RESUMEN
Loss of major histocompatibility complex class II (MHC II) expression is associated with poor patient outcome in diffuse large B-cell lymphoma (DLBCL). As MHC II molecules are lost with plasmacytic differentiation in normal cells, we asked whether MHC II loss in DLBCL is associated with an altered differentiation state. We used gene expression profiling, quantum dots, and immunohistochemistry to study the relationship between MHC II and plasma cell markers in DLBCL and plasmablastic lymphoma (PBL). Results demonstrate that MHC II(-) DLBCL immunophenotypically overlap with PBL and demonstrate an inverse correlation between MHC II and plasma cell markers MUM1, PRDM1/Blimp1, and XBP1s. In addition, MHC II expression is significantly higher in germinal center-DLBCL than activated B cell-DLBCL. A minor subset of cases with an unusual pattern of mislocalized punctate MHC II staining and intermediate levels of mRNA is also described. Finally, we show that PBL is negative for MHC II. The results imply a spectrum of MHC II expression that is more frequently diminished in tumors derived from B cells at the later stages of differentiation (with complete loss in PBL). Our observations provide a possible unifying concept that may contribute to the poor outcome reported in all MHC II(-) B-cell tumors.
Asunto(s)
Diferenciación Celular/genética , Antígenos de Histocompatibilidad Clase II/genética , Linfoma de Células B Grandes Difuso/genética , Células Plasmáticas/metabolismo , Análisis de Varianza , Antígenos CD20/genética , Antígenos CD20/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inmunohistoquímica , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Células Plasmáticas/patología , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Factores de Transcripción del Factor Regulador X , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína 1 de Unión a la X-BoxRESUMEN
While the acquisition of invasiveness is a critical step in early stage breast carcinomas (DCIS), no established molecular markers reliably identify tumor progression. The metastasis gene osteopontin is subject to alternative splicing, which yields 3 messages, osteopontin-a, osteopontin-b and osteopontin-c. Osteopontin-c is selectively expressed in invasive, but not in noninvasive, breast tumor cell lines, and it effectively supports anchorage independence. We evaluated osteopontin-c as a biomarker. The RNA message for osteopontin-c was present in 16 of 20 breast cancers (80%), but was undetectable in 22 normal specimens obtained from reduction mammoplasty. In contrast, osteopontin-a RNA was expressed at various levels in all 20 breast cancers, 11 tumor-surrounding tissues and 21 normal samples. The splice variant osteopontin-b was present at barely detectable levels in 18 of 20 cancers and in 6 of 22 normal breasts. By immunohistochemistry, 66 of 69 normal breasts were negative, while 3 showed low level staining. Among the breast cancers, 43 of 56 cores (77%) stained positive for osteopontin-c. When correlated with tumor grade, the staining for osteopontin-c increased from grade 1 to grade 3. In a total of 178 breast specimens analyzed, osteopontin-c was present in 78% of cancers, 36% of surrounding tissues and 0% of normal tissues. Furthermore, osteopontin-c detects a higher fraction of breast cancers than estrogen receptor (ER), progesterone receptor or HER2. In conjunction, osteopontin-c, ER and HER2 reliably predict grade 2-3 breast cancer. Hence, osteopontin-c is a diagnostic and prognostic marker that may have value in a diagnostic panel together with conventional breast cancer markers.