumour development. Immunol Today 14:491–499

    Article  CAS  PubMed  Google Scholar 

  • Garrido F, Ruiz-Cabello F, Cabrera T, Perez-Villar JJ, Lopez-Botet M, Duggan-Keen M, Stern P (1997) Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. Immunol Today 18(2):89–95

    Article  CAS  PubMed  Google Scholar 

  • Garrido F, Cabrera T, Aptsiauri N (2010) “Hard” and “soft” lesions underlying the HLA class I alterations in cancer cells: implications for immunotherapy. Int J Cancer 127(2):249–256

    CAS  PubMed  Google Scholar 

  • Koene GJ, Arts-Hilkes YH, van der Ven KJ, Rozemuller EH, Slootweg PJ, de Weger RA, Tilanus MG (2004) High level of chromosome 15 aneuploidy in head and neck squamous cell carcinoma lesions identified by FISH analysis: limited value of beta2-microglobulin LOH analysis. Tiss Antigens 64(4):452–461

    Article  CAS  Google Scholar 

  • Maleno I, López-Nevot MA, Cabrera T, Salinero J, Garrido F (2002) Multiple mechanisms generate HLA class I altered phenotypes in laryngeal carcinomas: high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21. Cancer Immunol Immunother 51(7):389–396

    Article  CAS  PubMed  Google Scholar 

  • Maleno I, Cabrera CM, Cabrera T, Paco L, López-Nevot MA, Collado A, Ferrón A, Garrido F (2004a) Distribution of HLA class I altered phenotypes in colorectal carcinomas: high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21. Immunogenetics 56(4):244–253

    Article  CAS  PubMed  Google Scholar 

  • Maleno I, Lopez Nevot MA, Seliger B, Garrido F (2004b) Low frequency of HLA haplotype loss associated with loss of heterozygocity in chromosome region 6p21 in clear renal cell carcinomas. Int J Cancer 109(4):636–638

    Article  CAS  PubMed  Google Scholar 

  • Maleno I, Romero JM, Cabrera T, Paco L, Aptsiauri N, Cozar JM, Tallada M, López-Nevot MA, Garrido F (2006) LOH at 6p21.3 region and HLA class I altered phenotypes in bladder carcinomas. Immunogenetics 58(7):503–510

    Article  CAS  PubMed  Google Scholar 

  • Méndez R, Ruiz-Cabello F, Rodríguez T, Del Campo A, Paschen A, Schadendorf D, Garrido F (2007) Identification of different tumor escape mechanisms in several metastases from a melanoma patient undergoing immunotherapy. Cancer Immunol Immunother 56(1):88–94

    Article  PubMed  Google Scholar 

  • Natrajan R, Louhelainen J, Williams S, Laye J, Knowles MA (2003) High-resolution deletion mapping of 15q13.2–q21.1 in transitional cell carcinoma of the bladder. Cancer Res 63(22):7657–7662

    CAS  PubMed  Google Scholar 

  • Ogino T, Shigyo H, Ishii H, Katayama A, Miyokawa N, Harabuchi Y, Ferrone S (2006) HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res 66(18):9281–9289

    Article  CAS  PubMed  Google Scholar 

  • Park WS, Park JY, Oh RR, Yoo NJ, Lee SH, Shin MS, Lee HK, Han S, Yoon SK, Kim SY, Choi C, Kim PJ, Oh ST, Lee JY (2000) A distinct tumor suppressor gene locus on chromosome 15q21.1 in sporadic form of colorectal cancer. Cancer Res 60(1):70–73

    CAS  PubMed  Google Scholar 

  • Paschen A, Méndez RM, Jimenez P, Sucker A, Ruiz-Cabello F, Song M, Garrido F, Schadendorf D (2003) Complete loss of HLA class I antigen expression on melanoma cells: a result of successive mutational events. Int J Cancer 103(6):759–767

    Article  CAS  PubMed  Google Scholar 

  • Paschen A, Arens N, Sucker A, Greulich-Bode KM, Fonsatti E, Gloghini A, Striegel S, Schwinn N, Carbone A, Hildenbrand R, Cerwenka A, Maio M, Schadendorf D (2006) The coincidence of chromosome 15 aberrations and beta2-microglobulin gene mutations is causative for the total loss of human leukocyte antigen class I expression in melanoma. Clin Cancer Res 12(11 Pt 1):3297–3305

