RESUMEN
Only a small proportion of cancers result from familial cancer syndromes with Mendelian inheritance. Nonfamilial, 'sporadic' cancers, which represent most cancer cases, also have a significant hereditary component, but the genes involved have low penetrance and are extremely difficult to detect. Therefore, mapping and cloning of quantitative trait loci (QTLs) for cancer susceptibility in animals could help identify homologous genes in humans. Several cancer-susceptibility QTLs have been mapped in mice and rats, but none have been cloned so far. Here we report the positional cloning of the mouse gene Scc1 (Susceptibility to colon cancer 1) and the identification of Ptprj, encoding a receptor-type protein tyrosine phosphatase, as the underlying gene. In human colon, lung and breast cancers, we show frequent deletion of PTPRJ, allelic imbalance in loss of heterozygosity (LOH) and missense mutations. Our data suggest that PTPRJ is relevant to the development of several different human cancers.
Asunto(s)
Adenocarcinoma/genética , Proteínas de Ciclo Celular/genética , Neoplasias del Colon/genética , Proteínas Tirosina Fosfatasas/genética , Adenocarcinoma/patología , Animales , Neoplasias de la Mama/genética , Proteínas de Ciclo Celular/química , Proteínas Cromosómicas no Histona , Mapeo Cromosómico , Neoplasias del Colon/inducido químicamente , Dimetilhidrazinas , Eliminación de Gen , Silenciador del Gen , Marcadores Genéticos , Humanos , Pérdida de Heterocigocidad , Neoplasias Pulmonares/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos , Proteínas Nucleares , Fosfoproteínas , Polimorfismo Genético , Carácter Cuantitativo Heredable , Proteínas Tirosina Fosfatasas Clase 3 Similares a Receptores , Proteínas de Saccharomyces cerevisiae , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido NucleicoRESUMEN
Aims. Chondroid lipoma (CL) is a benign tumor that mimics a variety of soft tissue tumors and is characterized by translocation t(11;16). Here, we analyze CL and its histological mimics. Methods. CL (n = 4) was compared to a variety of histological mimics (n = 83) for morphological aspects and immunohistochemical features including cyclinD1(CCND1). Using FISH analysis, CCND1 and FUS were investigated as potential translocation partners. Results. All CLs were strongly positive for CCND1. One of 4 myoepitheliomas, CCND1, was positive. In well-differentiated lipomatous tumors and in chondrosarcomas, CCND1 was frequently expressed, but all myxoid liposarcomas were negative. FISH analysis did not give support for direct involvement of CCND1 and FUS as translocation partners. Conclusions. Chondroid lipoma is extremely rare and has several and more prevalent histological mimics. The differential diagnosis of chondroid lipomas can be unraveled using immunohistochemical and molecular support.
RESUMEN
The classification of multifocal myxoid/round cell liposarcoma, which is defined as tumor presentation in at least two separate sites before manifestation in the lungs, as either metastasis or as a second primary tumor, has essential clinical consequences. Genetically, myxoid/round cell liposarcoma is characterized by t(12;16)(q13;p11) or t(12;22)(q13;q12), and various exon fusion transcripts are described with varying incidences, which permits their use as markers for clonality. Moreover, in solid tumors, analysis of loss of heterozygozity is valuable for clonality analysis. Therefore, fifteen multifocal myxoid/round cell liposarcoma patients with two to five metachronous (n = 12) or synchronous (n = 3) localizations were investigated. Using RT-PCR, the detailed molecular characteristics of the FUS-CHOP and EWS-CHOP breakpoints were determined. Loss of heterozygozity analysis at twelve loci was then used to further analyze clonal relationships. In all patients, tumor sites showed identical FUS-CHOP fusion products. In six patients, identical rare fusion transcripts were found, supporting a clonal relationship. Nine patients had the common exon5-FUS/exon2-CHOP fusion transcript, and two of these were identified as clonally related by loss of heterozygozity analysis. In all other patients, loss of heterozygozity analysis was highly suggestive of a clonal relationship, and no evidence for interpretation of a second primary tumor was found. This study supports the metastatic nature of apparent multifocal myxoid/round cell liposarcoma.
Asunto(s)
Liposarcoma Mixoide/genética , Liposarcoma Mixoide/patología , Metástasis de la Neoplasia/patología , Neoplasias Primarias Secundarias/patología , Proteínas de Fusión Oncogénica , Proteína FUS de Unión a ARN , Factor de Transcripción CHOP , Adulto , Anciano , Femenino , Humanos , Liposarcoma Mixoide/clasificación , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/análisis , Proteínas de Fusión Oncogénica/genética , Proteína FUS de Unión a ARN/análisis , Proteína FUS de Unión a ARN/genética , Factor de Transcripción CHOP/análisis , Factor de Transcripción CHOP/genéticaRESUMEN
Patients with diffuse large B-cell lymphoma (DLBCL) rarely show relapse after 4 years of complete remission (CR). In this study, we addressed the following questions: (1) Does late-relapsing DLBCL represent clonally related disease or a second malignancy; and (2) is there a characteristic biologic background? In 10 of 13 DLBCL patients with relapse after 4 to 17 years, a clonal relationship was established based on identical IgH-sequences and/or identical bcl2-IgH translocation. Most (77%) showed features of germinal center (GC) cells, as defined by expression of CD10, bcl-2, and bcl-6 protein and ongoing immunoglobulin heavy chain variable region (VH) hypermutation. A GC phenotype was seen in 8 (20%) of 38 control patients matched for age, stage, and (extra)nodal localization with relapse within 2.5 years (P =.005). In conclusion, we have found evidence that late-relapsing DLBCL represents truly clonally related disease episodes in most cases and that this clinical behavior may be related to the biologic features of GC cells.