RESUMEN
Mutations in SOCS1 are frequent in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. In the latter, SOCS1 mutations affect the length of the encoded protein (major mutations) and are associated with shorter patient survival. Two independent studies examined the prognostic impact of SOCS1 mutations in diffuse large B-cell lymphoma (DLBCL) and showed differing results. This may be due to the small number of included patients, the heterogeneity of patients' demographics and the distinct treatment schemes in these studies. To overcome the size limitations of these previous studies, we assessed SOCS1 mutations in the RICOVER-60 cohort. The cohort uniformly consists of elderly patients (aged 61-80 years) treated with the CHOP-14 scheme (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone at 14-day intervals) with or without an additional rituximab treatment. Patient outcomes were analysed with regard to overall SOCS1 mutation frequency, major and minor mutations and a novel impact-based classifier - against the treatment modalities. Patients harbouring putative pathogenic SOCS1 mutations showed significant reduced overall survival within the CHOP plus rituximab group. Hence, putative pathogenic SOCS1 mutations seem to efface the beneficial effect of the therapeutic CD20 antibody. Comparing published data of whole exome and transcriptome sequencing of a large DLBCL cohort confirmed that predicted deleterious SOCS1 mutations forecast pre-eminent survival in early onset DLBCL.
Asunto(s)
Biomarcadores de Tumor/genética , Linfoma de Células B Grandes Difuso/genética , Mutación , Proteína 1 Supresora de la Señalización de Citocinas/genética , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Cohortes , Ciclofosfamida/uso terapéutico , Análisis Mutacional de ADN/métodos , ADN de Neoplasias/genética , Doxorrubicina/uso terapéutico , Femenino , Genotipo , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Tasa de Mutación , Proteínas de Neoplasias/genética , Prednisolona/uso terapéutico , Pronóstico , Rituximab/administración & dosificación , Resultado del Tratamiento , Vincristina/uso terapéuticoRESUMEN
OBJECTIVE: To contribute to the understanding of potential genetic differences between different cleft types. METHOD: Analysis of family history concerning cleft type and search for cleft-type-specific associations in candidate genes performed in 98 individuals from 98 families. RESULTS: In a given family, the cleft type of a second case was more often identical to the index case than expected by chance. Each type of cleft (cleft lip [CL], cleft lip and palate [CLP], cleft palate only [CP], and submucous cleft palate only [SMCP]) was associated with different genes. CONCLUSION: Family history indicates some specificity of cleft types. The observed phenotype-genotype associations were compatible with this interpretation in that significant associations occurred with disjoint sets of genes in each cleft type. These observations indicate that CL, CLP, CP, and SMCP might represent genetically different entities.
Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Alelos , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Alemania , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A multifactorial aetiology with genetic and environmental factors is assumed for orofacial clefts. Submucous cleft palate (SMCP), a subgroup of cleft palates with insufficient median fusion of the muscles of the soft palate hidden under the mucosa, has a prevalence of 1:1,250-1:5,000. We described the prevalence of risk factors among 103 German patients with the subtype SMCP and genotyped 24 single nucleotide polymorphisms (SNPs) from 12 candidate genes for orofacial clefts. Analysis of risk factors yielded a positive history for maternal cigarette smoking during pregnancy in 25.2% of the patients, and this was significantly more frequent than in the normal population. The group of patients differed in allele frequencies at SNP rs3917192 of the gene TGFB3 (nominal P = 0.053) and at SNP rs5752638 of the gene MN1 (nominal P = 0.075) compared with 279 control individuals. Our results indicate a potential role of maternal smoking during pregnancy for the formation of SMCP. The analysis of genetic variants hints at the contribution of TGFB3 and MN1 in the aetiology of SMCPs.