    Article  CAS  PubMed  Google Scholar 

  • Poetsch M, Kleist B (2006) Loss of heterozygosity at 15q21.3 correlates with occurrence of metastases in head and neck cancer. Mod Pathol 19(11):1462–1469

    CAS  PubMed  Google Scholar 

  • Ramal LM, Maleno I, Cabrera T, Collado A, Ferron A, Lopez-Nevot MA, Garrido F (2000) Molecular strategies to define HLA haplotype loss in microdissected tumor cells. Hum Immunol 61(10):1001–1012

    Article  CAS  PubMed  Google Scholar 

  • Rhiem K, Klein A, Münch M, Kreutzfeld R, Ramser J, Wardelmann E, Schackert G, Von Deimling A, Wiestler OD, Schmutzler RK (2003) Chromosomal region 15q21.1 is A frequent target of allelic imbalance in advanced breast carcinomas. Int J Cancer 106(1):74–77

    Article  CAS  PubMed  Google Scholar 

  • Rolland P, Deen S, Scott I, Durrant L, Spendlove I (2007) Human leukocyte antigen class I antigen expression is an independent prognostic factor in ovarian cancer. Clin Cancer Res 13(12):3591–3596

    Article  CAS  PubMed  Google Scholar 

  • Romero JM, Jiménez P, Cabrera T, Cózar JM, Pedrinaci S, Tallada M, Garrido F, Ruiz-Cabello F (2005) Coordinated downregulation of the antigen presentation machinery and HLA class I/beta2-microglobulin complex is responsible for HLA-ABC loss in bladder cancer. Int J Cancer 113(4):605–610

    Article  CAS  PubMed  Google Scholar 

  • Ruiz-Cabello F, Cabrera T, Lopez-Nevot MA, Garrido F (2002) Impaired surface antigen presentation in tumors: implications for T cell-based immunotherapy. Semin Cancer Biol 12(1):15–24

    Article  CAS  PubMed  Google Scholar 

  • Seemayer TA, Cavenee WK (1989) Molecular mechanisms of oncogenesis. Lab Invest 60(5):585–599

    CAS  PubMed  Google Scholar 

  • Seliger B, Maeurer MJ, Ferrone S (2000) Antigen-processing machinery breakdown and tumor growth. Immunol Today 21(9):455–464

    Article  CAS  PubMed  Google Scholar 

  • Shrout J, Yousefzadeh M, Dodd A, Kirven K, Blum C, Graham A, Benjamin K, Hoda R, Krishna M, Romano M, Wallace M, Garrett-Mayer E, Mitas M (2008) Beta(2)microglobulin mRNA expression levels are prognostic for lymph node metastasis in colorectal cancer patients. Br J Cancer 98(12):1999–2005

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Fondo de Investigaciones Sanitarias (FIS), Red Genomica del Cancer (RETIC RD 06/0020), Plan Andaluz de Investigacion (Group CTS 143), Consejeria Andaluz de Salud (SAS), Proyecto de Excelencia de Consejeria de Innovacion (CTS 695), Proyecto de Investigacion I+D (SAF 2007-63262) in Spain; and from the Integrated European Cancer Immunotherapy project (OJ2004/C158, 518234).

Author information

Authors and Affiliations

  1. Department of Clinical Analysis, Hospital Universitario Virgen de las Nieves, Granada, Spain

    Isabel Maleno, Natalia Aptsiauri, Teresa Cabrera, Aurelia Gallego, Miguel Angel López-Nevot & Federico Garrido

  2. Department of Biochemistry and Molecular Biology 3 and Immunology, School of Medicine, University of Granada, Granada, Spain

    Teresa Cabrera, Miguel Angel López-Nevot & Federico Garrido

  3. Department of Dermatology, University Hospital Essen, 45122, Essen, Germany

    Annette Paschen

  4. Dept. de Análisis Clínicos, Hospital Universitario Virgen de las Nieves, Avd. Fuerzas Armadas 2, 18014, Granada, Spain

    Federico Garrido

Authors
  1. Isabel Maleno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natalia Aptsiauri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Teresa Cabrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aurelia Gallego
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Annette Paschen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Miguel Angel López-Nevot
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Federico Garrido
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Federico Garrido.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maleno, I., Aptsiauri, N., Cabrera, T. et al. Frequent loss of heterozygosity in the β2-microglobulin region of chromosome 15 in primary human tumors. Immunogenetics 63, 65–71 (2011). https://doi.org/10.1007/s00251-010-0494-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-010-0494-4

Keywords

Search

Navigation