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The Coincidence of Chromosome 15 Aberrations and ß2-Microglobulin Gene Mutations Is Causative for the Total Loss of Human Leukocyte Antigen Class I Expression in Melanoma

Authors' Affiliations: ¹ Skin Cancer Unit of the German Cancer Research Center Heidelberg and ² Institute of Pathology, University Clinics of Mannheim, Mannheim, Germany; ³ Department of Skin Carcinogenesis and ⁴ Division of Innate Immunity, German Cancer Research Center Heidelberg, Heidelberg, Germany; ⁵ Division of Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena, Italy; ⁶ Diagnostic Immunohistochemistry and Molecular Pathology Unit, Centro di Riferimento Oncologico, and ⁷ Cancer Bioimmunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy; and ⁸ Department of Pathology, Istituto Nazionale Tumori, Milano, Italy

Requests for reprints: Annette Paschen, Skin Cancer Unit of the German Cancer Research Center Heidelberg (Dermato-Oncology), University Hospital Mannheim, House 24, Theodor Kutzer Ufer 1, 68135 Mannheim, Germany. Phone: 49-621-383-2177; Fax: 49-621-383-2163; E-mail: a.paschen{at}dkfz.de.

Purpose: Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8⁺ T cells, is known to be caused by mutations in the ß2-microglobulin (ß2m) gene. We asked whether abnormalities of chromosome 15, harboring the ß2m gene on 15q21, in addition to ß2m gene mutations, are causative for the HLA class I–negative phenotype of melanoma cells.

Experimental Design: To answer this, we established primary cell lines from the ß2m-negative metastatic melanoma tissues of four different patients and analyzed them for ß2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH.

Results: Mutations at the ß2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions. Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between.

Conclusions: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) ß2m gene mutations.

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