RESUMEN
Two distinct primary cutaneous large B cell lymphomas are recognized: primary cutaneous follicle centre lymphoma (PCFCL), characterized by an excellent prognosis, and primary cutaneous large B cell lymphoma, leg-type (PCLBCL leg-type), with an unfavourable prognosis. To determine whether inhibition of the apoptosis pathways may underlie the difference in clinical outcome between PCFCL and PCLBCL leg-type, we investigated the expression of only apoptosis-related genes by microarray expression profiling. Unsupervised cluster analysis was carried out using 169 genes involved in apoptosis on a group of 21 previously untreated patients diagnosed with primary cutaneous large B cell lymphoma. Cluster analysis resulted in two separate groups which showed large overlap with the PCFCL and PCLBCL leg-type. One group was characterized by high expression levels of pro- and anti-apoptotic genes. The other group was characterized by high expression levels of apoptosis-inducing cytotoxic effector genes, possibly reflecting a cellular cytotoxic immune response. Our results suggest that the clinically favourable PCFCLs are characterized by a relatively intense cellular cytotoxic immune response and that PCLBCL leg-types are characterized by constitutive activation of the intrinsic mediated apoptosis pathway, with concomitant downstream inhibition of this apoptosis pathway. Thus, strategies neutralizing the function of apoptosis-inhibiting proteins might be effective in PCLBCL leg-type.
Asunto(s)
Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B Grandes Difuso/genética , Neoplasias Primarias Múltiples/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Análisis por Conglomerados , Citotoxicidad Inmunológica/genética , Femenino , Humanos , Inmunohistoquímica , Pierna , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Cuero Cabelludo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/mortalidad , Análisis de Supervivencia , TóraxRESUMEN
Intrinsic resistance of lymphoma cells to apoptosis is a probable mechanism causing chemotherapy resistance and eventual fatal outcome in patients with diffuse large B cell lymphomas (DLBCL). We investigated whether microarray expression profiling of apoptosis related genes predicts clinical outcome in 46 patients with primary nodal DLBCL. Unsupervised cluster analysis using genes involved in apoptosis (n = 246) resulted in three separate DLBCL groups partly overlapping with germinal centre B-lymphocytes versus activated B-cells like phenotype. One group with poor clinical outcome was characterised by high expression levels of pro-and anti-apoptotic genes involved in the intrinsic apoptosis pathway. A second group, also with poor clinical outcome, was characterised by high levels of apoptosis inducing cytotoxic effector genes, possibly reflecting a cellular cytotoxic immune response. The third group showing a favourable outcome was characterised by low expression levels of genes characteristic for both other groups. Our results suggest that chemotherapy refractory DLBCL are characterised either by an intense cellular cytotoxic immune response or by constitutive activation of the intrinsic mediated apoptosis pathway with concomitant downstream inhibition of this apoptosis pathway. Consequently, strategies neutralising the function of apoptosis-inhibiting proteins might be effective as alternative treatment modality in part of chemotherapy refractory DLBCL.
Asunto(s)
Perfilación de la Expresión Génica , Linfoma de Células B/genética , Linfoma de Células B Grandes Difuso/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Análisis por Conglomerados , Femenino , Granzimas/análisis , Humanos , Inmunohistoquímica/métodos , Linfoma de Células B/mortalidad , Linfoma de Células B/patología , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de SupervivenciaRESUMEN
UNLABELLED: Unravelling overlapping clusters of functionally linked genes is a major challenge to current clustering programs. Algorithm GRANK permits systematic study of overlap between clusters of genes of a similar expression profile and large variation across a series of microarrays. AVAILABILITY: GRANK is freely available from http://www.bio.vu.nl/microb/research/tumor.html provided one adheres to the end-user license agreement in the associated manual. SUPPLEMENTARY INFORMATION: Above website also supplies the in- and output files used in the example run.
