Microsatellite instability analysis in tumors with different mechanisms for total loss of HLA expression.
Down-regulation of the expression of major histocompatibility complex molecules is a frequent event that is associated with the poor immunogenicity of tumor cells. Acquired resistance to T-cell-based immunotherapy has been associated with loss of functional beta2-microglobulin expression. This anomaly appears to be particularly relevant in tumors exhibiting a defect in DNA-mismatch repair, and induces structural abnormalities in HLA cell-surface expression that are not reversible by cytokine treatment. We examined HLA expression in 118 melanoma, colon or larynx tumors to identify total loss of HLA class I expression with or without somatic beta2-microglobulin gene mutation. Microsatellite instability was investigated in these tumors to determine whether a replication error phenotype (RER+) implied a particular alteration in HLA phenotype. A total of 7.6% of the tumors showed the RER+ phenotype, and 12.7% were HLA-ABC-negative. In the RER+ group, only one tumor was HLA-ABC-negative and no beta2-microglobulin mutation was identified. In contrast, in the HLA-ABC-negative group, only one tumor showed microsatellite instability. None of the three melanomas that contained beta2-microglobulin mutation exhibited the mutator phenotype. These findings suggest that beta2-microglobulin mutation in human melanoma tumors may arise through a mechanism that does not necessarily involve microsatellite instability. Our results also indicate that somatic mutations of the beta2-microglobulin gene are not the main mechanism of total loss of HLA expression.
Jimenez
P
P
Departamento de Análisis Clínicos, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Spain.
Cantón
J
J
Concha
A
A
Cabrera
T
T
Fernández
M
M
Real
L M
LM
García
A
A
Serrano
A
A
Garrido
F
F
Ruiz-Cabello
F
F
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000276:immunology; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005805:Genes, MHC Class I; D006680:HLA Antigens / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007822:Laryngeal Neoplasms / Q000235:genetics / Q000276:immunology; D019656:Loss of Heterozygosity; D008545:Melanoma / Q000235:genetics / Q000276:immunology; D018895:Microsatellite Repeats; D016296:Mutagenesis; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology; D010641:Phenotype; D001613:beta 2-Microglobulin / Q000096:biosynthesis / Q000235:genetics
D000951:Antigens, Neoplasm; D004273:DNA, Neoplasm; D006680:HLA Antigens; D001613:beta 2-Microglobulin